Clinical trial NCT01829217
Conditions: Lung Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2013-05-01; Completion date: 2018-01-01
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug is being studied. It also means that the FDA has not yet approved sunitinib for your type of cancer.

Sunitinib has been approved by the FDA for treatment of gastrointestinal stromal tumors, advanced renal cell carcinoma and advanced pancreatic neuroendocrine tumors. While most chemotherapies work by interfering with cancer cell replication, sunitinib works by blocking certain protein signals within the cell. Because sunitinib works differently from standard intravenous chemotherapies, we call it a "targeted therapy." This drug has also been used in other research studies and information from those other research studies suggests that this agent may help to slow the growth of some NSCLC tumors.

In this research study, we are looking to see if sunitinib may stop certain NSCLC tumors from growing. The study focuses on a type of NSCLC, adenocarcinoma, which has previously been found to be more sensitive to other kinds of oral targeted therapies. This study will focus specifically on (1) adenocarcinoma tumors that do not carry a mutation in a known cancer gene (EGFR, KRAS, or ALK) and occur in patients that never smoked (less than 100 cigarettes in their lifetime) or (2) adenocarcinoma tumors that have a mutation in the RET gene.

Detailed description:
Primary Objectives

\- To evaluate the objective response rate (ORR) to sunitinib in never-smokers with lung cancers that are wild-type for EGFR, KRAS, and ALK in a single-arm phase II trial

Secondary Objectives

* To identify oncogenic alterations underlying sensitivity to sunitinib through performing nextgeneration sequencing (NGS) of lung cancers treated with sunitinib
* To explore the activity of sunitinib in lung cancers known to harbor a RET rearrangements and other genomic alterations in targets of sunitinib (e.g. cKIT, PDGFRa, PDGFRb).

Arms: arm 1: 42 day cycle, taken orally every day for the first 28 days followed by 14 days off
Interventions: intervention 1: Sunitinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
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Protocol Title: A phase II trial of sunitinib in never-smokers with lung adenocarcinoma: 
identification of oncogenic alterations underlying sunitinib sensitivity 
 
Version Date: March 18, 2015 
 
NCT Number: NCT01829217 
 
 


 
 
 
 
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Protocol Version Date:  March 18, 2015 
 
NCI Protocol #: N/A 
 
Local Protocol #: 13-086 
 
 
Title: A phase II trial of sunitinib in never-smokers with lung adenocarcinoma: identification of 
oncogenic alterations underlying sunitinib sensitivity 
 
Principal Investigator:  
Geoffrey R. Oxnard, MD 
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute 
450 Brookline Avenue, Boston, MA 02215 
Phone: 617-632-6049, Fax: 617-632-5786, Email: goxnard@partners.org 
 
Other Lead Investigators:  
Pasi A. Jänne, MD PhD, Medical Oncology, DFCI 
Rebecca Suk Heist, MD MPH, Medical Oncology, MGH 
Nikhil Wagle, MD, Medical Oncology, DFCI 
 
Statistician:  
Suzanne Dahlberg, PhD, DFCI 
Phone: 617-632-5580, Fax: 617-632-2444, Email: dahlberg@jimmy.harvard.edu 
 
Agent(s):   
Sunitinib,– Pfizer, Inc. 
 
 
 
  


Sunitinib in never-smokers with lung adenocarcinoma 
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SCHEMA 
 
 
Definitions 
   Treatment               Response        Treatment  
 Response 
R 
CR - Complete Response 
E                                    CR 
   CR 
PR - Partial Response 
G       Sunitinib               PR                  Sunitinib 
   PR 
PD - Progressive Disease 
   I        x1 cycle*             SD                   x1 cycle* 
     SD 
SD - Stable Disease 
S 
T                      P D           ( o f f s t ud y)  
   P D          ( o f f s t u d y )  
E 
R 
 
*Sunitinib is given once daily for 4 weeks followed by a 2 week rest.  The total cycle length is 6 
weeks (42 days). 
 


Sunitinib in never-smokers with lung adenocarcinoma 
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SYNOPSIS 
 
Study Title: 
 
A phase II trial of sunitinib in never-smokers with lung adenocarcinoma: 
identification of oncogenic alterations underlying sunitinib sensitivity 
Study Phase: 
II 
Study Rationale: 
Sunitinib is a multi-kinase inhibitor that may have heightened activity in 
a lung cancer population enriched for targetable oncogenes, such as 
never-smokers with adenocarcinomas that are wild-type for EGFR, 
ALK, and KRAS mutations 
Primary Objective(s): 
 
To evaluate the objective response rate to sunitinib in never-smokers 
with lung cancers that are wild-type for EGFR, KRAS, and ALK 
Secondary Objective(s): 
 
To identify oncogenic alterations underlying sensitivity to sunitinib 
through next-generation sequencing of lung cancers treated with 
sunitinib; and to explore the activity of sunitinib in lung cancers known 
to harbor a RET rearrangement 
Study Design: 
 
Open-label single-arm two-stage phase II study with comparison to 
historical data 
Study Population: 
 
Never-smokers (<100 cigarettes lifetime) with previously-treated 
advanced lung adenocarcinoma wild-type for EGFR, KRAS, and ALK; 
a subset of patients must be known to harbor RET rearrangements in 
their lung cancers and may have any smoking history; all subjects must 
have tumor biopsy tissue available for analysis 
Study Size: 
18 patients in the first stage (3 of whom must harbor RET 
rearrangements) and 17 patients in the second stage (3 of whom must 
harbor RET rearrangements) 
Drug, Dose, and Mode of 
Administration: 
Sunitinib to be given orally at 50 mg or 37.5 mg daily for 4 weeks, 
followed by 2 weeks off therapy 
Drug Manufacturer: 
Pfizer, Inc 
Duration of Treatment: 
Until disease progression or intolerable toxicity 
Efficacy Assessments: 
 
CT assessment of response and progression will be performed at the 
completion of every 6-week cycle 
Correlative Analysis: 
Baseline tumor biopsy material must be available for next-generation 
sequencing of candidate oncogenes 
Statistical Methods: 
 
A true response rate of 30% or more will be interpreted as evidence of 
activity. The null hypothesis to be tested is that the true response rate is 
10% or lower. If there are 7 or more responses among the 35 patients 
accrued, the treatment will be considered promising. This test has 90% 
power under the alternative hypothesis if the true response rate is 30%. 
Date of Original Approved 
Protocol: 
March 5, 2013  
Date of Most Recent 
Protocol Amendment (if 
applicable): 
N/A 
 
 
 


Sunitinib in never-smokers with lung adenocarcinoma 
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TABLE OF CONTENTS 
Synopsis ........................................................................................................................................................................ 2 
1. 
OBJECTIVES .................................................................................................................................................... 1 
1.1 
Study Design .................................................................................................................................................... 1 
1.2 
Primary Objectives .......................................................................................................................................... 1 
1.3 
Secondary Objectives ...................................................................................................................................... 1 
2. 
BACKGROUND ................................................................................................................................................ 1 
2.1 
Study Agent(s) ................................................................................................................................................. 1 
2.2 
Study Disease .................................................................................................................................................. 2 
2.3 
Rationale ......................................................................................................................................................... 3 
2.4 
Correlative Studies Background...................................................................................................................... 3 
3. 
PARTICIPANT SELECTION .......................................................................................................................... 3 
3.1 
Eligibility Criteria ........................................................................................................................................... 3 
3.2 
Exclusion Criteria ........................................................................................................................................ 5 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................... 6 
4. 
REGISTRATION PROCEDURES .................................................................................................................. 6 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ........................................................................... 6 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ....................................................................... 6 
4.3 
General Guidelines for Other Participating Institutions .......................................................................... 7 
4.4 
Registration Process for Other Participating Institutions ............................................................................. 7 
5. 
TREATMENT PLAN ........................................................................................................................................ 7 
5.1 
Pre-treatment Criteria ................................................................................................................................... 8 
5.2 Agent Administration ..................................................................................................................................... 8 
5.3 
Definition of Dose-Limiting Toxicity ............................................................................................................ 9 
5.4 
General Concomitant Medication and Supportive Care Guidelines ............................................................... 9 
5.5 
Duration of Therapy ......................................................................................................................................... 9 
5.6 
Duration of Follow Up .................................................................................................................................. 10 
5.7 
Criteria for Removal from Study ................................................................................................................... 10 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 10 
6.1 
Anticipated Toxicities .................................................................................................................................... 11 
6.2 
Toxicity Management .................................................................................................................................... 11 
6.3 
Dose Modifications/Delays ........................................................................................................................... 12 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 17 


Sunitinib in never-smokers with lung adenocarcinoma 
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7.1 
Sunitinib ........................................................................................................................................................ 17 
8. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 18 
8.1 
Pharmacokinetic Studies ............................................................................................................................... 18 
8.2 
Pharmacodynamic Studies ............................................................................................................................ 18 
9. 
STUDY CALENDAR ...................................................................................................................................... 19 
9.1 
Schedule of assessments ................................................................................................................................ 20 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 21 
10.1 Antitumor Effect– Solid Tumors .................................................................................................................... 21 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 27 
11.1 Definitions ..................................................................................................................................................... 27 
11.2 Procedures for AE and SAE Recording and Reporting ................................................................................. 28 
11.3 Reporting Requirements ................................................................................................................................ 28 
11.4 Reporting to the Study Sponsor ..................................................................................................................... 29 
11.5 Reporting to the Institutional Review Board (IRB) ....................................................................................... 29 
11.6 Reporting to the Food and Drug Administration (FDA) ............................................................................... 30 
11.7 Reporting to the NIH Office of Biotechnology Activities (OBA) ................................................................... 30 
11.8 Reporting to the Institutional Biosafety Committee (IBC) ............................................................................ 30 
11.9 Reporting to Hospital Risk Management....................................................................................................... 30 
11.10 Reporting to Pfizer ........................................................................................................................................ 30 
11.11 Monitoring of Adverse Events and Period of Observation ............................................................................ 31 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 31 
12.1 Data Reporting .............................................................................................................................................. 31 
12.2 Safety Meetings ............................................................................................................................................. 32 
12.3 Monitoring ..................................................................................................................................................... 32 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 32 
13.1 Protocol Review and Amendments ................................................................................................................ 32 
13.2 Informed Consent .......................................................................................................................................... 33 
13.3 Ethics and Good Clinical Practice (GCP) .................................................................................................... 33 
13.4 Study Documentation .................................................................................................................................... 33 
13.5 Records Retention ......................................................................................................................................... 34 
13.6 Multi-center Guidelines ................................................................................................................................. 34 
13.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) .............. 34 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 34 
14.1 Study Design/Endpoints ................................................................................................................................ 34 


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14.2 Sample Size/Accrual Rate .............................................................................................................................. 34 
14.3 Stratification Factors .................................................................................................................................... 35 
14.4 Analysis of Secondary Endpoints .................................................................................................................. 35 
14.5 Reporting and Exclusions .............................................................................................................................. 35 
15. 
PUBLICATION PLAN .................................................................................................................................... 35 
16. 
REFERENCES ................................................................................................................................................. 35 
17. 
APPENDICES .................................................................................................................................................. 37 


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1 
1. OBJECTIVES 
 
The objective of this study is to assess the activity of sunitinib, a multi-kinase inhibitor, in a lung cancer 
population enriched for underlying targetable oncogenes. We hypothesize that sunitinib will have 
heightened activity in never-smokers (<100 cigarettes lifetime) with lung adenocarcinoma that are wild-
type for EGFR, ALK, and KRAS mutations. We additionally hypothesize that the oncogenic alterations 
underlying sunitinib sensitivity in NSCLC can be indentified through next generation sequencing of lung 
cancers exhibiting sensitivity to sunitinib.  
 
1.1 
Study Design 
 
This is an open-label, single-arm phase II study of the multi-kinase inhibitor sunitinib in patients with 
previously-treated advanced lung adenocarcinoma. Eligible subjects either must be enriched for an 
oncogenic alteration by being a never smoker with a cancer that is wild-type for EGFR, KRAS, and ALK; 
or subjects must harbor a genomic alteration in a known target of sunitinib (RET, cKIT, PDGFRa, 
PDGFRb), such as a rearrangement, amplification, or known oncogenic mutation. Screening for RET 
rearrangements and other genomic alterations must be performed separately using a clinical assay to 
determine eligibility for this study, and will not be done as part of this protocol. We will enroll 18-35 
subjects in a two-stage design.  Subjects will receive intermittent-dosed sunitinib given daily for 4 weeks 
followed by 2 weeks off treatment. CT assessment of tumor response and progression will occur every 6 
weeks.   
 
 
1.2 
Primary Objectives 
 
• 
To evaluate the objective response rate (ORR) to sunitinib in never-smokers with lung cancers 
that are wild-type for EGFR, KRAS, and ALK in a single-arm phase II trial 
 
1.3 
Secondary Objectives 
 
• 
To identify oncogenic alterations underlying sensitivity to sunitinib through performing next-
generation sequencing (NGS) of lung cancers treated with sunitinib. 
 
• 
To explore the activity of sunitinib in lung cancers known to harbor a RET rearrangements and 
other genomic alterations in targets of sunitinib (e.g. cKIT, PDGFRa, PDGFRb). 
 
2. BACKGROUND 
 
2.1 
Study Agent(s) 
 
2.1.1 
Sunitinib 
 
Sunitinib is an oral small molecular multi-kinase inhibitor with activity against VEGFR, PDGFR, KIT, 
FLT-3 and RET (1). This agent is FDA approved for the treatment of advanced renal cell carcinoma 
(RCC), refractory gastrointestinal stromal disease (GIST), and progressive pancreatic neuroendocrine 
carcinoma (pNET).  
 
The most frequent adverse events in monotherapy studies include constitutional symptoms (fatigue, 
asthenia), gastrointestinal problems (nausea, diarrhea, mucositis/stomatitis, vomiting, constipation), and 


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myelosuppression (neutropenia, anemia, and thrombocytopenia). Dermatologic effects including yellow 
skin discoloration, rash, and hand-foot syndrome can occur. Decreases in left ventricular ejection fraction 
can occur and sunitinib may prolong the QT interval. Hypertension is also observed but is generally 
manageable with anti-hypertensive therapy. 
 
In non-small cell lung cancer (NSCLC), sunitinib has demonstrated an objective response rate of 1%-11% 
in three phase II studies (2-4). Waterfall plots from each of these studies demonstrate that a significant 
proportion of patients have meaningful tumor shrinkage. However, a phase III trial of erlotinib plus 
sunitinib versus placebo in 960 patients with previously treated NSCLC identified no improvement in 
survival (HR 0.92, CI 0.80-1.07) (5). Interestingly, sunitinib did improve both progression free survival 
(HR 0.80, CI 0.69-0.94) and response rate (7% vs. 10%, p=0.05), and there was a trend toward improved 
survival in Asian and North American sub-populations. The expected treatment-related toxicities of 
rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm; the 
incidences of treatment-related hemoptysis and pulmonary hemorrhage were similar between the two 
treatment arms. 
 
Two different dosing strategies have been studied in trials of sunitinib. Initial phase I studies established 
an intermittent dosing schedule of 50mg daily for 4 weeks followed by a 2 weeks treatment break (6). 
More recent studies found continuous dosing at 37.5 mg daily to be better tolerated, however a 
randomized trial comparing the two dosing schedules in advanced renal cell carcinoma found the 
intermittent schedule to be more efficacious (7). For this reason, the current study will use the intermittent 
dosing schedule.  
 
2.2 
Study Disease 
 
It has become clear over recent years that lung cancer in never-smokers is biologically distinct from other 
types of non-small cell lung cancer (NSCLC). Lung cancers in never-smokers almost exclusively exhibit 
adenocarcinoma histology and commonly carry underlying oncogenic alterations in EGFR and ALK, 
which can be effectively targeted using oral tyrosine kinase inhibitors (TKIs) (8, 9). Less common 
oncogenic alterations have been described in HER2, BRAF, and ROS1 (10-12); identification of targeted 
therapies for these oncogenes is a subject of active investigation. World-wide, lung cancer in never-
smokers is estimated to affect 300,000 people annually and is independently the 7th most common type of 
cancer (13). 
 
An important strategy for therapeutic progress in lung cancer occurring in never-smokers is to identify 
new “driver” oncogenes vulnerable to treatment with targeted therapies. For example, our group recently 
identified RET translocations in a subset of never- and light-smokers with lung adenocarcinoma (14), a 
finding confirmed by two other groups (15, 16). 10 patients with KIF5B-RET fusions were identified out 
of 526 tumors from never- or light-smokers (2%), constituting 6% of the 159 tumors without other 
identified driver mutations. This new oncogenic 
alteration may partly explain previous reports of 
sunitinib activity in NSCLC, as sunitinib was found 
to inhibit the growth of RET-transformed cells at 
nanomolar concentrations (Figure). RET 
translocations involving several other fusion genes 
have also been described in thyroid cancer, but the 
prevalence of these in NSCLC has not yet been 
explored (17). Additionally, cell lines with 
dependency on PDGFR (another target of sunitinib) 
have been described but this oncogene is not well 
studied in lung cancer patients (18).  


Sunitinib in never-smokers with lung adenocarcinoma 
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2.3 
Rationale 
 
Given that sunitinib inhibits multiple oncogenic kinases, including several with an emerging role in 
NSCLC, we believe that this drug may have an important role in the treatment of a subset of lung cancers. 
However, completed studies of sunitinib in unselected lung cancer populations have shown modest 
activity at best. In this study, we will target a population of lung cancers enriched for underlying 
oncogenes, hypothesizing that sunitinib demonstrate greater activity.  
 
Furthermore, by requiring tissue collection for genomic analysis, we will create an opportunity to identify 
new oncogenes associated with sunitinib sensitivity. Our collaborators in the Garraway laboratory at 
DFCI have developed next-generations sequencing technologies allowing efficient genomic 
characterization of small tumor specimens. This massively-parallel sequencing platform can identify 
missense mutations, deletions/insertions, copy number alterations, and translocations in genes of interest. 
Furthermore, by using a targeted sequencing effort, focusing on candidate genes of interest, cost is 
reduced and efficiency is improved (19). Indeed, such a massively-parallel sequencing assay has been 
adopted now for routine genotyping at the Center for Advanced Molecular Diagnostics at BWH, and has 
identified cases with RET rearrangements and PDGFR rearrangements. With this technology we plan to 
perform hypothesis-driven sequencing of genes encoding kinases targeted by sunitinib, limiting false 
discovery and maximizing the chance of identifying new biologically-relevant oncogenes. 
  
2.4 
Correlative Studies Background 
 
Next-generation sequencing (NGS) is a modern genomic technology that allows for comprehensive 
characterization of alterations in the cancer genome. Recently developed platforms perform massively 
paralleled sequencing which can capture missense mutations, deletions/insertions, copy number 
alterations, and translocations using a single assay. Furthermore, by using a targeted sequencing effort, 
focusing on candidate genes of interest, cost is reduced and efficiency is improved (19). Our collaborators 
in the Garraway laboratory at DFCI have established experience using NGS on paraffin embedded 
clinical specimens, and will perform the sequencing analysis for this study. By focusing only on those 
genes encoding known targets of sunitinib, we will perform a hypothesis-driven search for genomic 
alterations underlying sunitinib sensitivity. 
 
3. PARTICIPANT SELECTION 
Laboratory tests required for eligibility must be completed within 14 days prior to study entry. 
Baseline tumor measurements must be documented from tests within 28 days of study entry. 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to participate in the 
study: 
3.1.1 
Participants must have histologically or cytologically confirmed advanced (stage IV or recurrent) 
non-small cell lung cancer 
3.1.2 
Adenocarcinoma histology (including poorly differentiated NSCLC, favor adenocarcinoma) of any 
variant, including adenosquamous histology   
3.1.3 
Known to be wild-type for mutations in EGFR, KRAS, and ALK 


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3.1.4 
Must meet one of the following three criteria 
3.1.4.1 <100 cigarettes smoked lifetime 
3.1.4.2 Known to harbor a RET rearrangement; importantly, at least 3 patients out of the 
first 18 and 6 patients overall must harbor RET rearrangements in their lung 
cancers (note that screening for RET rearrangements will not be done as part of 
this study and must be done separately, prior to screening) 
3.1.4.3 Known to harbor another potentially targetable genomic alteration in RET, cKIT, 
PDGFRa, or PDGFRb; eligible genomic alterations include rearrangements, high 
level amplifications, insertions or deletions in the kinase domain, or point 
mutations that are known to be oncogenic. 
3.1.5 
Participants must have measureable 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 10 for the evaluation of measureable disease. 
3.1.6 
Must have received or been previously offered standard first-line chemotherapy for advanced non-
small cell lung cancer. 
 
3.1.7 
Age 18 years or older 
 
3.1.8 
Life expectancy of greater than 4 weeks 
 
3.1.9 
ECOG performance status of 0 or 1 
  
3.1.10 Participants must have normal organ and marrow function as defined below: 
• 
Absolute neutrophil count ≥ 1.5 K/UL 
• 
Platelets ≥ 100 K/UL 
• 
Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) 
• 
AST (SGOT) and ALT (SGPT) < 2.5 X institutional upper limit of normal; or, if due to 
liver metastases, ≤ 5.0 X institutional upper limit of normal 
• 
Estimated creatinine clearance ≥ 30mL/min (using Cockcroft-Gault, see Appendix B) 
• 
Urine protein ≤ 1+ on dipstick or routine urinalysis. If urine dipstick or routine urinalysis 
indicates proteinuria ≥ 2+, then a 24-hour urine must be collected and must demonstrate < 
100mg of protein in 24 hours 
• 
PTT ≤ 1.5 X institutional upper limit of normal 
• 
INR ≤ 1.5 
3.1.11 The effects of sunitinib on the developing human fetus are unknown. For this reason, 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. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she should inform her treating 
physician immediately. 
 
  
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 


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3.1.13 All patients must have adequate tumor tissue for the correlative analyses on study, or must undergo 
a biopsy to obtain adequate tissue; cases with limited tissue available should be reviewed with the primary 
investigator prior to enrollment. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for admission 
into the study. 
 
3.2.1 
Participants who have had chemotherapy within 4 weeks prior to entering the study, or lack of 
recovery from adverse events to grade 1 or less due to systemic agents administered more than 4 
weeks earlier. Due to the short half-life of erlotinib, patients can be eligible if 2 weeks have passed since 
receipt of erlotinib. 
3.2.2 
Receipt of radiation therapy within 2 weeks prior to entering the study, or lack of recovery from 
adverse events to grade 1 or less due to radiation administered more than 2 weeks earlier. 
3.2.3 
Major surgery within 4 weeks prior to entering the study 
3.2.4 
Participants may not be receiving any other study agents. 
3.2.5 
Known untreated, symptomatic, or progressive brain metastases; presence of carcinomatous 
meningitis; history of intracranial hemorrhage; or brain metastases requiring chronic steroids. 
3.2.6 
History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to sunitinib 
3.2.7 
Patients using of the following specific inhibitors and inducers of CYP3A4 are ineligible. The 
following inhibitors of CYP3A4 are prohibited within 7 days before beginning and during treatment with 
sunitinib: azole antifungals (ketoconazole, itraconozole), diltiazem, clarithromycin, erythromycin, 
verapamil, delavirdine, and HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfinavir). 
The following inducers of CYP3A4 are prohibited within 12 days before beginning and during treatment 
with sunitinib: rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort, efavirenz, 
tipranavir. Other inhibitors and inducers of CYP3A4 may be used if necessary, but their use is discouraged. 
See Appendix C for a list of examples of CYP3A4 inhibitors and inducers. 
3.2.8 
Grade 3 or 4 hemoptysis or hemorrhage within 4 weeks prior to study entry. 
3.2.9 
History of significant bleeding disorder unrelated to cancer, including: congenital bleeding 
disorders (e.g, von Willebrand's disease), acquired bleeding disorder within the past 12 months (e.g, 
acquired anti-factor VIII antibodies, including any ongoing or recent less than or equal to 3 months), 
significant gastrointestinal bleeding, or use of oral anticoagulant therapy. 
3.2.10 Poorly controlled hypertension, defined as systolic blood pressure ≥ 150mmHg or diastolic blood 
pressure of ≥ 95mmHg.  
3.2.11 Severe cardiovascular disease including symptomatic angina pectoris, symptomatic cardiac 
arrhythmia, or symptomatic congestive heart failure (New York Heart Association class II-IV). Subjects 
carrying a diagnosis of congestive heart failure which is asymptomatic are eligible so long as a baseline and 
follow-up echocardiogram are performed as per the study calendar (section 9.0). 


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3.2.12 Prolongation of corrected QT interval (QTc) > 480 milliseconds using Bazett’s formula 
3.2.13 Pregnant women are excluded from this study because sunitinib is an agent with the potential for 
teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in 
nursing infants secondary to treatment of the mother with sunitinib, breastfeeding should be discontinued if 
the mother is treated with sunitinib.  
3.2.14 Individuals with a history of a different malignancy are ineligible except for the following 
circumstances. Individuals with a history of other malignancies are eligible if they are deemed by the 
investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are 
eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, basal cell or squamous cell 
carcinoma of the skin, low risk localized prostate cancer.  
3.2.15 HIV-positive individuals on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with sunitinib. In addition, these individuals are at increased 
risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be 
undertaken in participants receiving combination antiretroviral therapy when indicated. 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Participants who are enrolled on study will reflect the patient population seen at the Dana Farber/Harvard 
Cancer Center. It is not anticipated that this study will either favor or disfavor the inclusion or 
underrepresented populations. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for Clinical 
Trials (QACT) central registration system. Registration must occur prior to the initiation of therapy. 
Any participant not registered to the protocol before treatment begins will be considered ineligible and 
registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that would cause treatment 
delays should be discussed with the Principal Investigator. If a participant does not receive protocol 
therapy following registration, the participant’s protocol status must be changed. Notify the QACT 
Registrar of participant status changes as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM Eastern 
Standard Time. In emergency situations when a participant must begin treatment during off-hours or 
holidays, call the QACT registration line at 617-632-3761 and follow the instructions for registering 
participants after hours. 
   
The registration procedures are as follows: 


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1. 
Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments. 
 
2. 
Complete the protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical/research record. To be eligible for registration to the 
study, the participant must meet each inclusion and exclusion criteria listed on the 
eligibility checklist. 
  
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for the 
treatment study. Registration to both treatment and ancillary studies will not be completed if 
eligibility requirements are not met for all studies. 
  
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-
632-2295. 
  
Exception: DF/PCC Affiliate sites must fax the entire signed consent form including HIPAA 
Privacy Authorization and the eligibility checklist to the Network Affiliate Office. The Network 
Affiliate Office will register the participant with the QACT. 
  
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on the 
study, and (c) randomize the participant when applicable. 
  
5. 
The QACT Registrar will send an email confirmation of the registration and/or 
randomization to the person initiating the registration immediately following the registration 
and/or randomization. 
  
4.3 
General Guidelines for Other Participating Institutions 
 
N/a  
 
4.4 
Registration Process for Other Participating Institutions 
 
N/a 
 
 
5. TREATMENT PLAN  
 
Sunitinib is an oral therapy which will be given using an intermittent dosing schedule, with each cycle 
lasting 6 weeks. Each cycle will consist of daily treatment with sunitinib for 4 weeks followed by 2 weeks 
off. Sunitinib dose will be 50mg daily during the 4 week treatment period, with the option of starting at 
37.5mg daily in heavily pretreated patients, or patients with co-morbidity considerations. Treatment will 
be administered on an outpatient basis. Expected toxicities and potential risks as well as dose 
modifications for sunitinib are described in Section 6 (Expected Toxicities and Dosing Delays/Dose 
Modification). No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the participant’s malignancy. 
 
Treatment Description 
Agent 
Pre-medications 
Dose 
Route 
Schedule 
Cycle Length 


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Sunitinib 
None 
50 mg 
po 
Daily for 4 weeks 
(28 days) 
Every 6 weeks (42 
days) 
Sunitinib 
None 
37.5mg 
po 
Daily for 4 weeks 
(28 days) 
Every 6 weeks (42 
days) 
 
5.1 
Pre-treatment Criteria 
 
5.1.1 
Cycle 1, Day 1 
All subjects should meet the study eligibility criteria on day 1 of the study in order to initiate treatment 
with sunitinib. Labs that are drawn on cycle 1 day 1 need to re-meet the eligibility criteria, and must be 
resulted before treatment. Physical examination, vital signs, and performance status should be reassessed 
on day 1 as well as serum chemistries and a CBC with differential. Additionally, all other baseline 
evaluations must have been completed, as detailed in the Study Calendar (Section 9). 
 
• 
ECOG performance status of 0 or 1 
• 
Systolic blood pressure < 150mmHg  
• 
Diastolic blood pressure of < 95mmHg 
• 
Absolute neutrophil count ≥ 1.5 K/UL 
• 
Platelets ≥ 100 K/UL 
• 
Total bilirubin ≤ 1.5 X institutional upper limit of normal 
• 
AST (SGOT) and ALT (SGPT) < 2.5 X institutional upper limit of normal; or, if due to 
liver metastases, ≤ 5.0 X institutional upper limit of normal 
• 
Creatinine clearance ≥ 30mL/min (using Cockcroft-Gault, see Appendix B) 
• 
Urine protein ≤ 1+ on dipstick or routine urinalysis. If urine dipstick or routine urinalysis 
indicates proteinuria ≥ 2+, then a 24-hour urine must be collected and must demonstrate < 
100mg of protein in 24 hours 
• 
PTT ≤ 1.5 X institutional upper limit of normal 
• 
INR ≤ 1.5 
5.1.2 
Subsequent Cycles 
During subsequent cycles, treatment dosing should be performed according to the dose modifications 
details in Section 6.3. In order to begin a new cycle of treatment, the following criteria must be met: 
 
• 
Absolute neutrophil count ≥ 1.0 K/UL 
• 
Platelets ≥ 50 K/UL 
5.2 
Agent Administration  
 
5.2.1 
Sunitinib 
 
• 
Administration – Sunitinib will be given orally on an intermittent schedule, with each 
cycle lasting 6 weeks. This will consist of 4 weeks (28 days) of daily dosing followed by a 2 
week treatment break. This schedule is then repeated every 6 weeks. The 6 week dose cycle 
should not be extended due to dose interruptions. However, the start of any cycle may be delayed for up 
to 4 weeks if time is needed for a subject to recover from toxicities from the previous cycle.  Any patient 
off sunitinib for more than 6 consecutive weeks must come off study. 
  
• 
Dosing – Daily dose will be 50 mg during the 4 week (28 day) treatment period. At the discretion 
of the treating investigator, a starting dose of 37.5 mg daily may be used based upon heavy pre-treatment 


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or co-morbidity considerations. Sunitinib may be administered with or without food. Sunitinib should be 
taken at approximately the same time each day. The study drug should not be crushed, chewed, or 
dissolved in water. Daily dose may be reduced for toxicity to 37.5 mg and 25 mg as per dose modification 
guidelines below for patients starting at 50mg. One dose reduction for toxicity to 25 mg is permitted in 
patients starting at 37.5mg.  
 
• 
Missed or vomited doses - If a subject forgets to take a dose, the last missed dose should be taken 
as soon as the subject remembers, as long as it is at least 12 hours before the next dose is due to be taken. 
The daily treatment schedule will be resumed the next day with the subject taking their scheduled dose at 
their usual time. In subjects who have emesis and are unable to retain sunitinib for 30 minutes or longer, 
every attempt should be made to obtain control of nausea and vomiting. The dose of sunitinib may be 
repeated if emesis occurs less than 30 minutes after taking the dose. 
 
5.3 
Definition of Dose-Limiting Toxicity 
 
N/a  
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Sunitinib is predominantly metabolized by the CYP3A4 isoenzyme. Drugs that induce CYP3A4 activity 
may decrease sunitinib plasma concentrations, while drugs that inhibit CYP3A4 may increase sunitinib 
plasma concentrations.  
 
The following inhibitors of CYP3A4 are prohibited within 7 days before beginning and during treatment 
with sunitinib: azole antifungals (ketoconazole, itraconozole), diltiazem, clarithromycin, erythromycin, 
verapamil, delavirdine, and HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, 
nelfinavir). The following inducers of CYP3A4 are prohibited within 12 days before beginning and 
during treatment with sunitinib: rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John’s 
Wort, efavirenz, tipranavir.  
 
Other inhibitors and inducers of CYP3A4 may be used if necessary, but their use is discouraged. See 
Appendix C for a list of examples of CYP3A4 inhibitors and inducers. If administration of a CYP3A4 
inhibitor cannot be avoided in subjects receiving sunitinib, close monitoring for toxicity requiring 
sunitinib dose reduction should be considered. Subjects should be advised not to consume grapefruit or 
pomegranate juice. 
 
Osteonecrosis of the jaw (ONJ) has been reported in individuals treated with sunitinib. As the risk for 
ONJ is increased with use of bisphosophonate medications, subjects receiving bisphosphonates in 
addition to sunitinib should be followed closely for jaw symptoms. 
 
Live attenuated vaccinations should not be obtained within 7 days of initiating sunitinib. 
 
5.5 
Duration of Therapy 
 
To assess for response, patients will undergo re-evaluation with a scan of measurable disease each 
cycle (approximately 6 weeks). At a minimum, all patients must undergo a CT scan of the chest and 
abdomen at each re-evaluation, and should additionally have scans of other sites every cycle to follow 
known sites of disease. Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, treatment may 
continue until one of the following criteria applies: 


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• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• 
Participant decides to withdraw from the study, or 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
Subjects who, at time of objective progression, are deemed to be gaining clinical benefit from sunitinib in 
the opinion of the treating investigator may continue treatment with sunitinib on study. For these patients, 
criteria for objective progression will have been met for the purposes of calculation of progression free 
survival. However, since RECIST criteria for progression were not intended to influence treatment 
decisions (20), treatment with sunitinib can continue until clinical progression or intolerable toxicity at 
the judgment of the treating investigator. 
 
Additionally, patients with progression in the brain only and without evidence of systemic progression 
can, after completion of local therapy to the brain (e.g. radiation therapy) continue treatment with 
sunitinib on protocol. For these patients, criteria for objective progression will have been met for the 
purposes of calculation of progression free survival, but treatment with sunitinib can continue until 
systemic progression or intolerable toxicity at the judgment of the treating investigator. 
 
5.6 
Duration of Follow Up  
 
Participants will be followed for survival every 3 months for one year after removal from study 
treatment, or until death, whichever occurs first. Participants removed from study for unacceptable 
treatment-related adverse events will be followed until resolution or stabilization of the adverse event or 
for one year, whichever is longer. 
  
5.7 
Criteria for Removal from Study  
 
Participants will be removed from study when any of the criteria listed in Section 5.5 applies. The 
reason for study removal and the date the participant was removed must be documented in the 
study-specific case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator (or Protocol Chair), Geoffrey Oxnard, MD at 617-632-
6049. 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity assessments 
will be done using the CTEP Active Version of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical 
treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 


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All adverse events experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and until the final study visit. Participants continuing to experience toxicity 
at the off study visit may be contacted for additional assessments until the toxicity has resolved or is 
deemed irreversible. 
  
6.1 
Anticipated Toxicities 
  
The most serious adverse events reported with sunitinib to date include left ventricular dysfunction, 
prolongation of QTc interval and hemorrhagic events. Decreases in left ventricular ejection fraction to 
below the lower limit of normal have been seen in > 10% of patients in several clinical trials reported by 
the manufacturer. QTc interval prolongation was seen only with supratherapeutic doses, which is in part 
why strong CYP3A4 inhibitors are prohibited. Myocardial infarction and cardiac ischemia have also been 
seen rarely. 
 
Bleeding events, including tumor hemorrhage, GI and GU bleeding have been reported. Less serious 
bleeding, primarily epistaxis, is more common. Like other drugs that inhibit VEGF signaling, sunitinib is 
associated with hypertension. All severity grades have been reported. Antihypertensive medications and 
dose modification and/or suspension of sunitinib may be required. 
 
Fatigue and GI adverse events (nausea, vomiting, diarrhea) have been commonly reported with sunitinib. 
Most of these symptoms are of the low-grade severity and they tend to improve during the two-week rest 
period of a 42-day cycle. 
 
Rarely seizures have been seen. Seizures may be a manifestation of reversible posterior 
leukoencephalopathy syndrome, recently described with other drugs that inhibit the VEGF signaling 
pathway. 
 
Skin toxicity is common with sunitinib. Yellow skin coloring is common, occurring after one week of 
treatment. Urine may also appear yellow. Skin discoloration upon direct contact of the skin with the 
capsules should be immediately washed with soap and water. A potentially more serious skin toxicity is 
erythema. Acral erythema appears similar to hand-foot syndrome, but the lesions are more hyperkeratotic. 
 
Periorbital edema, like that seen with imatinib, may occur. Painless splinter hemorrhages under the 
fingernails and less often, toenails, are also seen. Reversible hair depigmentation is also seen with 
sunitinib. The depigmentation can reverse during the 2-week off-treatment interval, resulting in altering 
bands of pigmentation and no pigmentation along a strand of hair. 
 
Hand-foot syndrome may be treated with topical emollients (such as Aquaphor), topical/systemic steroids, 
and/or antihistamine agents. Vitamin B6 (pyridoxine; 50-150 mg orally each day) may also be used. 
 
Elevations in liver transaminases and bilirubin have been observed in approximately 5-20% of patients. 
Fulminant hepatic failure, including with a fatal outcome, has been reported to occur in rare cases. 
  
6.2 
Toxicity Management 
 
 
There is no known antidote to treat an overdose of sunitinib and efforts should be directed at providing 
optimal supportive care. 
 
If a Grade 3 or Grade 4 adverse reaction develops with sunitinib use, and is possibly related to the study 
drug, treatment must be withheld until the event has resolved or improved except as noted in section 6.3. 


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Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the initial severity of 
the event.   
 
6.3 
Dose Modifications/Delays 
 
 
For subjects receiving sunitinib, dose interruptions or reductions may be required following potential 
drug-related toxicities. Fatigue, asthenia, mucositis/stomatitis, hypertension, hand-foot syndrome, 
bleeding, vascular thrombosis, thrombocytopenia/neutropenia, and other adverse events have been 
reported in response to treatment with sunitinib. 
 
At each visit during the Treatment Period, subjects should first be evaluated for the occurrence of adverse 
events and laboratory abnormalities. Specific recommendations for management of possible adverse 
events, along with guidelines for dose delay/modification or discontinuation of study treatment, are 
provided below. Adverse events are graded according to NCI Common Terminology Criteria for Adverse 
Events v. 4.0. 
 
If dose reduction is necessary, two dose reductions are permitted in a stepwise fashion for patients starting 
at 50mg (initially to 37.5mg and subsequently to 25mg if necessary). One dose reduction is permitted for 
patients starting at 37.5mg (down to 25 mg). If the toxicity does not recur or worsen, the dose can then be 
increased step-wise back to the next dose level (37.5mg or 50mg as appropriate), at the start of the next 
treatment cycle. Patients starting at 37.5mg are not permitted to be increased to the next dose level 
(50mg) at any time. Increases to the next dose level should only be initiated at the start of the next 
treatment cycle, not during a treatment cycle. 
 
 
 
 
 
 
Adverse Event 
Dose Modification Algorithm 
Hypertension 
 
(A) Asymptomatic and persistent SBP of 
≥150 and <170 mmHg, or DBP ≥90 and 
<110 mmHg, or a clinically significant 
increase in DBP of ≥20 mmHg. 
 
 
 
• 
Continue study treatment at same dose. 
• 
Adjust current dose of or initiate new antihypertensive 
medication(s). 
• 
Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled blood 
pressure (BP). If BP is not well-controlled within 2 
weeks, follow Step 1 in scenario (B). 
(B) Symptomatic, or SBP ≥170 mmHg, or 
DBP ≥110 mmHg, or failure to achieve 
well-controlled BP within 2 weeks in 
scenario (A). 
 
 
• 
Interrupt study treatment. 
• 
Adjust current or initiate new antihypertensive 
medication(s). 
• 
Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP. 
• 
Restart study treatment at same dose or lower dose at 
discretion of investigator once BP is well-controlled. 
Dose adjustment or discontinuation of 
antihypertensive medication(s) may be necessary 
during scheduled 2 week off treatment period. 
(C) Two or more symptomatic episodes of 
hypertension despite modification of 
Discontinuation of study treatment and follow-up per 
protocol. 


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antihypertensive medication(s) and 
reduction of study medication dose. 
Cardiac toxicity 
 
Grade 1 
Continue at same dose level. 
Grade 2 
Continue at same dose level 
*If asymptomatic decrease of left ventricular ejection 
fraction (LVEF) by absolute value of 20% and to < lower 
limit of normal (LLN) or non-urgent ventricular 
paroxysmal dysrhythmia requiring intervention, manage as 
Grade 3. 
Grade 3, or asymptomatic decrease of LVEF 
by absolute value of 20% and to <LLN, or 
non-urgent ventricular paroxysmal 
dysrhythmia requiring intervention 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 1. 
• 
Restart treatment with lower dose; monitor as 
clinically indicated. 
Grade 4 
Discontinuation of study treatment and follow-up per 
protocol. 
Hemorrhage/Bleeding/Coagulopathy 
 
Grade 1 
Continue study treatment at same dose; monitor as 
clinically indicated. 
Grade 2  
• 
Interrupt study treatment until the AE resolves to 
≤Grade 1. 
• 
Restart treatment with lower dose; monitor as 
clinically indicated. 
Grade 3 or 4, or Recurrent ≥Grade 2 
Discontinuation of study treatment and follow-up per 
protocol. 
Note: If abnormality is not clearly associated with clinical 
consequences, contact the Primary Investigator to discuss 
the potential for continuation of study treatment. If agreed, 
subject may restart treatment at lower dose. 
Venous Thrombosis 
 
Grade 2 
 
Continue study treatment with same dose; monitor as 
clinically indicated. 
Grade 3 or asymptomatic Grade 4 
 
• 
Interrupt study treatment. 
• 
Start to treat the subject with an anticoagulant . 
• 
Resume study treatment at same dose during the 
period of full-dose anticoagulation if all of the 
following criteria are met: 
1) The subject must have been treated with an 
anticoagulant for at least one week. 
2) No Grade 3 or 4 hemorrhagic events have occurred 
while on anticoagulation treatment. 
Subject should be monitored as clinically indicated 
during anticoagulation treatment and after resuming 
study treatment. 
Symptomatic Grade 4 
Discontinuation of study treatment and follow-up per 
protocol 
Arterial Thrombosis 
 
Any Grade  
Discontinuation of study treatment and follow-up per 
protocol. 
Neutropenia 
 


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Grade 1 or 2  
Continue study treatment at same dose; monitor as 
clinically indicated 
Grade 3 lasting ≥5 days  
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2.  
• 
Restart study treatment same dose. 
Grade 4  
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2. 
• 
Restart study treatment with lower dose. 
Recurrent Grade 3/4 event after initial 
dose reduction 
 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2.  
• 
Restart study treatment with lowest dose (25mg/day). 
Thrombocytopenia 
 
Grade 1 or 2  
Continue study treatment at same dose; monitor as 
clinically indicated 
Grade 3 lasting ≥5 days  
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2.  
• 
Restart study treatment with lower dose. 
Grade 4  
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2. 
• 
Restart study treatment with lower dose. 
Recurrent Grade 3/4 event after initial 
dose reduction 
 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2.  
• 
Restart study treatment with lowest dose (25mg/day). 
Fatigue (lethargy, malaise, asthenia) 
 
Grades 1 and 2 
Continue study treatment at same dose; monitor as 
clinically indicated. 
Grade 3 and 4 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2. Consider work-up of electrolyte 
abnormalities,  endocrine abnormalities such as 
hypothyroidism or adrenal insufficiency, and 
congestive heart failure. 
• 
Restart study treatment at lower dose 
Hand-foot Syndrome 
 
Grades 1 and 2 
Continue study treatment at same dose; monitor as 
clinically indicated. 
Grade 3 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 1.  
• 
Restart study treatment at same dose or lower dose at 
discretion of investigator. 
Grade 4 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2. 
• 
Restart study treatment at lower dose or discontinue at 
discretion of investigator 
Anemia 
 
Any grade 
No dose reduction rules are indicated for anemia unless 
due to hemorrhage or bleeding as noted above 
Diarrhea 
 
Grades 1 and 2 
Continue study treatment at same dose; monitor and 
manage as clinically indicated 


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Grade 3 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2.  
• 
Restart study treatment at same dose or lower dose at 
discretion of investigator. 
Grade 4 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2. 
• 
Restart study treatment at lower dose or discontinue at 
discretion of investigator 
Mucositis 
 
Any grade 
No dose reduction rules are indicated for mucositis 
Other Clinically Significant Adverse 
Events Possibly Related to Study Drug 
 
Grades 1 and 2 
Continue study treatment at same dose; monitor as 
clinically indicated 
Grade 3 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 1. 
• 
Restart study treatment at same dose or lower dose at 
discretion of investigator 
Recurrent Grade 3 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 1. 
• 
Restart study treatment at lower dose 
Grade 4 
• 
Interrupt study treatment until toxicity reduced to 
≤Grade 2. 
• 
Restart study treatment at lower dose or discontinue at 
discretion of investigator 
 
 
6.3.1 
Liver Toxicity 
 
In the event of treatment emergent hepatotoxicity, potential contributing factors such as concomitant 
medications, viral hepatitis, choledocholithiasis, and hepatic metastases should be investigated. 
Concomitant medications known to be hepatotoxic which may be contributing to liver dysfunction should 
be discontinued or replaced with alternative medications to allow for recovery of liver function. As 
generally understood, ALT >3 x ULN and concomitant bilirubin ≥2 xULN (>35% direct bilirubin), in the 
absence of elevated alkaline phosphatase or biliary injury, suggests significant liver injury. 
 
Event 
Dose Modification Algorithms 
(A) ALT of ≤ 3 x ULN 
Continue study treatment at current dose with LFTs 
monitored as per protocol. 
(B) ALT >3 x ULN to ≤8 x ULN without 
bilirubin elevation (defined as total bilirubin 
<2 x ULN or direct bilirubin ≤35%) and 
without hypersensitivity symptoms (e.g., 
fever, rash) 
Liver Event Monitoring Criteria: 
(1) Continue study treatment at current dose levels. 
(2) Perform the following assessments for exclusion of 
hypersensitivity and other contributing factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B and C 
- Liver imaging 
(3) Monitor subject closely for clinical signs and 
symptoms; perform full panel LFTs weekly or more 
frequently if clinically indicated until ALT/AST is reduced 
to Grade 1. 


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(C) ALT >8 x ULN without bilirubin 
elevation (defined as total bilirubin <2 x 
ULN or direct bilirubin ≤35%) and without 
hypersensitivity symptoms (e.g., fever, 
rash) 
1st occurrence – Liver Event Interruption Criteria3: 
(1) Interrupt study treatment until toxicity resolves to 
≤Grade 1 or baseline. Report the event to PI as an SAE 
within 24 hours of learning of its occurrence. Make every 
reasonable attempt to have subjects return to the clinic 
within 24 to 72 hours for repeat liver chemistries and liver 
event follow up assessments. 
(2) Perform the following assessments for exclusion of 
hypersensitivity and other contributing factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, 
cytomegalovirus, Epstein-Barr virus (IgM antibody, 
heterophile antibody, or monospot testing) 
- Liver imaging 
(3) Monitor subject closely for clinical signs and 
symptoms; perform full panel LFTs weekly or more 
frequently if clinically indicated until ALT/AST is reduced 
to Grade 1. 
(4) If the subject is benefiting from the study treatment, 
contact PI for possible re-challenge. Re-treatment may be 
considered at the same dose if ALL following criteria are 
met: 
- ALT/AST reduced to Grade 1 
- Total bilirubin <1.5 x ULN or direct bilirubin ≤35% 
- No hypersensitivity signs or symptoms 
- Subject is benefiting from therapy. 
Recurrence – Liver Event Stopping Criteria3: 
Discontinue sunitinib permanently and monitor subject 
closely for clinical signs and symptoms; perform full panel 
LFTs weekly or more frequently if clinically indicated 
until alanine ALT/AST is reduced to Grade 1. Report 
recurrence to PI. 
(D) ALT >3 x ULN with concomitant 
elevation in bilirubin (defined as total 
bilirubin ≥2 x ULN; with direct bilirubin 
>35%) or with hypersensitivity 
symptoms (e.g., fever, rash). 
Liver Event Stopping Criteria: 
(1) Discontinue study treatment immediately, report the 
event to PI as an SAE within 24 hours of learning of its 
occurrence. Make every reasonable attempt to have 
subjects return to the clinic within 24 hours for repeat liver 
chemistries and liver event follow up assessments. 
(2) Consult a gastroenterologist / hepatologist and perform 
the following assessments to identify potential co-factors: 
- Eosinophil count 
- Viral serology for hepatitis A, B, C and E, 
cytomegalovirus, Epstein-Barr virus (IgM antibody, 
heterophile antibody, or monospot testing) 
- Anti-nuclear antibody, anti-smooth muscle antibody, 
anti-mitochondrial antibody 
- Serum creatinine phosphokinase for possible muscle 
injury caused LFT elevation 
- Liver imaging 
(3) Monitor subject closely for clinical signs and 
symptoms; record the appearance or worsening of clinical 


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symptoms of hepatitis, or hypersensitivity, such as fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever rash or eosinophilia as relevant on the AE report 
form. Perform full panel LFTs weekly or more frequently 
if clinically indicated until LFTs are reduced to Grade 1. 
For isolated total bilirubin elevation without 
concurrent ALT increases (defined as ALT 
<3 x ULN). 
(1) Isolated hyperbilirubinemia (i.e., in the absence of 
elevated ALT or other signs/symptoms of liver injury) 
does not require dose modification.  
(2) If bilirubin is >2 x ULN in the absence of ALT 
elevation, fractionation of bilirubin elevation should be 
performed. If the bilirubin is predominantly indirect 
(unconjugated), continue sunitinib at the same dose. If 
bilirubin is >35% direct (conjugated), further evaluation 
for underlying cause of cholestasis should be performed. 
 
7. DRUG FORMULATION AND ADMINISTRATION  
  
7.1 
Sunitinib 
 
7.1.1 
Description 
 
Sunitinib is a small molecule multi-kinase inhibitor with activity against VEGFR2, KIT, RET, 
PDGFR, and FLT-3. The half-life of sunitinib is in the range of 40-60 hours. Approximately 61% of 
the sunitinib dose is eliminated in the feces and approximately 16% is recovered unchanged in the 
urine.  
 
Refer to the Product Information Sheet for information regarding the physical and chemical properties of 
sunitinib malate, capsules, and list of excipients 
  
7.1.2 
Form 
 
Sunitinib malate capsules are manufactured by Pfizer, inc, and consist of hard gelatin capsules containing 
sunitinib malate equivalent to 12.5, 25 and 50 mg sunitinib together with mannitol, croscarmellose 
sodium, povidone, and magnesium stearate. The 12.5mg dose is supplied as a hard gelatin capsule with 
orange cap and orange body, printed with “Pfizer” on the cap in white ink and “STN 12.5 mg” on the 
body. The 25mg dose is supplied as a hard gelatin capsule with caramel cap and orange body, printed 
with “Pfizer” on the cap in white ink and “STN 25 mg” on the body. The 50mg dose is supplied as a hard 
gelatin capsule with caramel top and caramel body, printed with “Pfizer” on the cap in white ink and 
“STN 50 mg” on the body. 
  
7.1.3 
Storage and Stability 
 
The sunitinib malate capsules are packaged in opaque plastic bottles, and should be stored at controlled 
room temperature (15 to 30C).  
  
7.1.4 
Compatibility 
 
N/a 
7.1.5 
Handling 


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The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper number of each 
strength capsule to the subject to satisfy dosing requirements for the study. The containers provided to the 
subject should be labeled with proper instructions for use. The lot numbers, dosing start dates and the 
number of capsules for each dosage strength must be recorded on the drug accountability pages of record 
for the site. The subject must be instructed to return all unused sunitinib in the provided packaging at each 
subsequent visit. 
 
7.1.6 
Availability 
 
Sunitinib is commercially available but will be supplied free-of-charge from Pfizer, Inc.. 
 
7.1.7 
Preparation 
 
N/a 
  
7.1.8 
Administration 
 
See section 5.2.1 for details on sunitinib admistration. 
 
7.1.9 
Ordering 
 
Sunitinib will be ordered from Pfizer inc. using an order form that has been provided. Drug will be provided 
from the commercial supply.  
 
7.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record 
of the inventory and disposition of the agent (investigational or free of charge) using the NCI Drug 
Accountability Record or another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for  Accountability and Storage 
of Investigational Agents” or to obtain a copy of the drug accountability form.) The overall Primary 
Investigator or designated research team member is responsible for assessing drug compliance (i.e. pill 
count) for all drugs used on the protocol. 
 
7.1.11 Destruction and Return 
 
Unused drug dispensed by the research pharmacy will be returned to the research pharmacy as soon as 
possible.  The returned unused investigational drug will not be retained by the research pharmacy.  
Returned unused investigational drug will be destroyed as soon as possible per institutional guidelines. 
  
8. CORRELATIVE/SPECIAL STUDIES  
8.1 
Pharmacokinetic Studies 
 
N/a 
8.2 
Pharmacodynamic Studies 


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8.2.1 
Laboratory Correlative Studies 
8.2.1.1 Collection of baseline tumor tissue 
All study participants will be required to consent to genomic analysis of their tumor as a condition of 
enrollment on protocol.  Patients will need to have an adequate tumor specimen for DNA extraction and 
correlative genomic analysis. 10 unstained slides or a tumor block of paraffin embedded archival tissue 
should be submitted for evaluation to: The Jänne Lab, Dana-Farber Cancer Institute, 77 Avenue Louis 
Pasteur, HIM 229, Boston, MA 02115. Tumor specimens (including surgical biopsies, core needle 
biopsies, or large volume pleural effusions) will be evaluated by a pathologist to ensure adequacy for 
DNA extraction. If an investigator is uncertain regarding tissue adequacy for a potentially eligible 
subject, then the case should first be reviewed with the Primary Investigator prior to study enrollment. 
Patients that do not have an adequate tumor specimen will require biopsy prior to study enrollment for 
the collection of tumor tissue. Biopsies performed for the purposes of obtaining tumor tissue for 
genomic analysis on study will be paid for by the study budget. Biopsies requiring general anesthesia 
will not be supported by study funds, but may be performed as clinically indicated. 
Germline DNA will additionally be extracted from peripheral leukocytes and studied as a control. Blood 
specimens should be collected prior to treatment in one 10 ml EDTA-containing (“purple top”) tube and 
sent to: The Jänne Lab, Dana-Farber Cancer Institute, 77 Avenue Louis Pasteur, HIM 229, Boston, MA 
02115. Blood specimens can be shipped at room temperature and do not need to be sent on ice.  
8.2.1.2 Next-generation sequencing of candidate targets of sunitinib 
Genomic DNA and germline DNA will both undergo massively parallel sequencing and will be 
compared in parallel. Rather than sequencing the entire genome, we will sequence the exons as well 
non-coding introns of candidate oncogenes mediating sunitinib sensitivity (e.g. RET, PDGFRB, KIT, 
VEGFR2, FLT3, etc). Sequencing will be performed in collaboration with the Garraway laboratory at 
DFCI, and will be performed at their laboratory. Germline sequencing will only include kinase genes 
being sequenced in the tumor so as to avoid incidental identification of clinically significant germline 
variants. 
9.  STUDY CALENDAR 
Baseline evaluations including a history, physical exam, vitals, relevant blood work, and baseline 
imaging are to be conducted within 4 weeks prior to start of protocol therapy. Laboratory studies 
drawn within 7 days of starting study drug may count as the Day 1 laboratory studies.  
Subjects will be evaluated on study every two weeks during the first cycle with a physical 
evaluation and a laboratory evaluation. During the subsequent two cycles, subjects will be 
evaluated on days 1 and 29 of each 6-week cycle. Patients will be evaluated only on Day 1 of 
additional cycles. Re-imaging of sites of disease should be performed before each new 
treatment cycle, which is typically every 6 weeks. Follow-up tumor assessments may be made 
within + 7 calendar days of the protocol-specified date. 
All assessments must be performed prior to administration of any study medication. All study 
assessments and medications should be administered within + 3 calendar days of the protocol-
specified date, unless otherwise noted.  
 
Test/Procedure 
Screening: 
Within 4 
Day 1 
Cycle 
Day 15 
Cycle 1 
Day 1  
Cycle 2 
Day 29 
Cycles 
Day 1 
All 
End of Study 
Within 30 


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Weeks of 
Start 
1 only 
only  
only 
1-3 
Other 
Cyclesg 
days of off 
study 
 Observations 
 
Informed Consent 
X 
 
 
 
 
 
 
History and Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs, weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
adverse events 
 
X 
X 
X 
X 
X 
X 
Review of Drug 
Diary 
 
 
X 
X 
X 
X 
X 
Dispense 4-week 
supply of sunitinib 
 
X 
 
X 
 
X 
 
Tests & Labs 
           
Serum chemistrya 
X 
Xb 
X 
X 
X 
X 
 
CBC with diff  
X 
Xb 
X 
X 
X 
X 
 
PT, PTT, INR 
X 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Urine pregnancy test  
X 
 
 
 
 
 
 
12-lead EKG 
X 
 
 
X 
 
 
 
Echocardiogram 
(X)c 
 
 
 
 
 
 
Confirm biopsy 
specimen available 
for correlative 
analysis 
X 
 
 
 
 
 
 
Collect blood for 
correlative analysisd 
 
X 
 
 
 
 
 
Imaging 
 
Chest/abdomen CT 
X 
 
 
Xe 
 
Xe, g 
Xe 
Brain MRI or CT 
X 
 
 
 
 
 
 
Additional imaging 
(X)f 
 
 
(X)f 
 
(X)f, g 
 
a: Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, phosphorus, 
potassium, total  protein, SGOT   [AST], SGPT [ALT], sodium, magnesium 
b: Laboratory studies drawn within 7 days of starting study drug may count as the Day 1 laboratory 
studies 
c: Baseline echocardiogram is only needed in patients carrying a diagnosis of congestive heart failure 
(CHF), noting that patients with symptomatic CHF are excluded from the study 
d: Blood should be collected into one 10 ml EDTA-containing (“purple top”) tube and sent to: The Jänne 
Lab, Dana-Farber Cancer Institute, 77 Avenue Louis Pasteur, HIM 229, Boston, MA 02115. 
e: window of +/- 7 calendar days is applicable for follow-up CT assessments  
f: Additional imaging should be performed as needed to follow measurable / non-measurable disease.  
g: After 8 cycles on therapy (48 weeks), imaging may be spread out to every 2 cycles (12 weeks) at the 
discretion of the treating clinician. 
9.1 
Schedule of assessments 
 
• 
History, vital signs, physical examination, and ECOG PS : On day 1, 15, 29 of cycle 1, on 
days 1 and 29 of cycles 2-3, and on day 1 of each subsequent cycle 


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• 
Labs: On day 1, 15, 29 of cycle 1, on days 1 and 29 of cycles 2-3, and on day 1 of each 
subsequent cycle 
• 
CT scans: On day 1 of each 6-week cycle (after 8 cycles on therapy, imaging may be spread 
out to every 2 cycles at the discretion of the treating clinician) 
• 
EKG: On day 1 of cycle 1 and cycle 2 
 
All assessments must be performed prior to administration of any study medication. All study 
assessments and medications should be administered within + 3 calendar days of the protocol-
specified date, unless otherwise noted. Follow-up tumor assessments may be made within + 7 
calendar days of the protocol-specified date. 
10. MEASUREMENT OF EFFECT  
 
Response rate is the primary endpoint of this trial. Participants with measurable and/or non-
measurable disease will be assessed by RECIST 1.1 criteria. For the purposes of this study, 
participants should be reevaluated before each new treatment cycle, which is typically every 6 weeks. 
In addition to a baseline scan, confirmatory scans should also be obtained 6 weeks following initial 
documentation of an objective response. The standard scan for all patients should be a CT of the 
chest and abdomen with IV contrast. Additional sites of disease (pelvis, neck, head) may also be 
scanned if there is known disease in these areas. Non-contrast scans are acceptable if IV contrast is 
contraindicated. Clinicians may perform additional scans if clinically indicated. 
10.1 
Antitumor Effect– Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every 6 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 6 weeks (not less than 4 weeks) 
following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guideline.(20) Changes in the 
diameter (unidimensional measurement) of the tumor lesions are used in the RECIST 1.1 criteria. 
10.1.1 Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study treatment will be 
evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants 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 participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective disease 
progression or die prior to the end of cycle 1 will also be considered evaluable.} 
10.1.2 Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) lesion that can be 
accurately measured in at least one dimension with longest diameter  >20 millimeters (mm) using 
conventional techniques (CT, MRI, x-ray) or  >10 mm with spiral CT scan. Measurable lesions must 
be at least 2 times the slice thickness in mm. All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). 


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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 < 15mm short axis, are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses identified by physical exam that are not 
measurable by reproducible imaging techniques, and cystic lesions are all considered non-measurable. 
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. Lesions must be accurately measured in 1 dimension with a minimum size of 
10 mm by CT or MRI (slice thickness no greater than 5 mm), 20 mm by chest x-ray. Nodes must 
have a short axis > 15 mm. The short axis should be included in the sum of the lesions in the 
calculation of response. Nodes that shrink to < 10 mm are considered normal. Target lesions should 
be selected on the basis of their size, be representative of all the involved organs, and should be 
lesions that can be followed with reproducible repeated measurements.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT or MRI can be considered target lesions if 
the soft tissue component meets the definition of measurability as defined above. Cystic lesions thought 
to represent cystic metastases can be considered as target lesions. However, if non-cystic lesions are 
present, these are preferred for selection as target lesions. Lesions in previously irradiated areas or areas 
subject to other loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression of that lesion.  
Non-target lesions. All other lesions, including small lesions < 10 mm or pathological lymph nodes 
measuring > 10 mm to < 15 mm in short axis, as well as truly non-measurable lesions, which include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses identified by physical exam that are not 
measurable by reproducible imaging techniques.  
10.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. 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 when both methods have been used to assess the anti-tumor effect of a 
treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 


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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. These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of 
extremities usually require specific protocols. 
Ultrasound (US). When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. US might 
also be useful to confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should follow the NCI 
Guidelines for using FDG PET as an indicator of therapeutic response (L.K. Shankar, J.M. Hoffman, S. 
Bacharach, M.M. Graham, J. Karp, A.A. Lammertsma, S. Larson, D.A. Mankoff, B.A. Siegel, A. Van 
den Abbeele, J. Yap, D. Sullivan. Consensus recommendations for the use of 18F-FDG PET as an 
indicator of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med, 47(6):901-
903, 2006). Patients should avoid strenuous exercise and be on a low carbohydrate diet for 24 hours prior 
to the scan. Patients should fast for 4 hours or longer prior to the FDG injection and should have a serum 
glucose of less than 200 mg/dL at the time of FDG injection. A 10-20 mCi dose of FDG should be 
injected for typical adult patients. For longitudinal studies with multiple scans, particular attention should 
be paid to ensure consistent patient preparation and acquisition parameters between the follow-up scan 
and the baseline scan. When designing a study where PET scans are going to be utilized as one of the 
modalities to evaluate efficacy, it is important to consult with physicians in nuclear medicine in designing 
the appropriate criteria to be utilized. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation has not 
yet been fully and widely validated. Their uses in this specific context require sophisticated equipment 
and a high level of expertise that may only be available in some centers. Therefore, the utilization of 
such techniques for objective tumor response should be restricted to validation purposes in reference 
centers. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained. 
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 subject to be considered in complete 
clinical response. Specific additional criteria for standardized usage of prostate-specific antigen (PSA) 
and CA-125 response in support of clinical trials are being developed. 
Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 


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10.1.4  Response Criteria  
10.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node must 
have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study with at least a 5 mm absolute increase in the sum 
of all lesions. The appearance of one or more new lesions* denotes disease 
progression.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or unevaluable data. In 
this case, a concise explanation must be given. 
Note: If tumor response data is missing for target lesions, the overall assessment must be UN unless 
there is new disease that would result in an overall assessment of PD. However, if there is missing or 
unevaluable data for non-target lesions, but data is available for all target lesions, the overall response 
for that time point will be assigned based on the sum LD of all target lesions. Additionally, the 
assessment of CR cannot be made if there is missing or unevaluable data for non-target lesions. In this 
case, the overall assessment would be PR. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not due to 
difference in scanning technique, imaging modality, or findings thought to represent something other 
than tumor (ex: new bone lesions may be healing or flare of pre-existing lesions). However, a lesion 
identified on a follow-up scan in an anatomical location that was not scanned at baseline is considered 
new and will indicate PD. If a new lesion is equivocal (because of small size, etc.), follow-up evaluation 
will clarify if it truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered.  
10.1.4.2 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 
subject to be considered in complete clinical response. 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesions and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions* (new lesions must be > 
slice thickness) and/or unequivocal progression of existing non-target lesions. 


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Overall level of substantial worsening that merits discontinuation of therapy. A useful test that 
can be applied when assessing non-targets for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease. 
Unknown (UN): Assessment of non-target lesions cannot be made due to insufficient or unevaluable 
data. In this case, a concise explanation must be given. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not due to 
difference in scanning technique, imaging modality, or findings thought to represent something other 
than tumor (ex: new bone lesions may be healing or flare of pre-existing lesions). However, a lesion 
identified on a follow-up scan in an anatomical location that was not scanned at baseline is considered 
new and will indicate PD. If a new lesion is equivocal (because of small size, etc.), follow-up evaluation 
will clarify if it truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered.  
10.1.4.3 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 participant's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
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 


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* 
In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
Note:   Participants 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 an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.  
10.1.5 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 recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded since the 
treatment started. 
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent 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. 
 
10.1.6 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of objective 
disease progression.  
10.1.7 Response Review 
An expert radiologist independent of the study will review all cases to objectively determine response 
classification. 


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11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 
Definitions 
11.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that develops 
or worsens in severity after starting the first dose of study treatment or any procedure specified in the 
protocol, even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests.  
11.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality 
that:  
• 
Results in death 
• 
Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might 
have caused death had it occurred in a more severe form. 
• 
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but planned 
prior to study entry are not considered SAEs if the illness or disease existed before the person was 
enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the trial 
(e.g., surgery performed earlier than planned). 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• 
Is a congenital anomaly or birth defect; or 
• 
Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
• 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• 
respite care 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  


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11.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as resulting from administration of 
the agent. For the purposes of this study, an adverse event is considered expected when it appears in the 
current adverse event list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study agent(s). 
11.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the Investigator’s 
Brochure, the package insert or when it is not included in the informed consent document as a potential 
risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the study treatment. 
Attribution will be assigned as follows: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment.  
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 
Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation time 
points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly observed, 
or detected by physical examination, laboratory test or other means, will be recorded in the participant’s 
medical record and on the appropriate study-specific case report forms.  
 
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 website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
11.3 
Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, each 
participating investigator is required to abide by the reporting requirements set by the DF/HCC. The study 
must be conducted in compliance with FDA regulations, local safety reporting requirements, and 
reporting requirements of the principal investigator.  
 


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29 
Each investigative site will be responsible to report SAEs that occur at that institution to their respective 
IRB. It is the responsibility of each participating investigator to report serious adverse events to the study 
sponsor and/or others as described below.  
11.4 
Reporting to the Study Sponsor 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, during treatment, or within 
30 days of the last dose of treatment must be reported to the DF/HCC Overall Principal Investigator on 
the local institutional SAE form. This includes events meeting the criteria outlined in Section 11.1.2, as 
well as the following: 
 
• 
Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are unexpected and 
possibly, probably or definitely related/associated with the intervention. 
 
• 
All Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically 
listed in the protocol as not requiring reporting. 
 
• 
All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of continuing review.  
 
Participating investigators must report each serious adverse event to the DF/HCC Overall Principal 
Investigator within 24 hours of learning of the occurrence. In the event that the participating investigator 
does not become aware of the serious adverse event immediately (e.g., participant sought treatment 
elsewhere), the participating investigator is to report the event within 24 hours after learning of it and 
document the time of his or her first awareness of the adverse event. Report serious adverse events by 
telephone, email or facsimile to: 
 
 
 
Geoffrey R. Oxnard 
 
 
 
Phone: 617-632-6049 
 
 
Email: goxnard@partners.org 
 
 
Fax: 617-632-5786 
 
Within the following 24-48 hours, the participating investigator must provide follow-up information on 
the serious adverse event. Follow-up information should describe whether the event has resolved or 
continues, if and how the event was treated, and whether the participant will continue or discontinue study 
participation. 
11.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator on the toxicity 
Case Report Forms.   
11.5 
Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI Office for 
Human Research Studies (OHRS). 


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11.6 
Reporting to the Food and Drug Administration (FDA) 
 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA. The DF/HCC Overall Principal Investigator will report to the FDA, 
regardless of the site of occurrence, any adverse event that is serious, unexpected and reasonably related 
(i.e., possible, probable, definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 7 calendar days after initial receipt of the 
information. 
 
All other serious unexpected experiences associated with the use of the study treatment will be reported to 
FDA as soon as possible but in no event later than 15 calendar days after initial receipt of the information. 
 
  
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-FDA-0178) using 
Form FDA 3500A (Mandatory Reporting Form for investigational agents) or FDA Form 3500 (Voluntary 
Reporting Form for commercial agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.  
11.7 
Reporting to the NIH Office of Biotechnology Activities (OBA) 
 
N/a 
11.8 
Reporting to the Institutional Biosafety Committee (IBC) 
 
N/a 
11.9 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject safety reports or 
sentinel events that require reporting according to institutional policy. 
11.10 Reporting to Pfizer 
 
Reportable SAEs include those occurring after the receipt of the first dose of sunitinib until 28 days after 
receipt of the last dose of sunitinib. These SAEs must be reported to Pfizer immediately for a death or 
life-threatening event, or within 24 hours of notification of PI for other types of SAEs. These time frames 
also apply to additional information concerning previously submitted reports of an SAE. 
 
As sunitinib is a mature oncology product, having been marketed for 5 years or more, SAEs are reported 
to Pfizer only if they fit into one of the following categories: 
• 
An SAE that is assessed by the investigator as both related to treatment with sunitinib and 
unexpected for sunitinib 
• 
Death that is not due to cancer progression, occurring during the study up to 28 days post 
the last day of sunitinib 
• 
An SAEs related to treatment that the investigator becomes aware of after the reporting 
period should be reported even if occurring more than 28 days after the last dose of sunitinib 
 
SAEs should be provided to Pfizer on the SAE form provided by the company, and faxed to Pfizer U.S. 
Clinical Trial Department at 866-997-8322 using the fax cover sheet provided. 


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11.11 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation of study 
intervention, throughout the study, and within 30 days of the last study intervention should be followed to 
their resolution, or until the participating investigator assesses them as stable, or the participating 
investigator determines the event to be irreversible, or the participant is lost to follow-up. The presence 
and resolution of AEs and SAEs (with dates) should be documented on the appropriate case report form 
and recorded in the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring visit 
to obtain additional case details deemed necessary to appropriately evaluate the SAE report (e.g., hospital 
discharge summary, consultant report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be related 
to participation in this study. Participating investigators should notify the DF/HCC Overall Principal 
Investigator and their respective IRB of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to the study.   
 
12. DATA AND SAFETY MONITORING 
12.1 
Data Reporting 
12.1.1 Method  
The QACT will collect, manage, and monitor data for this study.  
12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or electronic) to the QACT is as 
follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up 
visit date or call 


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12.2 
Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this trial. The committee is composed of clinical specialists with experience in oncology 
and who have no direct relationship with the study. Information that raises any questions about participant 
safety will be addressed with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring within 30 days for Phase I or II protocols; for gene transfer 
protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request.  
12.3 
Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the DF/HCC Overall 
Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were conducted 
and data were recorded, analyzed, and accurately reported in accordance with the protocol, institutional 
policy, Good Clinical Practice (GCP), and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue during 
protocol performance and completion.  
 
The sponsor / IND holder will work with the DFCI Clinical Trials Office to secure an appropriate 
monitoring plan that will include, but not be limited to, the following activities to ensure protocol and 
regulatory compliance and data integrity. Monitoring will be conducted by independent and qualified 
monitors. Monitoring activities will include: ongoing reviews of regulatory files, verifying participant 
eligibility and the consent process on 100% of participants, verifying safety events and study endpoints 
for all enrolled participants, and an ongoing review of CRF completion and query resolution. During 
these activities, monitors will assess for trends and perform additional monitoring based on identified 
areas of need. 
 
 
13. REGULATORY CONSIDERATIONS 
13.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g., advertisements used to recruit participants) and any other necessary documents must be 
submitted, reviewed and approved by a properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved by the 
IRB prior to implementation. Any changes in study conduct must be reported to the IRB. The 
DF/HCC Overall Principal Investigator (or Protocol Chair) will disseminate protocol amendment 
information to all participating investigators.  


Sunitinib in never-smokers with lung adenocarcinoma 
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All decisions of the IRB concerning the conduct of the study must be made in writing. 
13.2 
Informed Consent 
 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 
the person obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in the 
medical record or research file.  
13.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good and 
sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
 
• 
State laws 
• 
DF/HCC research policies and procedures        http://www.dfhcc.harvard.edu/clinical-
research-support/clinical-research-unit-cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be reported 
to the IRB according to the local reporting policy.  
13.4 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information enables 
the study to be fully documented and the study data to be subsequently verified. 
 


Sunitinib in never-smokers with lung adenocarcinoma 
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Original source documents supporting entries in the case report forms include but are not limited to 
hospital records, clinical charts, laboratory and pharmacy records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  
13.5 
Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable federal 
regulations and guidelines or institutional policies.  
13.6 
Multi-center Guidelines 
N/A  
13.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA)  
N/A  
 
14. STATISTICAL CONSIDERATIONS  
 
14.1 
Study Design/Endpoints 
 
This is an initial open-label, single-arm Phase 2 study of sunitinib administered to patients with lung 
adenocarcinoma who are never-smokers and whose tumors are wild-type for EGFR, KRAS, and ALK.  
The primary objective is to evaluate the objective response rate to sunitinib in never-smokers with lung 
cancers that are wild-type for EGFR, KRAS, and ALK.   
 
The primary endpoint will be objective response rate per RECIST 1.1. A true response rate of 30% or 
more will be interpreted as evidence of activity of sunitinib in this patient population. The null hypothesis 
to be tested is that the true response rate is 10% or lower. 
 
18-35 patients will be accrued to this study in a two-stage design. During stage one, 18 patients will be 
accrued; if there are 3 or more responses (CR+PR) observed among those 18 patients, we will continue to 
the second stage of accrual (90% exact binomial CI for 3 responses: [5%,38%]). Seventeen additional 
patients will then be accrued to the second stage. If there are 7 or more responses among the 35 patients 
accrued, the treatment will be considered promising. Patients who never begin protocol therapy will not 
be counted towards the total number of patients treated on study. Patients will be included in the response 
rate analysis irrespective of the starting dose of sunitinib received. 
 
This test has 90% power under the alternative hypothesis if the true response rate is 30%. The probability 
of stopping an arm early if the true response rate is 10% is 0.73 and is 0.06 if the true response rate is 
30%. The probability of concluding that the treatment is effective if the true response rate is 10% is 0.05.  
14.2 
Sample Size/Accrual Rate 
 
Never-smokers with lung adenocarcinoma are routinely genotyped at all participating institutions to 
determine EGFR, KRAS, and ALK status. We estimate that over 100 never-smokers with advanced lung 
adenocarcinoma are seen annually, with at least 30 each year being identified as “triple negative” for 


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35 
mutations in EGFR, KRAS, and ALK, this potentially eligible. We have a population that is generally 
highly interested in clinical trials of targeted therapies, so estimate we could accrue at least 15-20 patients 
each year from this population. With a total accrual of 35 patients planned, we estimate that accrual will 
take 24-30 months. 
14.3 
Stratification Factors 
 
N/a 
14.4 
Analysis of Secondary Endpoints 
 
In order to assess the activity of sunitinib in lung cancers known to harbor RET rearrangements, we are 
requiring that 3 of the first 18 patients and 6 of the total 35 patients harbor RET alterations in their cancer. 
With 6 RET-rearranged cases accrued by the end of the study, the probability of observing at least 3 
responses among them is 0.66, assuming that the underlying response rate to sunitinib in this patient 
population is 0.50. This probability increases to 0.88 if the underlying response rate is 0.65. 
 
Activity in lung cancers haboring other genomic alterations in RET, cKIT, PDGFRa, or PDGFRb will be 
assessed in an exploratory fashion, and used to develop future clinical trials. 
14.5 
Reporting and Exclusions 
14.5.1 Evaluation of toxicity: All participants will be evaluable for toxicity from the time of their first 
treatment. 
14.5.2 Evaluation of response: All participants included in the study must be assessed for response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible. Each participant 
should 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). By arbitrary convention, 
category 9 usually designates the "unknown" status of any type of data in a clinical database. Patients 
meeting the eligibility criteria and receiving at least 1 dose of study medication will be included in the main 
analysis of response rate.  
 
15. PUBLICATION PLAN 
The results will be made public within 24 months of the end of data collection. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the 
requirements of the International Committee of Medical Journal Editors. A full report of the outcomes 
should be made public no later than three (3) years after the end of data collection. Reporting of data and 
sharing of data with third parties will be at the discretion of the principal investigator. 
 
 
16. REFERENCES  
 


Sunitinib in never-smokers with lung adenocarcinoma 
Version date: March 18, 2015  
 
 
CONFIDENTIAL 
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36 
1. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 
2007;25:884-96. 
2. Socinski MA, Novello S, Brahmer JR, Rosell R, Sanchez JM, Belani CP, et al. Multicenter, Phase II 
Trial of Sunitinib in Previously Treated, Advanced Non–Small-Cell Lung Cancer. J Clin Oncol. 
2008;26:650-6. 
3. Novello S, Scagliotti GV, Rosell R, Socinski MA, Brahmer J, Atkins J, et al. Phase II study of 
continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. 
Br J Cancer. 2009;101:1543-8. 
4. Novello S, Camps C, Grossi F, Mazieres J, Abrey L, Vernejoux J-M, et al. Phase II Study of Sunitinib 
in Patients with Non-small Cell Lung Cancer and Irradiated Brain Metastases. Journal of Thoracic 
Oncology. 2011;6:1260-6 10.097/JTO.0b013e318219a973. 
5. Scagliotti GV, Krzakowski M, Szczesna A, Strausz J, Makhson A, Reck M, et al. Sunitinib Plus 
Erlotinib Versus Placebo Plus Erlotinib in Patients With Previously Treated Advanced Non–Small-Cell 
Lung Cancer: A Phase III Trial. J Clin Oncol. 2012. 
6. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and 
antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J 
Clin Oncol. 2006;24:25-35. 
7. Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. Randomized Phase II 
Trial of Sunitinib on an Intermittent Versus Continuous Dosing Schedule As First-Line Therapy for 
Advanced Renal Cell Carcinoma. J Clin Oncol. 2012. 
8. Mok TS, Wu Y-L, Thongprasert S, Yang C-H, Chu D-T, Saijo N, et al. Gefitinib or carboplatin-
paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-57. 
9. Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic Lymphoma 
Kinase Inhibition in Non–Small-Cell Lung Cancer. N Engl J Med. 2010;363:1693-703. 
10. Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H, et al. Somatic mutations of 
the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005;65:1642-6. 
11. Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al. Clinical Characteristics of Patients 
With Lung Adenocarcinomas Harboring BRAF Mutations. J Clin Oncol. 2011;29:2046-51. 
12. Bergethon K, Shaw AT, Ignatius Ou S-H, Katayama R, Lovly CM, McDonald NT, et al. ROS1 
Rearrangements Define a Unique Molecular Class of Lung Cancers. J Clin Oncol. 2012;30:863-70. 
13. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers - a different disease. Nat Rev Cancer. 
2007;7:778-90. 
14. Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, Jarosz M, et al. Identification of new ALK and 
RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18:382-4. 
15. Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, et al. KIF5B-RET fusions in 
lung adenocarcinoma. Nat Med. 2012;18:375-7. 
16. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in 
lung cancer. Nat Med. 2012;18:378-81. 
17. Lanzi C, Cassinelli G, Nicolini V, Zunino F. Targeting RET for thyroid cancer therapy. Biochem 
Pharmacol. 2009;77:297-309. 
18. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of phosphotyrosine 
signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-203. 
19. Wagle N, Berger MF, Davis MJ, Blumenstiel B, DeFelice M, Pochanard P, et al. High-Throughput 
Detection of Actionable Genomic Alterations in Clinical Tumor Samples by Targeted, Massively Parallel 
Sequencing. Cancer Discovery. 2012;2:82-93. 
20. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-
47. 
 


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17. APPENDICES  
 
Appendix A: Performance status criteria 
Appendix B: Cockcroft-Gault equation 
Appendix C: CYP3A4 inhibitors / inducers 
Appendix D: U.S. Physician Prescribing Information for Sunitinib 
 


Sunitinib in never-smokers with lung adenocarcinoma 
 
 
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38 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
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. 
 
 
 
 


Sunitinib in never-smokers with lung adenocarcinoma 
 
 
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39
Appendix B: Cockcroft-Gault equation 
 
 
CrCl for males (mL/min) =   
 
 
 
[140 - age (years)] X [weight (kg)1] 
(72) X [Serum creatinine (mg/dL)] 
 
CrCl for females (mL/min) =  
 
 
 
(0.85) X [140 - age (years)] X [weight (kg)1] 
(72) X [Serum creatinine (mg/dL)] 
 
For SI units: 
CrCl for males (mL/min) =   
 
 
 
[140 - age(years)] X [weight(kg)1] X (1.23) 
[serum creatinine (μmol/L)] 
 
CrCl for females (mL/min) =  
 
 
 
[140 - age(years)] X [weight(kg)1] X (1.05) 
[serum creatinine (μmol/L)] 
 
1 If the subject is obese (> 30% over ideal body weight), use ideal body weight in calculation of estimate 
CrCl 
 
 
 
 
 


Sunitinib in never-smokers with lung adenocarcinoma 
 
 
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40
 
Appendix C: CYP3A4 inhibitors / inducers 
 
CYP3A4 inhibitors 
 
 
 
Acetominophen 
Acetazolamide 
Amioderone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffiene 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetadine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Cyclophosphamide 
Cyclosporine 
Danazol 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradapine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapimil 
Vinblastine 
Vincristine 
Vinorelbine 
Zafirlukast 
Ziprasidone 
CYP3A4 inducers 
 
 
 
Aminoglutethimide 
Carbamazapine 
Fosphenytoin 
St. John’s wort 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance 
LL eds. Drug Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.)