Clinical trial NCT00567359
Conditions: Non-small Cell Lung Cancer
Keywords: NSCLC erlotinib epidermal growth factor receptor EGFR
Sponsor: Massachusetts General Hospital
Start date: 2007-12-01; Completion date: 2017-12-01
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor.

Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

Detailed description:
* Erlotinib is a pill taken daily and participants may continue to receive erlotinib for up to two years, as long as the cancer does not return and they do not experience any unacceptable side effects.
* While participants are receiving erlotinib, they will be asked to return to the clinic for study visits to monitor the status of their disease and their general health. For the first 5 months of erlotinib, they will return to the clinic monthly. After that they will return to the clinic every three months.

Arms: arm 1: None
Interventions: intervention 1: Erlotinib
Intervention descriptions: intervention 1: Oral drug taken daily around the same time. Starting dose is 150mg once daily.

Protocol documents:
Prot_SAP_000.pdf: 






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TABLE OF CONTENTS 
Schema 
1.0 INTRODUCTION..............................................................................................................5 
1.1 Overview.................................................................................................................5 
1.2 Background.............................................................................................................5 
1.2.1 Adjuvant Chemotherapy for Non-small Cell Lung Cancer ..................5 
1.2.2 Non-small Cell Lung Cancer and Tyrosine Kinase Inhibitors .............5 
1.2.3 EGFR TKIs in the Adjuvant Setting.....................................................6 
1.2.4 Mechanisms of Resistance to EGFR TKIs...........................................7 
1.2.5 Circulating Tumor Cells and the CTC-Chip.........................................7 
1.2.6 Pharmacokinetics and Safety of Erlotinib ............................................8 
1.3 Study Rationale.....................................................................................................10 
2.0 OBJECTIVES...................................................................................................................11 
2.1 Primary Objectives ...............................................................................................11 
2.2 Secondary Objectives ...........................................................................................11 
2.3 Exploratory Objectives.........................................................................................11 
3.0 ELIGIBILITY...................................................................................................................12 
3.1 Study Overview....................................................................................................12 
3.2 Inclusion Criteria ..................................................................................................12 
3.3 Exclusion Criteria.................................................................................................13 
3.4 Subject Registration..............................................................................................14 
4.0 STUDY TREATMENT....................................................................................................14 
4.1 Overview...............................................................................................................14 
4.2 Treatment Administration: Single Agent Erlotinib ..............................................14 
4.2.1 Treatment Agent.................................................................................14 
4.2.2 Dosage and Administration Schedule.................................................15 
4.2.2.1 Missed and Vomited Doses ....................................................15 
4.2.3 Dose Delays........................................................................................15 
4.2.4 Dose Modification Guidelines............................................................15 
4.3 Concomitant Therapy ...........................................................................................16 
4.3.1 Recommendations for Supportive Treatment.....................................16 
4.4 Discontinuation of Study Treatment.....................................................................19 
4.5 Study Medication Accountability.........................................................................19 
5.0 STUDY ASSESSMENTS................................................................................................19 
5.1 Safety Assessments...............................................................................................19 
5.1.1 Overview of Safety Assessments........................................................19 
5.1.2 History and Physical Examination......................................................20 
5.1.3 Laboratory Examinations....................................................................20 
5.1.4 Adverse Events...................................................................................20 
5.1.5 Serious Adverse Events......................................................................21 
5.1.6 Assessment of Adverse Events...........................................................22 
5.1.7 Reporting of Adverse Events..............................................................24 
5.1.8 Type and Duration of Follow-up of Patients after Adverse Events....26 
5.2 Efficacy Assessments...........................................................................................26 
5.2.1 Timing and Method of Efficacy Evaluation .......................................26 
5.3 Assessments at the Time of Study Discontinuation .............................................26 


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5.4 Molecular Assessments........................................................................................27 
5.4.1 EGFR Mutation Testing and FISH Analysis......................................27 
5.4.2 Circulating Tumor Cells (CTCs)........................................................28 
6.0 REQUIRED DATA..........................................................................................................29 
7.0 STATISTICAL PLAN......................................................................................................30 
7.1 Overview...............................................................................................................30 
7.2 Sample Size ..........................................................................................................30 
7.3 Data to be Analyzed..............................................................................................30 
7.4 Patient Disposition................................................................................................31 
7.5 Patient Characteristics ..........................................................................................31 
7.6 Primary Analysis..................................................................................................31 
7.7 Secondary Analyses..............................................................................................31 
7.8 Correlative Analyses.............................................................................................32 
8.0 QUALITY ASSURANCE OFFICE FOR CLINICAL TRIALS (QACT) EXTERNAL SITE 
MONITORING PLAN.....................................................................................................32 
9.0 APPENDICES..................................................................................................................34 
10.0 REFERENCES ...............................................................................................................62 
 


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INTRODUCTION 
 
1.1 Overview 
 
This Phase II, single-arm, open-label study will investigate the efficacy and safety of adjuvant 
erlotinib in patients with resected stage I-IIIA non-small cell lung cancer who have confirmed 
activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain. 
 
1.2 Background 
 
1.2.1 Adjuvant Chemotherapy for Non-small Cell Lung Cancer 
 
Of the estimated 170,000 patients with non-small cell lung cancer (NSCLC) who will be 
diagnosed in the United States in 20071, only approximately 37% will be potential candidates 
for surgical resection. Even after resection, many patients will die of distant relapse, with 
recurrence rates after resection varying from 30% in stage IA to 75% in stage IIIA2. This 
dismal prognosis, even in the setting of early stage disease, speaks to the need for better 
treatment after surgical resection.  
 
Adjuvant chemotherapy, by definition, is chemotherapy given after surgery to eradicate 
micrometastatic disease. Adjuvant treatment using platinum-based chemotherapy can increase 
long-term survival after resection in NSCLC, although the magnitude of benefit is small (4-
15%) and seems to be greater in patients with more advanced disease3-6. Although patients with 
resected stage IA and IB disease have relapse rates of 33% and 43% at 5 years2, there is no 
evidence that adjuvant chemotherapy improves survival in stage IA disease, and benefit in 
stage IB remains controversial7. Overall, the disease-free survival (DFS) for patients with 
resected stage I-IIIA NSCLC is approximately 60% at 2 years 3,6,8. 
 
It is clear that current chemotherapy regimens are inadequate, which reflects the inherent 
insensitivity of NSCLC to chemotherapy. Indeed, platinum doublet regimens such as those 
used in the adjuvant trials above have only 17-22% objective response rates when used in 
advanced disease9. Quite simply, larger benefits from adjuvant treatment will require more 
effective treatments. Fortunately, there is a population of NSCLC patients who are highly 
responsive to treatment, namely those with activating mutations in the epidermal growth factor 
receptor (EGFR). 
 
1.2.2 Non-Small Cell Lung Cancer and Tyrosine Kinase Inhibitors 
 
Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality in men and 
women in the U.S. Chemotherapy and biologically targeted agents can extend survival 
modestly for patients with locally-advanced or metastatic disease; however, discovery of novel 
ways to prolong the disease course is a top research priority.  
 
The epidermal growth factor receptor (EGFR; HER1 or ErbB1) belongs to the ErbB family of 
transmembrane receptor tyrosine kinases (RTKs). Because EGFR is expressed in almost all 
epithelial cells and tends to be dysregulated and overexpressed in tumor cells, including up to 


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80% of NSCLC10, inhibition of the EGFR has been a major area of clinical research in 
oncology. 
 
One strategy of EGFR inhibition is the use of small molecules such as gefitinib and erlotinib to 
target the RTK. These molecules compete with ATP for its binding site on the TK, providing 
reversible inhibition of EGFR RTK signaling11,12. In early clinical trials in previously treated, 
advanced NSCLC patients, gefitinib showed response rates in the 10-18% range13,14. It has 
been clear throughout all studies of gefitinib and erlotinib that subgroups of patients were 
benefiting from TKI treatment much more substantially than the majority. 
 
Three landmark studies of patients treated with gefitinib and erlotinib demonstrated that most 
of the patients with significant responses to treatment harbored somatic activating mutations in 
the EGFR gene 15-17. These mutations are most commonly overlapping deletions in exon 19 or a 
single point mutation in exon 21 (L858R). They lead to preferential activation of downstream 
survival pathways and are thought to condition the cell to be reliant upon, or “addicted to” 
EGFR signaling 18. This addiction to EGFR signaling confers exquisite sensitivity to signal 
blockade with TKIs. Since this discovery, the association of EGFR mutations with increased 
response and prolonged survival after TKI treatment has been repeatedly demonstrated. (for 
review see 19). 
 
In 2005 the phase III BR-21 trial was published, which showed a survival benefit to erlotinib in 
the second-line treatment of NSCLC when compared to placebo, but only showed an 8.9% 
response rate20. Post-hoc molecular analysis of a subset of samples from this and other trials of 
EGFR TKIs indicated that EGFR gene copy number and protein expression are also correlated 
with survival, although these markers appear to be less highly correlated with objective 
response21,22. While the exact role of individual biomarkers to predict clinical benefit from 
EGFR TKIs is still under investigation, it is clear that the majority of dramatic responses to 
EGFR TKI therapy are in the patients with EGFR mutations, although this does not seem to 
predict all of the clinical benefit. The relationship of EGFR mutation to protein expression and 
gene copy number is unclear, and little is known about these factors in early stage disease. 
 
1.2.3 EGFR TKIs in the Adjuvant Setting 
 
Several clinical trials have been designed to investigate EGFR TKIs in the adjuvant setting. A 
randomized phase III trial of adjuvant gefitinib in unselected NSCLC patients was started but 
closed early after it was recognized that some patients in the advanced setting were developing 
interstitial lung disease23, which is now an accepted but rare side-effect of this class of drugs. A 
second phase III trial, the RADIANT trial, is currently investigating 2 years of adjuvant 
erlotinib in resected NSCLC patients who have overexpression of EGFR protein by 
immunohistochemistry or EGFR gene copy number by FISH analysis.  
 
The only trial involving adjuvant treatment of EGFR mutant NSCLC was reported in 
preliminary form at the 2006 ASCO convention24, in which gefitinib was given for 21 days as 
induction therapy in 20 patients with light smoking history or tumors having bronchioloalveolar 
features. The primary endpoint was tumor response as defined as a reduction in bidimensional 
tumor size of 25%. On biopsy, 7 of these patients had activating EGFR mutations, and all 7 had 
at least a 10% reduction in bidimensional tumor volume after only 21 days of treatment. Five of 


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the 7 mutant tumors achieved the primary endpoint of 25% reduction in size, which is 
consistent with documented response rates in this population, and all patients with mutations 
and/or a 25% reduction in tumor size preoperatively received adjuvant gefitinib for 2 years 
afterward. No relapse or survival information is available, but the adjuvant component of this 
trial is limited by the inclusion of EGFR wild-type tumors and is not designed to detect a 
survival advantage after treatment with gefitinib. 
 
Finally, the SWOG 0023 trial randomized unselected patients with locally advanced NSCLC to 
gefitinib versus placebo after definitive chemoradiation25,26. This trial, recently updated at the 
2007 annual ASCO meeting26, showed that survival was actually worse in the gefitinib arm, 
although pneumonitis was no more common in the gefitinib arm than in the placebo arm. While 
pneumonitis is always a potential risk when taking an EGFR TKI, extensive experience in 
advanced disease now estimates this risk at 0.7% in the North American population27. All 
anticancer treatments must weigh risk versus potential benefit before proceeding. In unselected 
patients, who have been shown to have an estimated 9% chance of responding to erlotinib, this 
risk might seem excessive. This is especially true given the updated results of the SWOG 0023 
trial, in which the overall survival in an unselected population seemed to be adversely affected 
by adjuvant gefitinib. In patients with documented sensitizing mutations in the EGFR gene 
however, where response rates of >75% have been repeatedly described, the risk/benefit ratio 
swings much farther towards benefit. 
 
1.2.4 Mechanisms of Resistance to EGFR TKIs 
 
Despite the high rate of objective responses to erlotinib and gefitinib in advanced NSCLC 
patients with activating EGFR mutations, most patients eventually will progress while on 
therapy. One mechanism of resistance is the development of second mutations in the EGFR TK 
domain28. The best described mutation is the T790M point mutation, which alters the binding 
pocket of the ATP binding site such that erlotinib and gefitinib can no longer fit29. This 
mutation has been identified in up to 50% of tumors that relapse after initially responding to 
EGFR TKIs. Another such mutation is the insertion 20 mutation, which confers in vitro 
resistance to erlotinib and gefitinib, and has been identified in 3 patients who progressed on 
gefitinib therapy30. 
 
An additional 20% of patients who relapse after initially responding to EGFR inhibition harbor 
amplifications of the MET tyrosine kinase gene, which allows continued signaling through the 
PI3 kinase pathway independent of mutant EGFR31. Little is known about the remaining 30% 
of patients who relapse after initially responding, and this area is under active investigation. 
 
1.2.5 Circulating Tumor Cells (CTCs) and the CTC-Chip 
 
The detection of cancer recurrence currently relies on the radiographic detection of new lesions, 
when tumors already consist of at least 109 cells. Recurrent solid tumors are frequently 
considered incurable, suggesting a need for a more sensitive assay to detect recurrence at the 
micrometastatic stage when cure might still be possible. In addition, molecular analysis of 
cancer cells typically requires a tissue biopsy, which carries a degree of risk to the patient. The 
development of an assay for recurrence using peripheral blood would be tremendously useful in 
expanding the pool of patients for whom molecular analysis would be possible.  


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The ability to metastasize is one of the hallmarks of malignancy, and though its mechanisms 
are not fully described, circulating tumor cell (CTC) distribution through the bloodstream 
appears to be a vital step in the process.32,33 Successful capture and characterization of CTCs 
has tremendous potential as a vehicle to better understand the biology of the metastatic process, 
and provides an avenue to explore numerous clinical applications via non-invasive, patient-
specific genomic analysis. Unlike tumor-derived cells in bone marrow, which can be dormant 
and long-lived, CTCs have a short half-life (<1 day) and their presence indicates a recent influx 
from an active proliferating tumor.34 Hence, CTCs may reflect the clinical status of cancer 
patients in a dynamic fashion, and could potentially be useful in the early detection of relapse.  
 
At the MGH Cancer Center, we have been developing a device called a “CTC-chip” to capture 
and quantify CTCs from patient blood samples. Our CTC-chip is a microfluidic platform in 
which whole blood travels through a forest of micron-sized EpCAM antibody-coated 
microposts under precisely controlled laminar flow conditions. The arrangement and flow 
dynamics of the micropost array guides the smaller red blood cells to the periphery of the chip 
while larger nucleated hematologic and epithelial cells remain in the central portion. CTCs are 
captured directly onto the sidewalls of the EpCAM antibody-functionalized microposts and 
remain viable. We have successfully captured an average of 100 viable CTCs per mL of whole 
blood from 99% of tested advanced NSCLC patients (unpublished observation). The CTC-chip 
is an ideal tool for studying CTCs in NSCLC patients given its one-step process, the near-
universal isolation of large numbers of CTCs from cancer patients, and the ability to capture 
live cells suitable for molecular analyses. We have preliminary data that suggests that detecting 
EGFR mutations from CTCs captured via the CTC-chip is feasible and correlates with tumor 
tissue sample testing. 
 
1.2.6 Pharmacokinetics and Safety of Erlotinib (Tarceva®) 
 
Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially 
increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. Its half-life is 
about 36 hours and it is cleared predominantly by CYP3A4 metabolism.35 
 
The primary toxicities of erlotinib are diarrhea, rash, nausea, headache, mucositis/stomatitis, 
emesis, and fatigue. A rash occurred in 75% of erlotinib-treated NSCLC patients enrolled in 
BR.21.  Similar incidence of rash have occurred when erlotinib was administered concurrently 
with chemotherapy including gemcitabine, paclitaxel/carboplatin, and gemcitabine/cisplatin.  A 
papular, pustular rash manifesting most often on the face and upper trunk was common across 
all studies, but rash was rarely the cause of study drug discontinuation.  Other dermatologic 
manifestations reported in clinical studies or postmarketing use of erlotinib include nail 
changes, paronychia, painful fissures or cracking of the skin on the hands and feet, and hair 
growth abnormalities (alopecia, thinning hair, eyelash/eyebrow changes, hirsutism). 
The only dose-limiting toxicity is diarrhea, which is dose related and is generally controlled 
with the addition of loperamide therapy. Grade 3/4 rash and diarrhea occur in 9% and 6% of 
patients treated with erlotinib, respectively. Rash and diarrhea each result in drug 
discontinuation in about 1% of patients. Six percent and 1% of patients need dose reductions 


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for rash and diarrhea, respectively. The median time to onset of rash is 8 days and the median 
time to onset of diarrhea is 12 days.35 
 
There have been infrequent reports of serious interstitial lung disease (ILD), including 
fatalities, in patients receiving erlotinib for treatment of NSCLC or other advanced solid 
tumors. In a recent large randomized trial of erlotinib and placebo, the incidence of ILD was 
the same in both the placebo and erlotinib groups (0.8%).20 Symptoms can start from 5 days to 
more than 9 months after initiation of erlotinib. The overall incidence in erlotinib-treated 
patients from all studies (including uncontrolled studies and studies with concurrent 
chemotherapy) is approximately 0.6%. Included in this rate of ILD are reported diagnoses of 
pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, 
interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress 
syndrome, alveolitis, and lung infiltration, irrespective of investigator assessed causality. Most 
cases are associated with confounding or contributing factors such as concomitant/prior 
chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung 
cancer, or pulmonary infections. In the event of acute onset of new or progressive, unexplained 
pulmonary symptoms such as dyspnea, cough and fever, erlotinib therapy should be interrupted 
pending diagnostic evaluation. If ILD is diagnosed, erlotinib should be discontinued and 
appropriate treated instituted as necessary.35 
 
The influence of hepatic metastases and/or hepatic dysfunction on the pharmacokinetics of 
erlotinib is not yet known. However, erlotinib is cleared predominately by the liver, and caution 
should be used when administering erlotinib to patients with hepatic dysfunction. Erlotinib is 
also a strong inhibitor of the UDP-glucuronosyltransferase UGT1A1 enzyme responsible for 
the glucuronidation of bilirubin. Hyperbilirubinemia appears most often to be a side effect 
related to genetic polymorphisms of UGT1A1. Rare cases of hepatic failure (including 
fatalities) have been reported during the postmarketing use of erlotinib. Confounding factors 
for severe hepatic dysfunction have included pre-existing liver disease such as cirrhosis, viral 
hepatitis, hepatocellular carcinoma, hepatic metastases, or concomitant treatment with 
potentially hepatotoxic drugs. 
Rare cases of myocardial infarction (including fatalities) have been reported during the 
postmarketing use of erlotinib. 
No clinical studies have been conducted in patients with compromised renal function since 
erlotinib and its metabolites are not significantly excreted by the kidneys. 
Rare cases of acute renal failure or renal insufficiency have been reported (including fatalities). 
Many of these cases have been associated with dehydration associated with nausea, vomiting, 
diarrhea, and/or anorexia. There have been rare reports of renal failure in patients receiving 
erlotinib in combination with platinum-containing chemotherapy regimens. Febrile neutropenia 
has been reported in patients receiving concomitant chemotherapy. 
Co-administration of erlotinib with omeprazole, a proton pump inhibitor, decreased the 
exposure of erlotinib (AUC) by 46% and the maximum concentration (Cmax) by 61%. There 
was no change to Tmax or half-life. Therefore, drugs that alter the pH of the GI tract may alter 
the solubility of erlotinib and hence its bioavailability. 


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The exposure to erlotinib (AUC) increased to a moderate extent, by 39%, and the maximum 
concentration (Cmax) by 17%, when erlotinib was co-administered with ciprofloxacin, an 
inhibitor of both CYP3A4 and CYP1A2. 
Erlotinib clearance can be induced by smoking via CYP1A2 induction. Potential drug-drug 
interaction is expected when erlotinib is taken with CYP1A2 inducers or inhibitors. In a single-
dose study in healthy volunteers, the AUC was reduced by 64% in smokers when compared 
with nonsmokers.  In BR.21, current smokers achieved erlotinib trough plasma concentrations 
that were approximately 2-fold lower than never smokers.  Smokers should be advised to stop 
smoking while taking erlotinib as plasma concentrations of erlotinib are reduced due to the 
effect of cigarette smoking. 
Pretreatment or co-administration of erlotinib did not alter the clearance of a prototypical 
CYP3A4 substrate, midazolam. Therefore, significant metabolic interactions with other 
CYP3A4 substrates are unlikely. However, the oral bioavailability of midazolam decreased by 
up to 24% following erlotinib treatment, which was not attributed to a metabolic interaction. 
Erlotinib is both protein bound (92%–95%) and metabolized by hepatic cytochromes CYP3A4 
and CYP3A5 and pulmonary cytochrome CYP1A1. Therefore, a potential for drug–drug 
interaction exists when erlotinib is co-administered with drugs that are highly protein bound or 
that are CYP3A4 inhibitors/inducers. Co-administration of erlotinib with an inhibitor of 
CYP3A4 metabolism (ketoconazole, 200 mg po BID for 5 days) resulted in increased exposure 
to erlotinib as measured by an 86% increase in median erlotinib AUC and a 69% increase Cmax, 
compared with administration of erlotinib alone. Induction of CYP3A4 metabolism by a known 
enzyme inducer (rifampin, 600 mg po QD for 7 days) resulted in a 69% decrease in the median 
erlotinib AUC, compared with administration of erlotinib alone.  However, the effect of 
rifampin on Cmax was negligible. In another study, rifampicin pretreatment followed by co-
administration of rifampicin with a single 450 mg dose of erlotinib resulted in a mean erlotinib 
exposure (AUC) that was 57.6% of that observed following a single 150 mg erlotinib dose in 
the absence of rifampicin treatment.  Therefore, a potential for drug-drug interaction exists 
when erlotinib is co-administered with drugs that are highly protein bound or that are potent 
CYP3A4 inhibitors or inducers. 
See Appendix 5 for a list of known CYP3A4 inhibitors/inducers. Although caution and careful 
monitoring are recommended when use of these compounds are necessary, usage does not 
exclude subjects from participating in this trial, except for EIAEDs, see below. 
There is a demonstrated interaction between erlotinib and enzyme-inducing anti-epileptic drugs 
(EIAEDs), including carbamazipine, oxcarbazepine, phenytoin, fosphenytoin, 
phenobarbital, and primidone. In a clinical trial of erlotinib in patients with primary brain 
tumors, EIAEDs reduced exposure to single-agent erlotinib.36 As a result, patients will not be 
allowed to take EIAEDs while on this study. See Appendix 5 for a list of EIAEDs. 
 
International normalized ratio (INR) elevations and/or bleeding events have been reported in 
some cancer patients while on erlotinib alone and in combination with other chemotherapeutic 
agents, and concomitant NSAIDS or anti coagulants, including warfarin. 
 


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1.3 Study Rationale 
 
This Phase II trial will test the efficacy, safety, and tolerability of 2 years of adjuvant erlotinib in 
resected, early stage NSCLC patients with confirmed activating mutations in the EGFR gene. 
 
As described above, adjuvant chemotherapy for resected NSCLC provides a modest benefit but is 
not adequate to prevent relapse in a large proportion of patients. The most rational explanation for 
this failure is the inherent chemoresistance of NSCLC, with only a small percentage of patients (4-
15%) deriving benefit from even our most efficacious regimens.  
 
Patients with activating mutations of the EGFR, however, represent a unique population of NSCLC 
patients. In advanced disease, the response rates to EGFR TKIs in this group range from 58%37 to 
75%38 in prospective trials, and as high as 100%15,39,40 in retrospective analyses, numbers which are 
unprecedented in the treatment of NSCLC. If we extrapolate that 75% of patients with 
micrometastatic disease would have a similar benefit, we can hypothesize that adjuvant erlotinib 
could delay relapse or even potentially cure the majority of patients with resectable cancer who 
would otherwise relapse with adjuvant chemotherapy alone.  
 
This trial will provide a complement to the industry-initiated RADIANT trial, as lung cancers with 
EGFR mutations and lung cancers with EGFR protein overexpression and/or increased gene copy 
number may represent different populations of patients who may derive different levels of benefit 
from erlotinib treatment. Using biopsies at the time of disease recurrence, this trial will also allow 
us to collect EGFR-mutant NSCLC samples before and after treatment with erlotinib. These 
samples will provide invaluable information about the mechanisms of de novo and acquired 
resistance to EGFR TKIs, as well as allowing us to investigate the associations between EGFR 
mutations, protein expression, and gene copy number in primary and recurrent tumors. 
 
2.0 OBJECTIVES 
 
2.1  Primary Objectives 
 
The primary objective of this study is to determine the 2-year disease-free survival of patients 
with resected, early stage NSCLC who have activating mutations in the EGFR gene, after 
treatment with adjuvant erlotinib.  
 
2.2 Secondary Objectives 
 
The secondary objectives of this study are: 
1) To determine the safety and tolerability of 2 years of adjuvant erlotinib. 
2) To determine disease free survival in this patient sample. 
3) To determine overall survival in this patient sample. 
 


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2.3 Exploratory Objectives 
 
The exploratory objectives of this study are: 
1) To determine the relationship of EGFR mutation status to EGFR gene amplification and 
EGFR protein expression in early stage NSCLC. 
2) To determine the relationship of EGFR mutation status to EGFR gene amplification and 
EGFR protein expression in recurrent NSCLC. 
3) To identify secondary mutations responsible for resistance to erlotinib in recurrent 
NSCLC.  
4) To identify the frequency of MET amplification in recurrent, EGFR-mutant NSCLC. 
5) To study the ability to detect circulating tumor cells (CTCs) in patients with resected 
early stage NSCLC, to determine the relationship between CTC quantity over time to 
disease recurrence, and to identify the relationship between EGFR mutation status in 
CTCs and the primary and/or recurrent tumors. 
 
3.0 ELIGIBILITY 
 
3.1 Study Overview 
 
This is a Phase II, single-arm, open-label study designed to investigate the efficacy and safety 
of adjuvant erlotinib in patients with resected stage I-III non-small cell lung cancer who have 
confirmed activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase 
domain. 
 
3.2 Inclusion Criteria 
 
Patients may be enrolled only if they meet all of the following criteria: 
 
1) Pathologically confirmed diagnosis of non-small cell lung cancer of adenocarcinoma 
histology, including non-mucinous bronchioloalveolar carcinoma and mixed cell types such 
as adenocarcinoma with bronchioloalveolar features and adenosquamous carcinoma. 
2) Stage IA-B, IIA-B, or IIIA by theAmerican Joint Committee on Cancer (AJCC)   Seventh 
Edition  staging criteria, see Appendix 1. 
3) Patients must have undergone surgical resection with curative intent within 6 months of 
enrollment. 
4) Age equal to or greater than 18 years. 
5) Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point 
mutation. Other rare EGFR mutations may be eligible after discussion with the overall 
principal investigator.  Mutations detected at outside laboratories will be acceptable for 
enrollment. 
6) Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Status scale, see Appendix 2. 


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7) Neoadjuvant or adjuvant chemotherapy, radiation, and/or chemoradiation will be allowed as 
long as no more than 6 months have passed between surgical resection and enrollment. If 
patients receive sequential chemotherapy and radiation, they are allowed 9 months between 
surgical resection and enrollment.   At least 3 weeks ( ≥21 days)  must have passed since 
the completion of adjuvant chemotherapy.  
8) Adequate organ function including the following 
 Adequate bone marrow reserve:  
o Total white blood cell count (WBC)  3.0 x 109/L 
o Platelet count 100 x 109/L 
o Hemoglobin 9 g/dL 
 Hepatic: 
o Bilirubin: ≤ 1.25 times the upper limit of normal (ULN) 
o Alanine transaminase (ALT): ≤ 2.5 times the ULN 
o Aspartate transaminase (AST): ≤ 2.5 times the ULN 
 Renal: Serum creatinine ≤ 1.5 times the ULN, or creatinine clearance 
≥60mL/minute as calculated by the standard Cockcroft-Gault formula, see 
Appendix 3. 
9) Willingness to comply with protocol procedures.  
10) Willingness to participate in clinical research as evidenced by their signature on the 
informed consent form. 
 
3.3 Exclusion Criteria 
 
Patients meeting any of the following exclusion criteria will not be eligible to enter in the 
study: 
 
1) Radiographic evidence of recurrent NSCLC prior to erlotinib treatment.  
2) Confirmed T790M resistance mutation in the primary tumor sample. 
3) Prior exposure to EGFR tyrosine kinase inhibitors. 
4) Known hypersensitivity to erlotinib, gefitinib, or any closely related drug. 
5) Pregnant or breastfeeding. The effects of erlotinib on a fetus are unknown. For these 
reasons, female subjects of childbearing age must practice acceptable methods of birth 
control to avoid pregnancy. Male subjects must also practice acceptable methods of birth 
control to prevent pregnancy of a partner. 
6) Any evidence of clinically active interstitial lung disease. Note that patients with chronic, 
stable radiographic changes who are asymptomatic need not be excluded. 
7) Malignancies within the past 3 years except for adequately treated carcinoma of the cervix 
or basal or squamous cell carcinomas of the skin. 




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Within 6 months of surgical resection, patients with clinical characteristics suggesting a high 
probability of EGFR mutation will have their primary tumors screened for activating EGFR 
mutations (i.e. exon 19 deletions, L858R point mutation). Patient with confirmed mutations 
will be treated with daily oral erlotinib for a maximum of 2 years. 
 
4.2 Treatment Administration: Single agent Erlotinib 
 
4.2.1 Treatment Agent 
 
Substance:  
Erlotinib Hydrochloride 
Pharmaceutical Form:  
Tablets 
Source:  
Genentech, San Francisco, CA 
Procurement: 
Medication to be provided by OSI 
Unit strength: 
150 mg tablets 
Daily dose: 
See Section 4.2.2 
Duration of Use: 
Continuous daily dosing starting on Day 1 and continuing for 2 
years or until criteria for discontinuation are met, see Section 4.4 
Route of Administration: Oral (swallowed) 
Frequency: 
Once daily, on an empty stomach 
 
4.2.2 Dosage and Administration Schedule 
 
All patients will begin oral dosing of Erlotinib at 150 mg daily on day 1 of treatment and 
continue daily dosing without interruption. Patients should take their assigned daily dose at 
approximately the same time each day. Erlotinib should be taken on an empty stomach, 
1 hour before a meal or 2 hours after a meal. Patients will continue with daily treatment for 
a maximum of 2 years. 
 
4.2.2.1 Missed and Vomited Doses 
 
If a patient inadvertently does not take the Erlotinib dose at their usual time, he or she 
may take their daily doses anytime as long as it is at least 12 hours before the next 
dose is due to be taken. Erlotinib should be taken on an empty stomach. The daily 
treatment schedule will be resumed the next day with the patient taking the scheduled 
dose at the usual time. If an entire daily dose is skipped, the patient should resume 
treatment the following day with their regular dose. No “make-up dose” or increased 
dosing should occur. Patients should report all missed or delayed doses to the study 
staff. 
 
In subjects who have emesis and are unable to retain erlotinib for 30 minutes or 
longer, every attempt should be made to obtain control of nausea and vomiting. The 
dose of erlotinib may be repeated if emesis occurs within 30 minutes of taking the 
tablet. Patients should report all vomited doses to the study staff. 
 


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4.2.3 Dose Delays 
 
If a treatment-related toxicity of grade 3 or higher occurs, erlotinib should be held until the 
toxicity resolves to ≤ grade 1 or pre-treatment baseline. Subsequent treatment should be 
dose-reduced one dose level as per Section 4.2.4. The investigator also has the discretion to 
hold erlotinib treatment for any other toxicity, but in this case dose reduction is not 
required. Treatment may be held for up to 28 days. If the toxicity is not improved to ≤ grade 
1 or pre-treatment baseline within the 28-day period, the subject must be withdrawn from 
the study. 
 
4.2.4 Dose Modification Guidelines 
 
If a treatment-related toxicity of grade 3 or greater occurs, erlotinib should be held until the 
toxicity resolves to ≤ grade 1 or pre-treatment baseline, and then erlotinib should be dose-
reduced one level. Dose reduction levels for erlotinib are 100 mg and 50 mg.  The 
investigator also has the discretion to reduce the dose of erlotinib treatment by one dose 
level for any other toxicity, in consultation with the principal investigator.  
 
Note that no patient may undergo more than 2 dose reductions. If a third dose reduction 
becomes necessary, the subject must be withdrawn from the study.  
 
4.3 Concomitant Therapy 
 
Information about concomitant medications will be collected as part of this study during 
screening, at each evaluation visit, and at the time of study discontinuation, see Section 6.0. 
Patients are allowed to receive full supportive care therapies concomitantly during the study. 
No other chemotherapy, immunotherapy, hormonal cancer therapy, radiation therapy, surgery 
for cancer, or experimental medications will be permitted while the patients are receiving study 
therapy.  
 
Data on potential interactions between erlotinib and CYP3A4 inhibitors/inducers are lacking. 
Although caution and careful monitoring are recommended when use of these compounds are 
necessary, usage does not exclude subjects from participating in this trial in general. See 
Appendix 5 for a list of known CYP3A4 inhibitors/inducers. However, there is a demonstrated 
interaction between erlotinib and enzyme-inducing anti-epileptic drugs (EIAEDs), including 
carbamazipine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. In a 
clinical trial of erlotinib in patients with primary brain tumors, EIAEDs reduced exposure to 
single-agent erlotinib.36 As a result, patients will not be allowed to take EIAEDs while on this 
study. See Appendix 5 for a list of EIAEDs. 
 
Because of the potential for drug-drug interaction between erlotinib and warfarin, patients in 
this study who are receiving concomitant warfarin or coumarin derived anticoagulants, should 
have close monitoring of their INR and prothrombin time and adjustment of the anticoagulant 
dose as clinically indicated. 
 


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4.3.1 Recommendations for Supportive Treatment  
 
The following are recommendations for supportive treatment of expected side effects 
 
Rash: Management of Grade 1 or 2 erlotinib-associated acneiform rash should include 
continuation of erlotinib and symptomatic management such as moisturizing, analgesics for 
pain and oral antihistamines for pruritis, see Table 1. The following agents may be used to treat 
rash:  diphenhydramine, topical or oral corticosteroids, and topical (clindamycin) or oral 
antibiotics (tetracycline, minocycline, doxycycline). Topical drying agents are not 
recommended. High-potency topical corticosteroids (class I and II) may be effective if used 
early in therapy. The use of topical immunomodulatory agents, such as pimecrolimus (Elidel) 
and tacrolimus (Protopic), can also be attempted.35 Secondary infections of the rash can be 
treated with oral antibiotics. Systemic steroids are discouraged as treatment for skin toxicity 
due to lack of efficacy and potential worsening of the acneiform skin rash. If skin rash persists 
or worsens, dose reduction to 100 mg per day and/or treatment interruption of 5-14 days should 
be considered. If the dose of erlotinib is reduced for rash, subjects should be maintained at the 
reduced dose without attempt at dose re-escalation. If rash does not decrease to ≤ grade 1 
within 28 days of treatment interruption, then erlotinib should be discontinued and the patient 
should be withdrawn from the study. Subjects experiencing grade 4 rash should be considered 
for withdrawal from the study for excessive toxicity. 
 
Diarrhea: For Grade 1 or 2 diarrhea, early intervention should include initiation of anti-
diarrheal therapy as described in Table 1. For patients on erlotinib experiencing persistent grade 
2 diarrhea despite optimal medical management, consideration of dose reduction of erlotinib to 
100 mg per day should be considered as outlined in Section 4.2.4. Management of ≥ grade 3 
diarrhea should include holding erlotinib until the toxicity resolves to ≤ grade 1 or pre-
treatment baseline. Subsequent treatment should be dose-reduced one dose level. Subjects 
should be maintained at the reduced dose without attempt at dose re-escalation. If diarrhea does 
not resolve to ≤ grade 1 within 28 days of treatment interruption then the patient should be 
withdrawn from the study. Subjects experiencing grade 4 diarrhea should be considered for 
withdrawal from the study for excessive toxicity. 
 
ILD: Although quite rare, ILD can be life threatening. Therefore, patients should be monitored 
closely for symptoms consistent with ILD, such as new onset dyspnea without an obvious 
cause. In the event that ILD is suspected, erlotinib treatment should be discontinued and the 
patient should receive appropriate medical management. Although there is no proven therapy, 
systemic corticosteroids are often provided. Erlotinib should not be restarted in those patients 
suspected of having drug-related ILD. 
 


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Table 1. Recommended Guidelines for Management Selected Toxicities 
NCI-CTCAE (v 3.0) Grade 
Erlotinib Dose Modification 
Guideline for Management 
Diarrhea 
Grade 1 
None 
Consider loperamide (4 mg at first 
onset, followed by 2 mg q 2–4 
hours until free of diarrhea for 12 
hours) 
Grade 2 
None 
(Dose reduction of erlotinib is 
necessary if diarrhea persists over 
48–72 hours despite optimal 
medical management) 
Loperamide (4 mg at first onset, 
followed by 2 mg q 2–4 hours until 
diarrhea free for 12 hours) 
Grade 3 
Interrupt then dose reduce erlotinib.  
Erlotinib should not be re-escalated. 
Interrupt erlotinib until resolution 
to Grade 1, and restart at next 
reduced dose 
Grade 4 
Discontinue study treatment.
Pulmonary Events if possibly ILD 
All Grades 
Temporarily interrupt erlotinib 
pending the diagnostic evaluation. 
If the pulmonary adverse event is 
assessed as related to erlotinib, 
discontinue the patient from study 
treatment. 
Unexplained dyspnea, either new 
or progressive, should be 
aggressively evaluated.   
Rash 
Grade 1 and 2 
Tolerable rash 
None 
Any of the following: oral 
antibiotics (tetracycline, 
minocyclinea, doxycycline), topical 
clindamycin, diphenhydramine, 
topical or oral corticosteroids at 
discretion of investigator 
Grade 3 
Intolerable rash 
Consider interruption and or dose 
reduction if unresponsive to 
symptomatic management.  
Re-escalation is allowed. 
Manage as described above 
Grade 4 
Discontinue study treatment. 
Manage as described above 
a Recommended dose:  200 mg po bid (loading dose) followed by 100 mg po bid for  
7–10 days. 


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4.4 Discontinuation of Study Treatment 
Patients enrolled on the study will be treated continuously for a maximum of 2 years. Patients 
will be discontinued from study treatment under the following conditions: 
1) The patient has completed 2 years of treatment.
2) Evidence of recurrent disease on surveillance radiographs. When possible and
medically appropriate, tissue biopsies should be obtained to prove recurrence.
3) Retreatment criteria are not met within the specified time frame, see Sections 4.2.3.
4) Study therapy exhibits unacceptable toxicity.
5) Investigator or patient requests withdrawal.
6) Severe non-compliance to protocol.
7) Death.
8) Patient lost to follow-up.
4.5 Study Medication Accountability 
At the time of study closure, the unused, used and expired study drug will be destroyed at the 
site per Institutional SOPs and OSI should be provided with documentation when this has 
occurred.  
Patients who discontinue study treatment will undergo follow-up procedures as described in  
Sections 5.0 and 6.0. 
5.0 STUDY ASSESSMENTS 
5.1 Safety Assessments 
5.1.1 Overview of Safety Assessments 
A secondary objective of this study is to identify the safety and tolerability of 2 years of 
adjuvant erlotinib. Safety measurements that will be used in the study include physical 
examinations and clinical laboratory tests (hematology, blood chemistries, creatinine and liver 
function tests). Patients will be rated for toxicity using the NCI CTC version 3.0, see Appendix 
4. Standard toxicity assessment will occur in the screening phase, monthly for the first 6
months of treatment, and then every 3 months until treatment is discontinued. For a table of the
required data, see Section 6.0.
Treating investigators are responsible for monitoring the safety of patients who have entered 
this study and for alerting the Institutional Review Board (IRB) to any event that seems 
unusual, even if this event may be considered an unanticipated benefit to the patient. All 
patients experiencing an adverse event that is serious or that caused the patient to discontinue 


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before completing the study must be followed through an appropriate health care option, until 
the event resolves or is explained. 
 
5.1.2 History and Physical Examination 
 
The relevant interval history should be obtained during screening, at monthly intervals for the 
first 3 months (months 4 and 5 are optional and at the discretion of the treating MD) and then 
every 3 months until treatment is discontinued, at months 30, 36, 48, 60 after 2 years of 
treatment have been completed, and at the time of study discontinuation. Interval history should 
include elicitation of interim illnesses and adverse events. 
 
A problem-focused physical examination (PE) will be performed during screening, monthly for 
3 months (months 4 and 5 are optional and at the discretion of the treating MD) and then every 
3 months until treatment discontinuation, at months 30, 36, 48, 60 after 2 years of treatment 
have been completed, and at the time of study discontinuation. Every PE should include 
measurement of body weight, vital signs, and evaluation of the ECOG performance score, see 
Appendix 2. Measurement of height need only occur at the screening PE. Visit windows after 
screening/baseline for months 1-3 is +/- 7 days.  Starting month 4, the window is extended to 
+/- 14 days 
 
5.1.3 Laboratory Examinations 
 
Laboratory examinations to be performed during screening for the treatment phase include 
hemoglobin, white blood cell count including neutrophil count (sum of polysegmented 
granulocytes and band forms), platelets, bilirubin, alkaline phosphatase, ALT, AST, blood urea 
nitrogen (BUN), creatinine, calcium, electrolytes (sodium, potassium), and a pregnancy test 
(urine or plasma for women of child-bearing age).  
 
Laboratory examinations to be performed at the initiation of treatment, monthly for 6 months 
and then every 3 months until treatment discontinuation, at months 30, 36, 48, 60 after 2 years 
of treatment have been completed, and at the time of study discontinuation include hemoglobin, 
white blood cell count including neutrophil count (sum of polysegmented granulocytes and 
band forms), platelets, bilirubin, alkaline phosphatase, ALT, AST, blood urea nitrogen (BUN), 
creatinine, calcium and electrolytes (sodium, potassium). If screening blood tests were 
performed within 7 days of starting treatment they do not need to be repeated on day 1.  
 
5.1.4 Adverse Events 
 
An Adverse Event (AE) is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational (medicinal) product or other 
protocol-imposed intervention, regardless of attribution. 
This includes the following: 
 AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with NSCLC that were 
not present prior to the AE reporting period  


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 Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies) 
 If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention 
 Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period 
 Diagnoses and/or symptoms associated with NSCLC should be reported as AEs if they 
worsen or change in character. Clinical progression of NSCLC should not be reported 
as an AE. 
A consistent methodology of non-directive questioning for eliciting AEs at all patient 
evaluation time points should be adopted.  Examples of non-directive questions include:  
 “How have you felt since your last clinical visit?” 
“Have you had any new or changed health problems since you were last here?” 
All AEs should be documented, whether or not the AE is considered serious. A description of 
the event, including its date of onset and resolution, any action taken, and outcome should be 
provided along with the investigator’s assessment of causality. An event that is due to 
unequivocal progression of disease should not be reported as an AE. 
 
5.1.5 Serious Adverse Events 
 
An event that fulfills at least one of the following criteria will be designated a serious adverse 
event (SAE). Study site personnel must immediately report SAEs to the IRB, no later than the 
end of the next business day after becoming aware of the event. 
 
 Results in death 
 Requires or prolongs hospitalization (i.e. the AE required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or 
routine check-ups are not SAEs by this criterion) 
 Is immediately life-threatening  
 Results in severe or permanent disability or incapacity 
 Is a congenital abnormality or birth defect 
 Is considered a significant medical event by the investigator based on medical 
judgement. 
 
Does not meet any of the above serious criteria but may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 
All SAEs will be recorded once the patient has entered in the study, even if study drug has not 
yet been administered. After discontinuation from treatment, subjects must be followed for 
SAEs for 30 calendar days after the last dose of study drug. SAEs occurring more than 30 days 
after the last dose of study drug(s) will not be reported unless the investigator feels that the 
event may have been caused by the study drug(s) or a protocol procedure. Any events that are 
unequivocally due to progression of disease should not be reported as a SAEs. 


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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity. An AE of severe intensity need not necessarily be considered serious. For example, 
nausea that persists for several hours may be considered severe nausea, but not an SAE. On the 
other hand, a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be an SAE. To assess severity of an adverse event, please refer to the NCI 
CTC version 3.0 (Appendix 4) and Appendix 6. 
 
The causality of SAEs (relationship to the study drug) must be considered by the investigator 
by answering the question, “Do you consider that there is a reasonable possibility that the 
event may have been caused by the drug?” See Appendix 6 for more guidance on this issue. 
 
All SAEs should be reported and submitted per institutional guidelines. The investigator is 
responsible for ensuring that all AEs and SAEs that are observed or reported during the study 
are recorded on the CRF and reported to the Sponsor in accordance with protocol instructions.  
 
5.1.6 Assessment of Adverse Events 
 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation time points 
during the study. All AEs and SAEs whether volunteered by the patient, discovered by study 
personnel during questioning, or detected through physical examination, laboratory test, or 
other means will be recorded in the patient’s medical record and on the appropriate AE or SAE 
clinical report form page. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity 
(see Table 2), regulatory seriousness criteria if applicable, suspected relationship to the 
investigational product (see following guidance), and actions taken. 
While most hospitalizations require reporting of an SAE, some events do not require reporting.  
Examples would be: 
 Elective or previously scheduled surgery 
 Procedures for pre-existing conditions that have not worsened after the initiation of 
treatment 
 Pre-specified study hospitalizations for observation 
 
 


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Table 2 
Adverse Event Grading (Severity) Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific 
NCI-CTCAE grading criteria) 
Transient or mild discomfort ( 48 
hours); no interference with the patient’s 
daily activities; no medical 
intervention/therapy required 
2 
Moderate (apply event-specific  
NCI-CTCAE grading criteria) 
Mild to moderate interference with the 
patient’s daily activities; no or minimal 
medical intervention/therapy required 
3 
Severe (apply event-specific  
NCI-CTCAE grading criteria) 
Considerable interference with the 
patient’s daily activities; medical 
intervention/therapy required; 
hospitalization possible 
4 
Very severe, life threatening,  
or disabling (apply 
event-specific NCI-CTCAE 
grading criteria) 
Extreme limitation in activity; significant 
medical intervention/therapy required, 
hospitalization probable 
5 
Death related to AE 
 
Note:  Regardless of severity, some events may also meet regulatory serious criteria.  
Refer to definitions of an SAE (see Section 5.1.7). 
a Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or 
reported AE is not in the NCI-CTCAE listing. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
 YES 
There is a plausible temporal relationship between the onset of the AE and administration of 
the investigational product, and the AE cannot be readily explained by the patient’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to the investigational product; and/or the AE abates or resolves upon discontinuation 
of the investigational product or dose reduction and, if applicable, reappears upon re-challenge. 
 NO 
Evidence exists that the AE has an etiology other than the investigational product (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to administration of the 
investigational product (e.g., cancer diagnosed 2 days after first dose of study drug).  
 






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Sites may be directly contacted directly to request these specimens. Results of these tests will 
be provided to back to sites upon request. 
 
Available unstained sections of paraffin-embedded tumor from patients will undergo 
microdissection, after which genomic DNA will be extracted. Tumor DNA will be directly 
sequenced to look for EGFR mutations, including EGFR exons 18-21, using standard 
procedures.  As noted, L858R and exon 19 deletion EGFR mutations detected at other centers 
or using other methods will also be acceptable.   Mutation analysis will be also be performed, 
whenever possible, on biopsy tissue taken at the time of recurrence to look for changes in the 
mutation profile of recurrent tumors. 
 
Tumor sections will also undergo fluorescence in-situ hybridization (FISH) analysis using 
standard procedures and employing fluorescent probes for the EGFR locus on chromosome 7p 
and for chromosome 7q as a reference. A ratio of 7p:7q of > 2.0 will be considered EGFR locus 
amplification. The distribution of EGFR copy number in the cellular population will be used to 
assess for polysomy, using the standard criteria described previously.41 Samples of tumor taken 
at the time of disease recurrence will additionally undergo FISH testing to detect amplification 
of MET31. Dr. A. John Iafrate will collaborate on the molecular analyses. 
 
Tumor sections will also be stained for EGFR protein expression using immunohistochemistry with 
commercially available antibodies against human EGFR. 
 
 
 
5.4.2  Circulating Tumor Cells (CTCs)  
 
CTCs will be measured in freshly obtained peripheral blood using the CTC-Chip (as described 
in the background section) at baseline and every 6 months at the same time as the scheduled 
surveillance scans. CTC analysis will be restricted to the patients enrolled at the MGH and 
DFCI sites as the blood needs to be tested rapidly and cannot currently be done at outside 
institutions. The association of CTCs with radiographic disease recurrence will be assessed. 
EGFR mutation testing will be performed on isolated CTCs to determine the relationship 
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c 
Laboratory Studies – screening studies include CBC, LFTs, BUN, Cr. Studies at the start of each cycle of treatment 
include CBC, LFTs, BUN, Cr, calcium and electrolytes. If screening labs done ≤ 7 days of study start, they do not need 
to be repeated on Day 1 
d 
Radiological evaluation – CT scans of the chest, abdomen, and pelvis will be performed at baseline, every 6 months 
for the first 36 months, and then annually until 60 months to check for recurrent disease. 
e 
CTC – Circulating tumor cell assay on peripheral blood will be performed at baseline, every six months for 3 years, 
and then annually until 60 months at the time of radiographic evaluations. Only done at MGH and DFCI. 
f 
EGFR testing - EGFR sequencing, FISH for EGFR and MET gene copy number, and immunohistochemistry for 
EGFR protein expression. Testing for the initial screening can take place anywhere in the patient’s treatment as long as 
adjuvant erlotinib can start within 6 months of surgery. 
g 
Survival follow-up - After discontinuation from the study for any reason, where possible the patient, patient’s family, 
or the patient’s current physician must be contacted every 12 weeks for survival information until death.  All 
subsequent chemotherapy, radiation, surgical or other anti-cancer therapies are to be collected until death.  A statement 
of death form should be submitted at any point during the study when a patient has died.  In addition, any patient who 
discontinued study treatment for reasons other than objective disease recurrence should continue, where possible, to 
have objective tumor surveillance scans per routine practice guidelines. 
h     Selected adverse events will be captured. Please see Appendix 4 for complete list of events and codes 
i      Months 4 and 5 are optional and at the discretion of the investigator 
 
7.0 STATISTICAL PLAN 
 
7.1 Overview 
 
This is a Phase II single-arm open-label study of adjuvant erlotinib in patients with resected, early 
stage NSCLC who have activating mutations in the EGFR gene. The primary objective of this 
study is to determine the 2-year disease free survival (DFS) rate in this population. Secondary 
objectives are to determine the overall safety and tolerability of 2 years of adjuvant erlotinib, as 
well as to determine the disease-free survival and overall survival in this population. 
 
7.2 Sample Size 
 
This trial will enroll a total of 100 patients.  
 
Based on data from a large single institution experience of early stage resected NSCLC cases 
known to harbor EGFR mutations and treated with adjuvant erlotinib or gefitinib, we would expect 
the 2-year DFS to be approximately 76% at baseline across all stages as reported for a group of 114 
patients.42 When a similar group of patients at the same institution were treated with adjuvant 
erlotinib or gefitinib, their 2-year DFS increased to 88%, which gives us an idea of the expected 
magnitude of benefit. 
 
With 100 patients, the study will have 90% power to observe an improvement in DFS at 2 years 
from a historical control of 76%, to 86% for patients treated on our study with adjuvant erlotinib, 
using the one-sided binomial proportion hypothesis test with significance level of 0.1. This degree 
of improvement is reasonable to expect since metastatic NSCLC patients with EGFR mutations 
have a response rate to erlotinib of about 75% and their progression-free survival on upfront 
erlotinib is about 9 months, as opposed to the 3 months typically observed with combination 
chemotherapy.37, 38, 40 The trial will be deemed successful if at least 82 patients are alive and 
progression free by 2 years. 
 


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7.3 Data to Be Analyzed 
 
All enrolled patients treated with at least one dose of study drug will be included in the safety and 
efficacy analyses on an intention to treat basis. All enrolled patients treated with at least one dose 
of study drug and with sufficient and appropriate tumor samples for molecular analysis will be 
included in the correlative science analyses. 
 
7.4 Patient Disposition 
 
A detailed description of patient disposition will be provided. It will include: 
 A definition of patient enrollment 
 A summary of data regarding patient discontinuation of study treatment 
 A summary of data regarding patient inclusion and exclusion in efficacy and safety 
analyses 
 
7.5 Patient Characteristics 
 
Patient characteristics will include a summary of the following: 
 Patient demographics 
 Baseline disease characteristics 
 Significant medical history and co-morbidities 
 Concomitant therapies 
 Other characteristics as appropriate 
 
7.6 Primary Analysis 
 
The primary objective of this study is to determine the 2-year disease free survival (DFS) of 
patients with resected, early stage NSCLC and activating EGFR mutations that are treated with 2 
years of adjuvant erlotinib. 2-year DFS is the percentage of patients alive and free from disease 
recurrence 2 years after enrollment. 
 
7.7 Secondary Analyses 
 
All enrolled patients treated with at least one dose of study drug and undergoing at least one 
radiographic study for documentation of disease status will be included in the secondary analyses. 
These analyses will include the following: 
 
 Toxicity profiles and tolerability of 2 years of adjuvant erlotinib. 
 Estimate of the median disease-free survival and median overall survival. 
 Kaplan-Meier curves and quartiles for DFS and OS. 
 


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The overall safety profile erlotinib will be assessed by examining the number, severity, and timing 
of adverse events. Toxicities will be graded according to the NCI CTC version 3.0, see Appendix  
4. Safety analyses will include the following: 
 
 Summaries of the adverse event rates, by dose level 
 Listings and frequency tables categorizing laboratory and nonlaboratory AEs by 
maximum NCI CTC grade and relationship to study drug 
 
DFS is calculated from the date of enrollment to the date when objective tumor recurrence is 
observed or until death if the patient has not recurred. OS is assessed from the time of enrollment 
until the time of death, and surviving patients will be censored at the date they are last known to be 
alive. 
 
7.8 Correlative Analyses 
 
All enrolled patients must have tissue available for screening for EGFR mutations. Those who are 
treated with at least one dose of study drug and have sufficient and appropriate samples for 
analysis, either from the primary tumor or biopsy material from recurrent tumors, will be included 
in the correlative science analyses. These studies are aimed at defining the association of EGFR 
mutations, EGFR amplification, and EGFR protein expression, as well as investigating the 
mechanisms of resistance to adjuvant erlotinib. Correlative science analyses will include the 
following: 
 Evaluation of the association of EGFR mutation with EGFR amplification and/or EGFR 
protein expression in early and relapsed disease. 
 Evaluation of EGFR mutation status, EGFR amplification, MET amplification, and EGFR 
protein expression in recurrent versus primary NSCLC after treatment with adjuvant 
erlotinib in order to determine mechanisms of resistance. 
 Evaluation of the relationship of CTCs to disease recurrence, and the relationship of the 
EGFR mutational status of CTCs to that of the primary and/or recurrent tumor samples 
 
8.0 QUALITY ASSURANCE OFFICE FOR CLINICAL TRIALS (QACT) EXTERNAL SITE 
MONITORING PLAN 
 
8.1 The QACT will provide the following services: 
 
o Central Registration: All 100 of the participants accrued to protocol 07-259 will be registered 
through the QACT prior to beginning protocol treatment. All of the eligibility checklists and 
consents will be reviewed for completeness and accuracy by the QACT Protocol Registrars 
before registration will occur, as is standard practice. 
 
o Data Collection and Computerization: This trial will have data collected through the electronic 
data collection (eDC) system, Inform.  The QACT will coordinate the training of all sites on 
this web–based application and the QACT Data Analyst will be QA and QC’ing data that is 
electronically entered. This eDC system will also allow for the Overall PI and DFCI study team 
to view the status of data collection at all sites in a real time basis. The QACT Data Analysts 
will also be providing formal missing form reports on an on-going basis, as well as help 
prepare the data for interim and final analysis by biostatistics. 


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o Site Monitoring/Auditing: After a site has accrued 2-3 participants, the QACT will be 
conducting an on-site audit. This is anticipated to occur within the first year of enrollment. 
Similar to the cooperative group auditing structure, one visit to each site will be planned during 
the 18 month expected enrollment period of the trial. If significant violations are uncovered 
during the audit, a follow-up audit may be requested. The final audit reports for the external 
sites will be reported to the Overall PI, as well as the Audit Subcommittee, as is standard 
practice.  
 


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9.0 
APPENDICES 
 
Appendix 1: AJCC Seventh Edition Staging for Non-Small Cell Lung Cancer43 
 
 
Definition of TNM: 
Primary tumor (T) 
 
TX: Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in 
sputum or bronchial washings but not visualized by imaging or bronchoscopy  
 
T0: No evidence of primary tumor  
 
Tis: Carcinoma in situ  
 
T1: Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the 
main bronchus) . The uncommon superficial spreading tumor of any size is classified as T1 
even when extending to the main bronchus, as long as the invasive component is limited to the 
bronchial wall.  
 
T1a: Tumor ≤2 cm in greatest dimension 
 
T1b: Tumor >2 cm but ≤3 cm in greatest dimension 
 
T2: Tumor >3 cm but ≤7 cm or tumor with any of the following features (T2 tumors with these 
features are classified T2a if ≤5 cm) 
 
Involves the main bronchus, ≥2 cm or more distal to the carina  
 
Invades the visceral pleura  
 
Associated with atelectasis or obstructive pneumonitis that extends to the hilar 
region but does not involve the entire lung  
 
T2a: Tumor >3 cm but ≤5 cm in greatest dimension 
 
T2b: Tumor >5 cm but ≤7 cm in greatest dimension 
 
T3: >7 cm or one that directly invades any of the following: chest wall (including superior 
sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in 
the main bronchus <2 cm distal to the carina but without involvement of the carina; or 
associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) 
in the same lobe 
 
A tumor of any size that directly invades any of the following: chest wall (including superior 
sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main 
bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated 
atelectasis or obstructive pneumonitis of the entire lung  
 
T4: Tumor of any size that invades any of the following: mediastinum, heart, great vessels, 
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) 
in a different ipsilateral lobe 
Regional lymph nodes (N)  
 
NX: Regional lymph nodes cannot be assessed  
 
N0: No regional lymph node metastasis  
 
N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and 
intrapulmonary nodes including involvement by direct extension of the primary tumor  
 
N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)  


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 
N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s)  
Distant metastasis (M) 
 
MX: Distant metastasis cannot be assessed  
 
M0: No distant metastasis  
 
M1a: Separate tumor nodule(s) in a contralateral lobe, tumor with pleural nodules or malignant 
pleural or pericardial effusion 
 
M1b: Distant metastasis 
 
Stage Grouping 
Occult Carcinoma 
TX 
N0 
M0 
Stage 0 
Tis 
N0 
M0 
Stage IA 
T1a,b 
N0 
M0 
Stage IB 
T2a 
N0 
M0 
Stage IIA 
T1a,b  
N1 
M0 
 
T2a 
N1 
M0 
 
T2b 
N0 
M0 
Stage IIB 
T2b 
N1 
M0 
 
T3 
N0 
M0 
Stage IIIA 
T1, T2 
N2 
M0 
 
T3 
N1, N2 
M0 
 
T4 
N0, N1 
M0 
Stage IIIB 
T4 
N2 
M0 
 
Any T 
Any N 
M0 
Stage IV 
Any T 
Any N 
M1a,b 
 


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Stage Grouping 
 
Appendix 2: ECOG Performance Status Scale44 
 
 
ECOG 0 Fully active, able to carry on all pre-disease performance without restrictions 
ECOG 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, eg. light housework, office work 
ECOG 2 Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours 
ECOG 3 Capable of only limited self-care, and confined to bed or chair more than 50% of 
waking hours 
ECOG 4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
ECOG 5 Deceased 
 
 


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Appendix 3: Cockcroft-Gault Formula for Creatinine Clearance45 
 
 


85
.0
,
72
)
100
/
(
)
140
(
min)
/
(
by
multiply
women
for
mL
mg
Creatinine
Serum
kg
in
weight
years
in
age
mL
CrCl




 
 
 




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Appendix 5: Potential CYP3A4 Inhibitors and Inducers 
 
CYP3A4 Inhibitors 
Atazanavir 
Delaviridine 
Indinavir 
Nelfinavir  
Ritonavir 
Saquinavir 
Amiodarone 
Cimetidine  
Ciprofloxacin  
Clarithromycin  
Diclofenac 
Diethyl-dithiocarbamate 
Diltiazem  
Doxycycline 
Erythromycin 
Flucanazole  
Fluvoxamine 
Gestodene  
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole  
Ketoconazole 
Mifepristone  
Nefazodone 
Nicardipine 
Norfloxacin  
Norfluoxetine 
Mibefradil  
Quinidine 
Telithromycin 
Troleandomycin 
Verapamil 
Voriconazole 
 
CYP3A4 Inducers/EIAEDs 
Aminoglutethomide 
Carbamezepine 
Fosphenytoin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Primidone 
Rifamycins 
St. John’s Wort 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6: Identifying and Attributing Cause to a Serious Adverse Event 
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE 
EVENT (SAE) 
Life threatening 
“Life threatening” means that the patient was at immediate risk of death from the adverse event as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s death.  
“Life threatening” does not mean that had an adverse event occurred in a more severe form it might 
have caused death (ie, hepatitis that resolved without hepatic failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious adverse event, although the 
reasons for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered adverse events if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgment should be exercised in deciding whether a case is serious in a situation 
where important medical events may not be immediately life threatening or result in death, 
hospitalization, disability or incapacity but may jeopardize the patient or may require medical 
intervention to prevent one or more outcomes listed in the definition of serious.  These should usually 
be considered as serious.  Examples of such events are: 
 
 Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
 Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
 Intensive treatment in an emergency room or at home for allergic bronchospasm 
 Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
 Development of drug dependency or drug abuse 
Disease progression 
Any events or hospitalization that are unequivocally due to progression of disease must not be reported 
as serious adverse events. 


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FURTHER GUIDANCE ON THE ASSESSMENT OF CAUSALITY 
The following factors should be considered when deciding if there is a “reasonable possibility” that an 
adverse event (AE) may have been caused by the investigational product. A “reasonable possibility” 
could be considered to exist for an AE when 1 or more of these factors exist. 
 
 Time course of events and exposure to suspect drug:  Has the patient actually 
received the suspect drug?  Did the AE occur in a reasonable temporal relationship to 
the administration of suspect drug? 
 Consistency with known drug profile:  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  OR could the AE be anticipated from its pharmacological 
properties? 
 De-challenge experience:  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
 No alternative cause:  The AE cannot be reasonably explained by another etiology, 
such as the underlying disease, other drugs, other host, or environmental factors. 
 Re-challenge experience:  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  AstraZeneca would not normally recommend or support a 
re-challenge. 
 Laboratory tests:  Has a specific laboratory investigation confirmed the relationship? 
In contrast, there would not be a “reasonable possibility” of causality if none of the above criteria 
apply, or if there is evidence of exposure and a reasonable time course, but any de-challenge (if 
performed) is negative or ambiguous, or there is another more likely cause of the AE. 
 
In difficult cases, other factors could be considered such as the following: 
 Is this a recognized feature of overdose of the drug? 
 Is there a known mechanism? 
Ambiguous cases should be considered as having a “reasonable possibility” of causal relationship, 
unless additional evidence becomes available to refute this. 
 


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DFCI IRB Protocol #: 07-259 
 
 
 
 
 
APPENDIX 7 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan (DSMP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Data Safety Monitoring Plan Table of Contents 
 
1.0  Introduction ……………………………………………………………….........46 
  
1.1  Purpose 
1.2  Data and Safety Monitoring Plan Components 
 
2.0     General Roles and Responsibilities …………………………………………...47 
 
  
2.1  Protocol Chair 
 
 
 
2.2  Coordinating Center 
 
 
 
2.3  Participating Institution 
 
 
 
3.0     DF/HCC Quality Assurance Office for Clinical Trials ………………………48 
 
 
 
3.1  Organizational Structure 
 
 
 
 
4.0 Protocol Development …………………………………………………………..49 
 
 
 
 
  4.1   Activation of a Protocol 
 
 
 
 
  4.2   Coordinating Center Support Function 
 
 
5.0   Protocol Management ……………………………………………………………50 
 
 
 
5.1 Protocol Distribution 
 
 
 
5.2 Protocol Revisions and Closures 
 
 
5.3 Informed Consent Requirements 
 
 
5.4 IRB Documentation 
 
 
 
5.5 IRB Re – Approvals 
 
 
 
5.6 Participant Confidentiality and Authorization 
 


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5.7 Participant Registration 
 
 
 
5.8 DF/HCC Multi-center Protocol Case Number 
 
 
5.9 DF/HCC Multi-center Protocol Registration Policy 
 
 
5.10 Schedule of Data Submission  
 
 
5.11 Data Form Review 
 
 
 
5.12 Missing and Deficient Memorandum 
 
 
6.0 Requisitioning Investigational Drug …………………………………………………….58
 
 
 
 
     
 7.0   Safety Assessments and Toxicity Monitoring ………………………………………….58
 
 
 
 
      
7.1 Serious Adverse Events 
 
 
 
7.2 Guidelines for Reporting Serious Adverse Events 
 
 
 
 
 
 
8.0 Protocol Violations and Deviations ………………………………………………………59 
 
 
 
          
 
8.1 Definitions   
 
 
 
             8.2 Reporting Procedures 
 
 
 
9.0 Quality Assurance …………………………………………………………………………..60 
 
 
 
        9.1 Ongoing Monitoring of Protocol Compliance 
 
 
            9.2 Evaluation of Participating Institution Performance 
 
 
            9.3 On-Site Auditing 
 
 
 
 
            9.4 Substandard Performance 
 
 
 
 
 
 
 
 


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1.0 
INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol.  
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) 
Multi-center protocol will comply with Federal regulations (21 CFR Part 11); Good Clinical 
Practice (GCP) Guidelines; and  Health Insurance Portability and Accountability Act (HIPAA) 
requirements. 
 
1.2 Multi-Center Data and Safety Monitoring Plan Components 
The Multi-Center Data and Safety Monitoring Plan includes the following components: 
 
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with Dana-
Farber/Harvard Cancer Center on a research  protocol where DF/HCC is the Lead Institution. 
Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates are not viewed 
as outside sites in this definition. 
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, 
BIDMC, CH, BWH) will be the Lead Institution and will be responsible for the coordination, 
development, submission, and approval of a protocol as well as its subsequent amendments per 
the DFCI IRB and applicable regulatory guidelines (FDA, OBA etc.).  
 
DF/HCC Contract Principal Investigator:  Investigator located at the Lead Institution who 
will be charged with the responsibility of the administration of the DF/HCC Project. This most 
often will be the Protocol Chair, but occasionally this may be the overall grant or contract 
holder, as applicable. 
 
Protocol Chair:  The Protocol Chair is the Principal Investigator for the DF/HCC protocol 
submitted as the Lead Institution.  For applicable protocols, the Protocol Chair will be the 
single liaison with any regulatory agencies (FDA, OBA etc.).  
 
Participating Institution:  A participating institution is an institution that desires to 
collaborate with DF/HCC and commits to accruing participants to a DF/HCC protocol.  The 
participating institution acknowledges the Protocol Chair as having the ultimate authority and 
responsibility for the overall conduct of the study.    
 
Coordinating Center: The Lead Institution is the Coordinating Center for the DF/HCC Multi-
center Protocol. The Coordinating Center will provide the administrative support to the 
Protocol Chair in order that he/she may fulfill the responsibilities outlined in the DSMP.  In 
addition to the Lead Institution, the Quality Assurance Office for Clinical Trials (QACT) 
provides support services to assist the Protocol Chair.  
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 


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The Protocol Chair (DF/HCC Principal Investigator), Coordinating Center (Lead Institution or 
designee), and the Participating Institutions will all agree to the general responsibilities as follows 
(specific procedures for these general responsibilities are detailed in the DSMP): 
 
2.1 Protocol Chair (DF/HCC Principal Investigator) 
 
The Protocol Chair, Lecia Sequist, will accept responsibility for all aspects of the Multi-Center 
Data and Safety Monitoring Plan to: 
 
Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments.    
 
Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the protocol. 
 
Assure all participating institutions are using the correct version of the protocol. 
 
Monitor progress and overall conduct of the study at all participating institutions.  
 
Ensure all DFCI IRB, and DF/HCC reporting requirements are met 
 
Review data and maintain timely submission of data for study analysis.  
 
Identify participating institutions and obtain accrual commitments. The Protocol Chair 
will also submit a protocol attachment labeled as “Participating Investigators” to the 
DFCI IRB that provides the names and contact information for all participating 
institutions that perform the function of recruiting, enrolling, and treating participants for 
the protocol.  The Coordinating Center (Lead Institution or designee) must be designated 
on the title page. Revisions to the list will be submitted to the DFCI IRB as an 
administrative protocol amendment to reflect changes in staff and assignment of 
responsibility as they occur. 
 
    2.2   Coordinating Center (Lead Institution) 
 
The Coordinating Center is the DF/HCC Lead Institution’s study team or designee (i.e Medical 
Monitor, Clinical Research Organization). The DF/HCC Lead Institution will ensure that all 
participating sites within the Multi-Center Protocol demonstrate their intent and capability of 
complying with Federal Regulations, GCPs and Health Insurance Portability and 
Accountability Act (HIPAA) requirements.   To assist the Protocol Chair in meeting his/her 
responsibilities as required by the DSMP, the DF/HCC Lead Institution’s study team or 
designee will assume the following general responsibilities: 
 Assist in protocol review. 
 Maintain copies of Institutional Review Board (IRB) approvals from all 
participating institutions. 
 Maintain updated roster of participants.  
 Verify eligibility. 
 Verify response. 
 Collect data on protocol specific CRFs. 
 Prepare all submitted data for review by the Protocol Chair. 
 Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to Protocol Chair for timely review.   
 Distribute external Serious Adverse Event safety reports.  
 Monitor and audit Participating Institutions either by on-site inspection of 


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selected participant records and/or with submitted source documents and research 
records submitted to the Lead Institution.  
    
In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical Trials 
provides the following support services to assist the Protocol Chair: 
 Develop protocol specific case report forms (CRF/eCRFS). 
 QA/QC data of protocol specific CRFs.  
 Provide Central Participant Registration. 
 Confirm eligibility and consent.  
 Provide auditing services (funding and QACT approval required). 
 
    2.3   Participating Institution 
 
The Participating Institution(s) will be identified on the title page for each protocol.   In 
addition, each participating institution will provide to the Lead Institution or designee a list of 
the key personnel assigned to the role for oversight of data management at their site. All sites 
must have office space, office equipment, and internet access that meet HIPAA standards. 
The general responsibilities for each participating institution are as follows: 
 
 Commit to accrual to the Lead Institution’s (DF/HCC) protocol. 
 Submit protocol and/or amendments to their local IRB. 
 Update Coordinating Center (Lead Institution or designee) with research staff changes on        
a timely basis. 
 Register participants through the QACT.  
 Submit source documents, research records, and CRFs per protocol specific                              
submission guidelines to the Coordinating Center (Lead Institution or designee).  
 Submit Serious Adverse Event reports directly to the Coordinating Center (Lead                      
Institution or designee).  
 Submit deviations and violations to the Coordinating Center (Lead Institution or     
            designee). 
 For protocols using investigational agents, the participating institution will                
            order their own investigational agents regardless of the supplier (i.e. NCI,  
            pharmaceutical company). 
 
3.0 DF/HCC QUALITY ASSURANCE OFFICE FOR CLINICAL TRIALS 
 
The DF/HCC QACT is a unit that has been developed to collect, manage, and monitor data for 
DF/HCC trials.  The DF/HCC QACT is located administratively in the office of the Senior Vice 
President for Clinical Research, at Dana-Farber Cancer Institute.  The QACT uses DF/HCC 
computerized institutional databases for participant registrations and for the management of trial 
data as well as a set of quality assurance programs designed to monitor DF/HCC trials.   
 
3.1 Organizational Structure 
 
The DF/HCC Quality Assurance Office for Clinical Trials administrative structure consists of: 
 


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DF/HCC Quality Assurance Officer for Clinical Trials: Oversees the functions of the 
DF/HCC QACT. 
 
QACT Assistant Director for Data: Provides direct oversight to the QACT Data Analysts 
assigned to CRF design, data collection and computerization for DF/HCC trials.  
 
The DF/HCC QACT Data Analysts will be assigned on a protocol by protocol basis. Each 
protocol’s data analyst is responsible for database management, data entry, data quality 
assurance, and protocol specific correspondence related to the collection and quality assurance 
of data. 
 
QACT Assistant Director for Monitoring: Provides direct oversight to the QACT Protocol 
Registrars and Clinical Research Auditors. 
 
The DF/HCC Protocol Registrars are responsible for the confirmation of each participant’s 
eligibility and consent prior to protocol registration.  
 
If funded and QACT approved, the DF/HCC Clinical Research Auditors may assist the Lead 
Institution in their auditing responsibilities for multi-center trials. The QACT auditor is 
responsible for systematically evaluating participant safety, protocol compliance, institutional 
SOPs, ICH GCP and Federal regulation compliance, data accuracy and investigational drug 
handling to assure a high standard of quality for DF/HCC trials. 
 
 
4.0 PROTOCOL DEVELOPMENT 
 
4.1 Activation of a Protocol 
 
The Protocol Chair is responsible for the coordination, development, and approval of the 
protocol as well as its subsequent amendments, and reporting SAEs, violations and deviations 
per DFCI IRB guidelines and if applicable, FDA or OBA Guidelines.  Further, the Protocol 
Chair will be the single liaison with the FDA or OBA, as applicable. 
 
To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards: 
 
 Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the 
protocol as an appendix. 
 Identify participating institutions and obtain accrual commitments. The Protocol 
Chair will also submit a protocol attachment labeled as “Participating Investigators” 
to the DFCI IRB and if applicable FDA or OBA, that provides the names and 
contact information for all participating institutions that perform the function of 
recruiting, enrolling, and treating participants for the protocol. The Coordinating 
Center (Lead Institution or designee) must be designated on the title page.  
 Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the Protocol Chair. 
 Ensure that there is only one version of the Protocol and that all Participating 


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Institutions use the correct version.  
 Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the Participating Institutions.  
 Communicate with the site-PI's via email and periodic teleconferences as necessary, 
including a site initiation teleconference" 
 
4.2 
Coordinating Center Support Function 
 
The DF/HCC Lead Institution’s study staff or designee will provide administrative and clerical 
support to the Protocol Chair for the development and distribution of the protocol.  
 
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee include: 
 
 Review of the protocol and consent to check for logistics, spelling, and 
consistency.  Provide the Protocol Chair a list of queries related to any 
inconsistencies. 
 Provide necessary administrative sections, including paragraphs related to 
registration logistics, data management schedules, and multi-center guidelines.  
 Maintenance of contact list of all participating institutions in the DF/HCC Multi-
center Protocol and the distribution of updates to the sites as needed.  
 Derivation of the study calendar, if applicable. 
 Assistance in preparation and maintenance of case report forms.  
 Maintain and document communication with all participating institutions.  
 
 
5.0 PROTOCOL MANAGEMENT 
 
The Coordinating Center (Lead Institution or designee) is responsible for assuring that each 
Participating Institution in the DF/HCC Multi-center Protocol has the appropriate assurance on file 
with the Office of Human Research Protection (OHRP).   Additionally, the Lead Institution or 
designee must maintain copies of all IRB approvals, for each participating institution.  
 
 
 
5.1 
Protocol Distribution 
 
The Coordinating Center (Lead Institution or designee) will distribute the final approved 
protocol and any subsequent amended protocols to all Participating Institutions.    
 
5.2 
Protocol Revisions and Closures 
 
The participating institutions will receive phone, fax, mail or e-mail notification of protocol 
revisions from the Lead Institution or designee.  It is the individual participating institution’s 
responsibility to notify its IRB of these revisions. 
 
Non life-threatening revisions: Participating institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Lead Institution or designee. 


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Non-life-threatening protocol revisions should be implemented within 90 days from receipt of 
the notification. 
 
Revisions for life-threatening Causes: Participating institutions will receive telephone 
notification from the Lead Institution or designee concerning protocol revisions required to 
protect lives with follow-up by fax, mail or e-mail.  Life-threatening protocol revisions will be 
implemented immediately. 
 
Protocol Closures and Temporary Holds: Participating institutions will receive fax, e-mail, 
or phone notification of protocol closures and temporary holds, with follow-up by mail from 
the Lead Institution or designee. Closures and holds will be effective immediately.  In addition, 
the Lead Institution or designee will update the Participating institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol closures. 
 
5.3 Informed Consent Requirements 
 
 
 
The Principal Investigator (PI) at each participating site will identify the physician members of 
the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. It is DF/HCC policy that Nurses and Fellows cannot obtain consent to greater than 
minimal risk trials.   
 
5.4 IRB Documentation 
 
The following must be on file with the DF/HCC Lead Institution or designee prior to 
participant registration: 
 
 Approval Letter of the institution's IRB (An Expedited IRB first approval is 
NOT acceptable) 
 IRB approval for all amendments 
 
It is the individual institution's responsibility to notify its IRB of protocol revisions.  
Participating institutions will have 90 days from receipt to provide the DH/HCC Lead 
Institution or designee their IRB approval for Major Amendments* to a protocol.    
 
* DF/HCC defines a Major Amendment as: A substantive change in the study which may 
increase or decrease the risk to study participants.  Major revisions require full IRB approval.  
The following criteria are examples of revisions to a protocol that are considered to be major 
amendments:  
 
 
 
 
 
Change of eligibility (inclusion/exclusion) criteria 
 
Change in design of protocol 
 
Change in statistical section 
 
Change in sample size/accrual (e.g., doubling the sample size) 
 
Change in informed consent 
 
Change of estimated dropout rate 
 
Change of treatment or intervention 




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 
Copy of required laboratory tests: WBC, plt, hemoglobin, bilirubin, ALT, AST, 
serum creatinine, result of tumor EGFR mutation testing 
 
Copy of baseline medical exam that contains the following: Date of original  
        diagnosis; surgery date and type of surgery; PS; histology; Stage of disease (1A- 
        IIIA); smoking status; EGFR mutation status/results and prior treatment 
including 
        chemotherapy and radiation.   
 
Signed informed consent form 
 
HIPAA authorization form (if separate from the informed consent document) 
 
The research DF/HCC Multi-center Protocol participating site will then call or e-mail the Lead 
Institution or designee to verify eligibility. To complete the registration process, the Lead 
Institution or designee will: 
 Register the participant on the study with the DF/HCC Quality Assurance Office              
for Clinical Trials (QACT) 
 Fax or e-mail the participant case number, and if applicable the dose treatment 
level, to the participating site 
 Call the research nurse or data manager at the participating site and verbally 
confirm registration 
 
5.8 DF/HCC Multi-center Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the participant 
is assigned a five digit protocol case number.  This number is unique to the participant on this 
trial and must be used for QACT CRF/eCRF completion and written on all data and QACT 
correspondence for the participant. 
 
5.9 DF/HCC Multi-center Protocol Registration Policy 
 
    5.9.1  Initiation of Therapy: Participants must be registered with the DF/HCC QACT 
before receiving treatment.  Treatment may not be initiated until the site receives a 
faxed or e-mailed copy of the participant’s Registration Confirmation memo from 
the DF/HCC QACT. Therapy must be initiated per protocol guidelines.  The 
Protocol Chair and DFCI IRB must be notified of any exceptions to this policy.  
 
5.9.2 Eligibility Exceptions: The DF/HCC QACT will make no exceptions to the 
eligibility requirements for a protocol without DFCI IRB approval.  The DF/HCC 
QACT requires each institution to fully comply with this requirement. 
 
5.9.3 Verification of Registration, Dose Levels, and Arm Designation: A registration 
confirmation memo for participants registered to DF/HCC Multi-Center Protocol 
will be faxed or emailed to the registering institution within one working day of the 
registration. Treatment may not be initiated until the site receives a faxed or e-
mailed copy of the registration confirmation memo.  
 


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5.9.4 Confidentiality: All documents, investigative reports, or information relating to the 
participant are strictly confidential. Any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Lead Institution or 
designee must have the participant’s full name & social security number “blacked 
out” and the assigned DF/HCC QACT case number and protocol number written in 
(with the exception of the signed informed consent document). Participant initials 
may only be included or retained for cross verification of identification. 
  
 
5.10  Schedule of Data Submission 
 
The DF/HCC QACT develops a set of electronic case report forms, (CRF/eCRFs) for use 
with the DF/HCC Multi-Center Protocol.  These forms are designed to collect data for each 
study. Prior to the registration of the first patient, the Participating Institution will designate a 
study coordinator(s) that will be trained using the DF/HCC data capture system, INFORM.  
Registration/accrual can not occur without a trained study coordinator.  The schedule for 
submission of case report forms to the DF/HCC QACT is generally specified in each 
protocol. When not specified in the protocol, the DF/HCC QACT will require the forms to be 
submitted as follows: 
 
COMMON FORMS & REPORTS 
 
Eligibility Checklist, (Informed Consent/ Participant Authorization for the 
Release of Personal Health Information) 
 
On-study Form 
 
Baseline Assessment Form (Baseline disease assessment/measurement) 
 
Treatment Forms 
 
Adverse Event Forms 
 
Response Assessment Form (Follow-up disease assessment/Measurement) 
 
Off-Treatment/Off Study Form 
 
Follow-Up/Survival Forms 
Note: It is necessary to send only ONE copy of all paper Case Report Forms.  
   
5.10.1  Eligibility Checklist 
 
Purpose - Outlines protocol-specific eligibility criteria and includes the following: 
              
Participant Demographics (sex, race, ethnicity, initials, date of birth) 
1) Parameters for eligibility 
2) Parameters for exclusion 
3) Parameters for stratifications 
If a time frame is not specified in the protocol, tests must be completed as follows: 
 Lab tests required for eligibility must be completed within 14 days prior to study 
enrollment by the QACT. 
 Non-lab tests required for eligibility must be performed within 30 days prior to 
study entry. Example: radiological scans 
 
Schedule for Submission - Completed prior to participant registration. The                       
Informed Consent/ Participant Authorization for the Release of Personal         


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            Health Information should be submitted with the Eligibility Checklist at the time                
of registration. 
 
5.10.2 On-study Form (includes: Study entry, prior therapy and baseline assessments) 
 
Purpose - documents the following items: 
 Demographic data 
 Prior therapy 
 Past medical and surgical history 
 
Description of participant’s physical status at protocol registration 
 
Disease site specific data 
 
Schedule for Submission - Submitted to DF/HCC QACT within 14 days after 
registration. 
 
5.10.3 Baseline Assessment Form 
 
Purpose – Documents objective and subjective disease status as defined by the protocol. 
Records all pertinent radiographic and laboratory measurements of disease utilized in 
determining response evaluations.  
 
Schedule of Submission – Submitted within 14 days after registration. 
 
5.10.4 Treatment Form 
 
Purpose - Records the following information related to the time the participant receives 
protocol treatment: 
 
 
 Participant, Protocol, Affiliate information 
 Protocol treatment and supportive therapy per treatment cycle 
 Protocol specific laboratory values per treatment cycle 
 All medications other than protocol chemotherapy agents used to treat 
concomitant    diagnoses, if applicable 
 
Schedule for Submission – Submitted within 10 days after the last day of the cycle.   
 
5.10.5 Adverse Event Report Form  
 
Purpose – Documents adverse events that occur while the participant is receiving 
treatment and for up to 30 days after the last dose of treatment.  All adverse events are 
to be graded by number using the toxicity grading scale required by the protocol.  
Only selected adverse events are being followed.  Please, refer to the protocol for a 
complete list.  This form is not for IRB submission, but for recording the AE in the 
research database. 
 


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Schedule for Submission – Submitted within 10 days after the last day of the cycle. 
 
5.10.6 Response Assessment Form 
 
Purpose – Documents objective and subjective response as defined by the protocol. 
Records all pertinent radiographic and laboratory measurements of disease utilized in 
determining response evaluations.  
 
Schedule of Submission – Submitted within 10 days after the completion of  
the cycle required for response evaluation.  
 
5.10.7    Off Treatment/Off Study Form 
 
Purpose - The Off Treatment/Off Study Form is submitted when the participant is  
removed from the study or has completed all protocol treatment.  Note: If the 
participant dies while on protocol, the Off Study Form is the last form submitted. 
 
Schedule of Submission – Submitted within 14 days after completing treatment or taken 
off study for any reason. 
 
5.10.8    Follow up / Survival Form 
 
Purpose - Summarizes participant status at a given point in time after being removed 
from treatment.  
 
Schedule of Submission – Submitted within 14 days after the protocol defined follow 
up visit date or call.    
 
 
 
 5.11 Data Form Review 
 
When data forms arrive at the DF/HCC QACT, they are reviewed for: 
  
Timeliness:  
Did the form arrive on time as specified in the protocol? 
 
 
 
 
Completeness:  
Is all the information provided as required per protocol? 
 
Participant Eligibility:  
Does the participant meet the eligibility requirements for the study based on the demographic 
data, lab values and measurements provided? 
 
Stratification:  
Are the stratification parameters consistent with what was given at the time of registration? 
 


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Protocol Treatment Compliance:  
Was the patient compliant with the study medication?  The patient diary should be reviewed 
and old drug returned at each visit.  Documentation of compliance should be captured in 
subject’s medical record although there is not a data form for this information.  
  
Adverse Events (Toxicities):  
Did the participant experience adverse events (toxicities or side effects) associated with the 
treatment? Was the treatment delayed due to the adverse event? What was the most severe 
degree of toxicity experienced by the participant? 
 
Notations concerning adverse events will address relationship to protocol treatment for each 
adverse event grade.  All adverse events encountered during the study will be evaluated 
according to the NCI Common Toxicity Criteria assigned to the protocol and all adverse 
events must be noted on the participant's Adverse Event (Toxicity) Forms. 
 
Response:  
Did the participant achieve a response?  What level of response did they achieve?  On what 
date did the participant achieve the response and how was the response determined? 
 
Response criteria are defined in the protocol.  A tumor assessment must be performed prior to 
the start of treatment and while the participant is on treatment as specified by the protocol.   
 
Objective responses must have documentation such as physical measurements, x-rays, scans, 
or laboratory tests.   
 
A subjective response is one that is perceived by the participant, such as reduction in pain, or 
improved appetite. 
 
5.12 Missing and Deficient Memorandum 
 
Data submissions are monitored for timeliness and completeness of submission. Participating 
institutions are notified of their data submission delinquencies in accordance with the 
following policies and procedures: 
 
Incomplete or Questionable Data 
 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written query from the DF/HCC QACT Data Analyst.  Responses to the query 
should be completed and returned within 14 days.  Responses may be returned on the written 
query or on an amended case report form. In both instances the query must be attached to the 
specific data being re-submitted in response.   
 
Missing Forms 
 
If study forms are not submitted on schedule, the participating institution will receive a 
Missing Form Report from the DF/HCC QACT noting the missing forms.  These reports are 
compiled by the DF/HCC QACT and distributed a minimum of three times a year.  


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6.0 REQUISITIONING INVESTIGATIONAL DRUG 
 
 
 
The ordering of investigational agent is to be done by each site directly via Genentech/OSI.  
 
Each site should check with the local Director of Pharmacy and/or the Research Pharmacy to 
ensure that the agent is in stock. If the agent is not stocked, ensure that the agent can be ordered 
once the protocol is approved by the local IRB.  
 
7.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
 
All participants receiving investigational agents will be evaluated for safety.   The safety 
parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by 
participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria assigned to the protocol (CTCAE Version 3.0) and recorded prior to each course 
of therapy.  Life-threatening toxicities should be reported immediately to the Protocol Chair 
and Institutional Review Board (IRB).  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
7.1 
Serious Adverse Events 
 
A serious adverse event (SAE) is any adverse drug experience at any dose that results  in any 
of the following outcomes: death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant 
or may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions in a 
participant who has never had seizure activity in the past that do not result in inpatient 
hospitalization, or the development of drug dependency or abuse. 
 
Unless otherwise specified in the protocol, the study will utilize the Cancer Therapy 
Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 for Toxicity and Adverse Event reporting.  A copy of the CTC or CTCAE 
Criteria can be downloaded from the CTEP home page (http://ctep.info.nih.gov).   
 
7.2 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is delineated in 
the protocol.  
 
 
 
 
 
In addition, the Participating Institutions must report the serious adverse events to the 
Protocol Chair and the Coordinating Center (Lead Institution) at the time SAEs are submitted.  


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The Lead Institution will maintain documentation of all Adverse Event Reporting and be 
responsible for communicating all SAEs to all Participating sites. 
 
8.0 PROTOCOL VIOLATIONS AND DEVIATIONS 
 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or “protocol 
deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the DFCI IRB, the 
definitions for protocol violation and deviation as described by the DFCI IRB will be applied for 
reporting purposes for all institutions participating in the DF/HCC Multi-center Protocol.  
   
8.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
 
8.2 Reporting Procedures 
 
The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record to describe all protocol deviations and violations.  
The Protocol Chair will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from DFCI IRB. 
The Participating institution must submit the deviation request to the Protocol Chair and Lead 
Institution or designee, who will submit the deviation request to the DFCI IRB. Upon DFCI 
IRB approval the deviation should be submitted to the participating site’s own IRB, per its 
policy. 
Protocol violations occurring at a participating institution will be submitted to that site’s own 
IRB.   A copy of the participating institution’s IRB report and determination will be 
forwarded to the DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail 
within 10 business days after the original submission.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the participating 
institution, the DF/HCC Lead Institution or designee will submit the report to the Protocol 
Chair for review. Subsequently, the participating institution’s IRB violation/deviation report 
will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
9.0 QUALITY ASSURANCE 
 
1) The quality assurance process for a clinical trial research study requires verification of protocol 
compliance and data accuracy. As the Coordinating Center, the DF/HCC Lead Institution or 
designee with the aid of the QACT provides quality assurance oversight for the DF/HCC Multi-
center Protocol. 


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9.1  Ongoing Monitoring of Protocol Compliance 
 
 
All data submitted to the DF/HCC QACT 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 Lead 
Institution or designee and if applicable QACT Data Analysts assigned to the Protocol will 
perform the ongoing protocol compliance monitoring with the support of the participating 
institution’s Coordinators, the Principal Investigators, and the Protocol Chair.  
 
9.2 Evaluation of Participating Institution Performance 
 
9.2.1 
 Eligibility Checklist: Eligibility criteria are checked on a protocol-specific eligibility 
checklist and faxed to the DF/HCC QACT prior to registration on protocol.  The checklist and 
informed consent document are reviewed by a DF/HCC QACT Protocol Registrar before the 
participant can be registered on a protocol.  The DF/HCC QACT cannot make exceptions to the 
eligibility requirements. 
 
9.2.2  Accrual of Eligible Participants: Annual accrual rates for eligible participants enrolled 
onto therapeutic clinical trials is calculated for each institution. Institutions are expected to 
maintain the minimum annual average accrual as defined by the protocol grant or contract.  
 
 
9.3 On-Site Auditing 
 
9.3.1 DF/HCC Sponsored Trials 
 
For all DF/HCC sponsored protocols: 
The participating institutions may be required to submit subject source documents to the 
DF/HCC Lead Institution or designee for monitoring. Also, the participating institution 
may be subject to on-site monitoring conducted by the DF/HCC Lead Institution or 
designee. 
 
After a site has accrued 2-3 participants, the QACT will be conducting an on-site audit. 
This is anticipated to occur within the first year of enrollment. If significant violations are 
uncovered during the audit, a follow-up audit may be requested. The final audit reports 
for the external sites will be reported to the Overall PI, as well as the DF/HCC Audit 
Committee, as is standard practice.  
 
9.3.2 Participating Institution 
 
It is the participating institution’s responsibility to notify the DF/HCC Lead Institution or 
designee of all scheduled audit dates (internal or NCI) and re-audit dates (if applicable), 
which involve the DF/HCC Multi-Center Protocol. All institutions will forward a copy of 
final audit and/or re-audit reports and corrective action plans (if applicable) to the 
DF/HCC Lead Institution or designee within 12 weeks after the audit date.  
 


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9.3.3 Coordinating Center (Lead Institution or designee)  
 
The Protocol Chair will review all DF/HCC Multi-Center Protocol Final Audit reports 
and corrective action plans if applicable. The Lead Institution or designee must forward 
these reports to the DF/HCC QACT per DF/HCC policy for review by the DF/HCC Audit 
Subcommittee. Based upon the audit assessments the DF/HCC Audit Subcommittee could 
accept or conditionally accept the audit rating and final report. Conditional approval could 
require the Protocol Chair to implement recommendations or require further follow-up.  
For unacceptable audits, the Audit Subcommittee would forward the final audit report and 
corrective action plan to the Clinical Investigations Policy and Oversight Committee and 
the DFCI IRB as applicable. 
 
9.4 Sub-Standard Performance 
 
 
 
The Protocol Chair, and DFCI IRB, is charged with considering the totality 
of an institution’s performance in considering institutional participation in the DF/HCC 
Multi-Center Protocol. 
 
9.4.1 Corrective Actions: Institutions that fail to meet the performance goals of accrual, 
submission of timely accurate data, and adherence to protocol requirements will be 
recommended for a six- month probation period. Such institutions must respond with a 
corrective action plan and must demonstrate during the probation period that deficiencies 
have been corrected, as evidenced by the improved performance measures. Institutions 
that fail to demonstrate significant improvement will be considered by the Protocol Chair 
for revocation of participation. 
 
 
 


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