Conditions: Lung Cancer, Nonsmall Cell
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy of crizotinib as induction therapy in participants with surgically resectable ALK rearrangement, ROS1 rearrangement, or MET exon 14 mutation positive NSCLC.

Detailed description:
Participants with stage IA-IIIA, surgically resectable lung adenocarcinoma with an activating alteration in ALK, ROS1 or MET will receive neoadjuvant treatment with crizotinib. This neoadjuvant treatment will last 6 weeks and on the last day of dosing of crizotinib, participants will undergo surgical resection, followed by 5 years of follow-up via chart review.

Arms:
arm 1: Patients enrolled in this study will be treated with 6 weeks of induction therapy with crizotinib. On the last day of dosing, patients will then undergo surgical resection. 5 years of follow-up will be done via chart review.

Interventions: intervention 1: Crizotinib
Intervention descriptions: intervention 1: Crizotinib is an oral receptor tyrosine kinase inhibitor of ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). Crizotinib will be given as a neoadjuvant therapy before surgical resection. The recommended dose of crizotinib is 250mg orally. Participants on this trial will receive this dose, unless dose modification is necessary.

Protocol document:
Prot_SAP_001.pdf: 
ARM Study: A phase II trial to evaluate crizotinib in the neoadjuvant setting in non-small cell lung 
cancer patients with surgically resectable, ALK, ROS1, or MET-oncogene positive non-small cell 
lung cancer 
 
Tejas Patil, MD 
 
NCT03088930 
Protocol Version date October 20, 2020 


ARM Trial 
Page 1 of 33 
 
 
 
 
Protocol Number: 
16-2025 
 
Study Reference Number:   Pfizer #WI216247 
 
Project Title: 
ARM Study: A phase II trial to evaluate crizotinib in the 
neoadjuvant setting in non-small cell lung cancer patients with 
surgically resectable, ALK, ROS1, or MET-oncogene positive 
non-small cell lung cancer 
 
 
 
 
Version Date: 
10/20/2020 
 
Principal Investigator:  
Tejas Patil, MD 
University of Colorado Denver, Anschutz Medical Campus 
Division of Medical Oncology 
Mail Stop 8113 HSC 
12631 E. 17th Avenue 
Academic Office One (AO1), Room 8515 
Aurora, CO   80045 
(720) 848-9264 
tejas.patil@cuanschutz.edu 
 
Coordinating Center: 
University of Colorado Cancer Center 
Participating Sites:  
Multiple Centers 
 


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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Page 2 of 33 
 
 
 
STATEMENT OF COMPLIANCE 
This is an investigator-initiated study.  The lead Principal Investigator (PI), Tejas Patil, MD, is 
conducting the study and acting as the sponsor.  As the sponsor-investigator, both the 
legal/ethical obligations of a PI and those of a sponsor will be followed. 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
applicable United States (US) laws and applications, including but not limited to United States 
(US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
 
 
The PI will assure that no changes to the protocol will take place without documented approval 
from the Institutional Review Board (IRB). All personnel involved in the conduct of this study 
have completed Human Subjects Protection Training.  
 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments.  
 
 
 
 
Sponsor-Principal Investigator: 
Tejas Patil, MD 
 
 
  
 
 
Print/Type Name  
 
 
 
Date:    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
PI Signature  
 


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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LIST OF ABBREVIATIONS 
AE – Adverse Event 
ALK- anaplastic lymphoma kinase 
AST - Aspartate Aminotransferase  
ALT -  Alanine Aminotransferase 
ALP – Alkaline Phosphatase 
DNA - Deoxyribonucleic acid 
DFS – Disease free survival 
EGFR – Epidermal growth factor receptor 
FDG-PET - Fluorodeoxyglucose - Positron Emission Tomography 
IHC – Immunohistochemistry 
MET – MET gene 
NGS – Next generation sequencing 
NSCLC – Non-small cell lung cancer 
OS – Overall survival 
PERCIST - Positron Emission Tomography (PET) Response Criteria in Solid Tumors 
PFS – Progression free survival 
RECIST - Response Evaluation Criteria in Solid Tumors 
ROS1 – v-ROS oncotype 1 
RNA – Ribonucleic acid 
RTK – Receptor tyrosine kinase 
SAE – Serious Adverse Event 
TKI – Tyrosine kinase inhibitor 
ULN –Upper limit of normal 
 
 
I. 
Hypotheses and Specific Aims:   
A. Hypothesis:  
Evaluation of tumor tissue early in treatment will allow for identification of early 
adaptive mechanisms of cell survival in the setting of oncogene-targeted therapy. 
We hypothesize that neoadjuvant treatment of early stage NSCLC with ALK, 
ROS1, or MET exon 14 mutations will allow for both identification of early 
mechanisms of resistance and demonstrate similar response rates to metastatic 
disease.  
B. Specific Aims 
1. Primary Objective:  
To evaluate the efficacy of crizotinib as induction therapy in participants with 
surgically resectable ALK rearrangement, ROS1 rearrangement, or MET exon 
14 mutation positive NSCLC.  The primary endpoint of the study will be objective 
response rate by RECIST 1.1. 
2. Secondary Objectives: 
To evaluate secondary measures of clinical efficacy in early stage ALK, ROS1, 
or MET-mutant NSCLC participants treated with crizotinib induction therapy.  


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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Page 4 of 33 
 
Secondary endpoints of efficacy will include: pathological response rate defined 
as < 50% viable tumor present histologically in the resected tumor specimen, 
metabolic response rate on paired FDG-PET scan (defined by PERCIST criteria), 
disease-free survival (DFS), and overall survival (OS). 
3. Translational Objective: 
To evaluate resected tumor samples using genetic, proteomic, and cell imaging 
techniques to understand mechanisms leading to incomplete tumor response 
following oncogene-targeted therapy with crizotinib. Additionally, we will monitor 
plasma samples for evidence of tumor DNA at diagnosis and at post neoadjuvant 
treatment on day of resection 
 
II. 
Background and Significance:  
Incomplete responses to oncogene-targeted treatments in patients with oncogenic driver 
mutations in non-small cell lung cancer (NSCLC) are the initial source of tumor cell 
resistance and ultimately disease progression arises from this survival niche1. Studies of 
resistance mechanisms have focused on evaluation of patients with metastatic disease 
who have progressed after targeted treatment.2-6 This has allowed for significant 
advances in understanding the complex mechanisms of acquired resistance that 
develop, but has not yet permitted long-term disease control for the majority of patients 
with metastatic disease. An alternate approach to sequential targeted therapy is upfront 
combination therapy to potentially improve the depth of response, progression free 
survival and ultimately overall survival.7 In order to inform potential frontline combination 
strategies it will be necessary to understand tumor cell survival mechanisms early in 
therapy.  
 
An approach to studying remnant tumor samples following oncogene-targeted therapy 
would be the administration of tyrosine kinase inhibitors for a defined period of time prior 
to surgical resection in oncogene-defined patient populations. Neoadjuvant studies of 
chemotherapy for patients with early stage, resectable NSCLC (stages IB-IIIA) have 
been performed previously. A meta-analysis of 15 trials (2385 patients) demonstrated 
significant but modest improvements in overall survival at 5 years from 40 to 45% (HR 
0.87, 95% CI 0.78-0.96, P=0.007), time to distant recurrence at 5 years improved from 
60% to 70% (HR 0.69, 95% CI 0.58-0.82; p<0.001) and a recurrence free survival 
improvement from 30% to 36% at 5 years across all stages (HR 0.85, 95% CI 0.76-0.94, 
P=0.002).8 In addition to providing benefit to patients by potentially improving overall 
survival and reducing the risk of disease recurrence, evaluation of the tumor response 
to targeted therapy in the neoadjuvant setting provides an excellent opportunity to study 
disease, given that patients will be undergoing definitive surgical as a predetermined part 
of their treatment plan. Evaluation of the response to neoadjuvant treatment with 
targeted therapies has not been extensively undertaken in NSCLC. In 2009 Kappers et 
al. reported the successful induction treatment of a patient with a stage IIIA epidermal 
growth factor receptor (EGFR) mutated NSCLC.9 This was followed up by a phase II 
study in 60 non-squamous patients with early stage lung cancer treated with erlotinib for 
21 days prior to surgery. Seven patients had an EGFR mutation, 40% (3 of 7) had a 
pathological response with > 50% tumor necrosis at the time of resection. In patients 
with wildtype EGFR, only 20% (8 of 35 patients) had > 50% necrosis in their tumors at 


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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the time of resection.10 Another phase II study of gefitinib in patients with biopsy proven 
stage I disease were treated with gefitinib for 28 days. Of the 35 evaluable patients, 6 
had EGFR activating mutations. In this study those patients with EGFR mutations all 
demonstrated tumor reduction and the only significant predictor of a partial response to 
neoadjuvant treatment was EGFR mutation status.11 A follow-up evaluation of the 
pathologic features of responses to treatment in this cohort demonstrated that 
responding tumors showed large areas of fibrosis and that within these fields there were 
focal residual viable tumor cells, but that there was no significant correlation between the 
degree of fibrosis and the observed radiologic changes recorded. These results indicated 
that persistor populations are present after treatment with TKIs. These remnant tumor 
cell populations and tumor-resident, non-cancer cell populations are important to 
characterize to help increase the chances of disease eradication. More recently a small 
series highlighted the neoadjuvant treatment of two patients with stage IIIA, ALK-positive 
NSCLC with crizotinib prior to resection. They noted significant reduction in tumor size 
and FDG avidity on PET scan.12 In addition to providing potential benefit to patients by 
improving overall survival and reducing the risk of disease recurrence, evaluation of the 
tumor response to targeted therapy in the neoadjuvant setting provides an excellent 
opportunity to carry out extensive analyses on the residual tumor cell burden, given that 
patients will be undergoing definitive surgical resection as a predetermined part of their 
treatment plan.  
 
Efforts to accomplish this goal with EGFR tyrosine kinase inhibitors in patients with 
EGFR sensitizing mutations are currently under way (Drs. Trever Bivona and Collin 
Blakely at UCSF, personal communication). We propose a complimentary clinical trial in 
which patients with ALK rearrangements, ROS1 rearrangements, and MET exon 14 skip 
mutations would receive neoadjuvant crizotinib. The characteristics and clinical 
relevance of these target genes is described below.  
 
Fusion of the echinoderm microtubule-associate protein-like 4 (EML4) gene, or less 
commonly other gene partners, with the anaplastic lymphoma kinase (ALK) gene 
generates a chimeric gene (EML4-ALK) and protein that has tumor transforming 
potential.13 In an unselected patient population ALK fusions have been identified in 1 to 
7% of patients with non-small cell lung cancer (NSCLC) depending on the cohort 
evaluated.13-17 Another fusion gene with oncogenic properties is ROS1. Rearrangements 
in this gene have been found in 1-2% of patients with lung cancer.17-19 The ROS1 gene 
itself was initially identified as the homolog of the transforming v-ros sequence from the 
UR2 avian sarcoma virus, a receptor tyrosine kinase (RTK) with no known ligand.20 It 
has been found to have oncogenic activity in brain, cholangiocarcinoma and ovarian 
cancer, in addition to NSCLC.21 Finally, the MET gene encodes an RTK whose natural 
ligand is the hepatocyte growth factor (HGF). This RTK can be modified in many ways 
to become an oncogenic, for the purposes of this study we will be focusing on exon 14 
mutations (~4% of patients), however, we will permit enrollment of MET fusions and MET 
Y1003X mutations given their demonstrated oncogenic potential.17,22-25 Though 
individually each of these mutations makes up a small percentage of the total NSCLC 
population, their composite prevalence approaches 10% of an unselected population. 
Each of these oncogenic drivers can be successfully targeted by the US-FDA approved 
tyrosine kinase inhibitor crizotinib.26-28 
 


COMIRB Number: 16-2025 
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PI:  Dr. Patil  
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In ALK-positive NSCLC, frontline treatment with crizotinib demonstrated a progression 
free survival of 10.9 months compared with 7 months for the control arm of platinum 
doublet and the overall response rate (ORR) was 74% compared with 45%.29 The 
disease control rate in this study was 92% with crizotinib and 81% with standard of care 
chemotherapy. This is important because it demonstrates that the vast majority of 
patients with an ALK rearrangement will respond to neoadjuvant treatment therefore, 
from a surgical standpoint the risk of progression while receiving neoadjuvant treatment 
is very low. In ROS1-positive NSCLC, the response rate to treatment was 72% and the 
disease control rate was 90% in the expansion cohort of the phase I study.30 Additionally, 
the median progression free survival in this population was 19.2 months, though the 
upper limit has not yet been reached. Similarly, MET is another RTK in which mutation 
(exon 14 skipping) or other alteration can result in oncogenic activity.23,25,27,31 Clinical 
trials evaluating the efficacy of crizotinib in these populations are ongoing but in the 
setting of exon 14 mutations the disease control rate and ORR in a series of 3 patients 
treated with crizotinib was 100%, with all patients demonstrating a partial response.24  
 
In metastatic ALK, ROS1, and MET positive NSCLC resistance mechanisms are being 
characterized.2,3,32,33,34 As noted, resistance mechanisms include not only secondary 
mutations of target genes or other related pathway genes but also can include target 
gene amplification and influence of secondary pathways as well as phenotypic switching 
from epithelial to mesenchymal patterns of growth.5,22,35 These mechanisms of 
resistance were initially identified in EGFR mutated tumors treated with EGFR TKIs, 
however, similar mechanisms have begun to be identified these three molecular 
subtypes of NSCLC as well.2,3 We have previously reported mechanisms of resistance 
of a cohort of ROS1 patients as well as an expanded cohort of ALK positive patients with 
disease progression on tyrosine kinase inhibitor (TKI) therapy. In this evaluation we 
found that in ALK positive patient’s kinase domain mutations make up 33% of the 
resistance mechanisms while copy number gains and alternative mutations make up 
another 33% and 33% remain unknown. Additionally, we found an increase in the 
number of mutations as the number of TKI treatments expanded.36 Gainor et al. recently 
reported that in a cohort of 83 ALK positive patients treated with ≥1 prior ALK TKI. They 
also found that in addition to an increasing number of resistance mutations developing 
as patients were treated with more than one ALK TKI. They also identified clinical 
evidence of EMT as a resistance mechanism in ALK positive NSCLC, a finding that had 
previously been identified in EGFR mutated NSCLC.37 Characterization of resistance 
mechanisms in ROS1 patients has been slower to develop due to the lower frequency 
of the ROS1 fusion and the prolonged PFS on crizotinib. We reported that in our cohort 
of 7 patients that the majority of tumors had unknown mechanisms of resistance, 
although resistance mutations and bypass signaling via an activating KIT mutation have 
been observed.36,38 Little is known about the resistance mechanisms of crizotinib in MET 
positive tumors however, a case report of a kinase domain mutation in MET have been 
reported indicating that this gene also demonstrates similar mechanisms of resistance.39 
 
Each of the oncogene subgroups listed above not only demonstrates substantial clinical 
response to crizotinib but also demonstrates that despite initial response resistance 
typically develops via multiple different mechanisms. Residual disease from incomplete 
responses forms the basis for the development of drug resistance. Currently the majority 
of effort in overcoming resistance has been focused on evaluation and treatment after 


COMIRB Number: 16-2025 
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PI:  Dr. Patil  
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resistance develops. However, we feel that it is also critical to investigate responses to 
treatment early in the tumor time course as early tumor responses to treatment with 
crizotinib and other TKIs are poorly understood. A neoadjuvant approach to both patient 
treatment and resistance development is needed to advance our understanding of tumor 
resistance. We hypothesize that neoadjuvant treatment with crizotinib, an ALK, ROS1, 
and MET targeted TKI, in patients with one of these genetic alterations (in total 
comprising ~10% of patients with NSCLC) will accomplish these goals.   
 
              
III. 
Research Methods 
A. Description of Population to be Enrolled:   
Participants eligible for this study will be newly diagnosed with stage IA-IIIA NSCLC 
and who harbor an activating alteration in ALK, ROS1, or the MET gene 
B. Eligibility Criteria: 
 
1. Inclusion: 
(1) Stage IA-IIIA NSCLC by 8th edition AJCC staging (that is deemed to be 
surgically resectable by a board-certified thoracic surgeon as part of standard 
clinical practice).   
(2) Staging by PET-CT scan (required) and MRI brain (if clinically indicated) 
showing no evidence of metastatic disease (mediastinoscopy is not required 
unless imaging is indeterminate and is then considered standard of care) 
(3) Documented evidence of an ALK rearrangement (by FISH, IHC, or NGS), 
ROS1 rearrangement (by FISH or NGS), or MET oncogene as defined by 
MET exon 14 skipping (NGS), MET Y1003X mutation or MET gene fusion 
(NGS) in NSCLC tumor specimen by a CLIA-approved laboratory.  
(4) Measurable disease defined by RECIST 1.1 criteria. 
(5) Life expectancy of at least 24 months. 
(6) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
(7) Age ≥ 18 years 
(8) Have normal QT interval on ECG evaluation QT corrected Fridericia (QTcF) 
of ≤ 450 ms in males or ≤ 470 ms in females 
(9) Adequate organ function 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets  
≥75,000/µL 
Hemoglobin 
≥ 10g/dL 
AST /ALT  
≤ 2.5 x upper limit of normal (ULN) 
Total serum bilirubin 
≤ 1.5 x ULN (≤3.0 × ULN for patients 
with Gilbert syndrome or if liver 
function abnormalities are due to 
underlying malignancy) 
Serum creatinine 
≤ 1.5 x ULN 
Serum amylase 
≤ 1.5 x ULN 
Serum lipase 
≤ 1.5 x ULN 


COMIRB Number: 16-2025 
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PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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(10) 
Negative serum pregnancy test within 14 days of D1 of treatment in 
women of child bearing potential. 
(11) 
If fertile, willing to use highly effective form of contraception (defined as a 
combination of at least two of the following methods: condom or other 
barrier methods, oral contraceptives, implantable contraceptives, 
intrauterine devices) during the dosing period and for at least 4 months 
after the dosing period. 
(12) 
Ability to provide signed informed consent and willing and able to comply 
with all study requirements. 
 
2. Exclusion: 
(1) Stage IIIB or IV NSCLC as per 8th edition AJCC staging 
(2) History or the presence of pulmonary interstitial disease, or drug-related 
pneumonitis. 
(3) Malabsorption syndrome or other GI illness that could affect oral absorption 
of the study drug 
(4) Inability to swallow oral medications 
(5) Have significant, uncontrolled, or active cardiovascular disease, specifically 
including but not restricted to: 
• 
Myocardial infarction (MI) within 6 months of trial enrollment 
• 
Unstable angina within 6 months of trial enrollment 
• 
Congestive heart failure (CHF) within 6 months prior to trial enrollment 
• 
Any history of ventricular arrhythmia 
• 
Cerebrovascular accident or transient ischemic attack within 6 months of 
D1 of treatment 
• 
Clinically significant atrial arrhythmia or severe baseline bradycardia 
defined as resting heart rate < 50 beat per minute 
• 
Uncontrolled hypertension defined as baseline SBP> 160 and DBP > 
100 on 3 separate clinic visits or past history of hypertensive urgency, 
emergency, or encephalopathy  
(6) Have active infection requiring antibiotics 
(7) Pregnant or lactating female. 
(8) Prior treatment with an ALK, ROS1, or MET inhibitor 
(9) Any prior anticancer therapy for this diagnosis 
(10) 
Any active cancer diagnosis (basal or squamous cell cancers allowed) 
within the last 5 years for which the patient is receiving active therapy or 
which is untreated. Any cancer diagnosis within the last 5 years that is 
considered “treated” and/ or on surveillance may be included in the trial. 
(11) 
Have any condition or illness that, in the opinion of the investigator would 
compromise patient safety or interfere with evaluation of the study drug 
(including but not limited to HIV and HCV) 


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C. Study Design and Research Methods   
1. Study Schema 
 
 
• 
If negative for ALK, ROS1, or MET alteration patient will proceed with standard 
of care treatment at discretion of treating physicians. A report of the genetic 
testing will be provided to the investigating physician. 
 
2. Study Timeline 
(a) Scientific Review Committee and IRB approval – 3 months 
(b) Participant Enrollment – 12-18 months.  
(c) Participant Treatment:  
• 
Therapy:  6 weeks, +/- 1 week, with the last day of dosing on 
morning of surgical resection 
• 
Treatment Follow up: Treatment after completion of 6 weeks of 
crizotinib and surgical resection is at the discretion of the patient’s 
treating physician. This may include adjuvant chemotherapy and or 
radiation dependent on pathologic analysis of resection specimen. 
• 
Study Follow up: 5 years- by chart review. Patients should receive 
scans at approximately 6-month intervals from the time of surgical 
resection for the first 2 years, then annually for 3 years. 
 
(d) 
Tissue Biopsy and Plasma Molecular Analyses – This step will be 
done concurrently with patient enrollment and standard of care 
pathologic analysis of surgically resected tumors. Plasma analysis for 
circulating tumor DNA will be done through Guardant Health. 


COMIRB Number: 16-2025 
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PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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(e) 
Compiled Data Analysis – 2-3 months 
 
D. Study Enrollment and Withdrawal 
1. Patient Enrollment 
(a) 
Participants will be recruited to participate in this study from the University 
of Colorado Thoracic Surgery and Oncology Clinics and the University of 
California San Francisco. The initial contact with the research subject will 
be made by an investigator who has a treatment relationship with the 
subject. As stated, this will typically be done in the thoracic surgery or 
thoracic multi-disciplinary clinics. Questions may also be addressed to the 
Principal Investigator.   
(b) 
This trial will not exclude potential subjects from participation on the basis 
of ethnic origin or gender.  Participants (including women and minorities) 
will be included in this study provided they meet all eligibility criteria. 
(c) 
Screening size: We will be using the ORR as the efficacy outcome to 
power the study. With 35% as the historical ORR derived from 
neoadjuvant chemotherapy and 60% as the desirable rate, 26 subjects 
will provide 80% power to detect this 25% absolute difference with a type 
I error rate of 0.05 using a single stage design.  
We estimate that the cumulative percentage of patients that will have 
ALK, ROS1, or MET activating alterations will be approximately 10%, 
therefore, we will need to screen ~260 patients to obtain 26 evaluable 
participants.  
(d) 
Screening Tests:  
1) Plasma evaluation for circulating tumor DNA will consist of a research 
blood draw in which 4 additional tubes of blood will be drawn (Streck 
tubes, approximately 10 mL per tube). This will occur before initiation 
of treatment with study drug (though must be done at least 48 hours 
after any invasive biopsy) and prior to surgical resection. Additionally, 
an optional ctDNA will be available to patients after definitive 
treatment with each follow-up CT scan (if available via their treating 
oncologist) 
  
2) Screening tests for mutational analysis will be performed on biopsy 
specimens and verification of mutation status will occur at a CLIA 
certified lab prior to administration of study drug. The Biorepository 
Manager will be responsible for shipping UCH specimens to Pfizer if 
necessary. 
 
The tissue screening will be done per institutional practice by or by 
Pfizer:  
 
Clinical Pharmacogenomics Laboratory 
Building 220, Room V1387 
Pfizer Global Research & Development 


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Eastern Point Road 
Groton, CT 06340 
 
This is a wholly owned Pfizer test facility and CLIA certified 
laboratory. The activities that will occur at the facility are: sample 
receipt and accessioning, nucleic acid extraction, NGS processing 
and report generation.  
 
(i) Central pathology assessment (i.e. H/E) is expected to occur at the 
University of Colorado.  
 
(ii) Screening Test: Either a CLIA approved laboratory evaluation or via 
the Oncomine Universal Dx test at Pfizer which provides a set of 
primers that target key regions of 52 unique human genes (47 
excluding copy number variations) comprised of approximately 700 
somatic variants in a single kit for use with the Ion Torrent™ PGM Dx 
next generation sequencing (NGS) system to generate the variant 
calls.  The Oncomine Universal Dx Test allows concurrent analysis of 
DNA and RNA, enabling sequencing of 35 hotspot genes, 19 genes 
associated with copy number gain and 23 fusion genes, all in a single 
workflow using the Ion PGM System. The assay also leverages Ion 
AmpliSeq technology's low DNA and RNA sample input requirements 
from FFPE tissue (10 ng of extracted nucleic acid per reaction for a 
total of 20 ng per sample) to enable accurate and reliable sequence 
analysis across a large range of tumor sample types. This is a subset 
of genes utilized by the NCI-MATCH trial with the same sequencing 
technology.40 
 
Oncomine Focus Assay Gene List 
 
 
 
 
 
ABL1  
ERBB2  
GNAQ  
MYC  
AKT1  
ERBB4  
HRAS  
MYCN  
AKT3  
ERBB3  
IDH1  
NRAS  
ALK  
ERG  
IDH2  
NTRK1  
AR  
ESR1  
JAK1  
NTRK2  
AXL  
ETV1  
JAK2  
NTRK3  
BRAF  
ETV4  
JAK3  
PDGFRA  
CCND1  
ETV5  
KIT  
PIK3CA  
CDK4  
FGFR1  
KRAS  
PPARG  
CDK6  
FGFR2  
MAP2K1  
RAF1  
CTNNB1  
FGFR3  
MAP2K2  
RET  
DDR2  
FGFR4  
MET  
ROS1  
EGFR  
GNA11  
MTOR  
SMO  
 
2. Participant Removal / Withdrawal from the Study 
(a) 
Removal of Participants from Protocol Therapy:  


COMIRB Number: 16-2025 
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• 
Participants who are removed from the study protocol therapy who 
are still eligible for surgery will proceed with standard of care 
treatment as per their treating oncologist. 
• 
Additionally, the reason for discontinuation of protocol therapy will be 
documented. 
• 
In case a participant decides to prematurely discontinue protocol 
therapy (“refuses treatment”) the participant should be asked if she 
or he may still be contacted for further scheduled study 
assessments. The outcome of that discussion should be 
documented in both the medical records and in the study case report 
forms. 
 
(b) 
Study Withdrawal:  
• 
Participants are free to withdraw from participation in the study at 
any time upon request 
• 
If a participant decides to withdraw from the study (and not just from 
protocol therapy) all efforts should be made to complete and report 
study assessments as thoroughly as possible. The investigator 
should contact the participant or a responsible relative by telephone 
or through a personal visit to establish as completely as possible the 
reason for the study withdrawal.  
• 
A complete final evaluation at the time of the participant’s study 
withdrawal should be made with an explanation of why the 
participant is withdrawing from the study. If the reason for removal of 
a participant from the study is an adverse event, the principal 
specific event will be recorded on the study case report form. 
 
• 
An investigator may terminate participation in the study if any clinical 
adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the 
study would not be in the best interest of the participant. 
 
E. Treatment Plan / Study Agent 
Once mutational status is verified, 26 participants with stage IA-IIIA, surgically 
resectable lung adenocarcinoma with an activating alteration in ALK, ROS1, or 
MET will be treated with 6 weeks of crizotinib induction therapy. There is no pre-
specified limit or quota for each of the molecular subgroups. 
 
1. Study Agent Information 
Crizotinib (Zalkori ®) is an oral receptor tyrosine kinase inhibitor of ALK, 
Hepatocyte Growth Factor Receptor (HGFR, c-Met), and ROS1 (c-ros). The 
recommended dose of crizotinib is 250mg orally, twice daily with or without 
food. Participants on this trial will receive this dose. The drug is distributed 
as a gelatin capsule. Crizotinib is FDA approved for the treatment of 
patients with metastatic non-small cell lung cancer whose tumors are ALK 


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or ROS1 positive. The full details of the prescribing information are listed on 
the FDA drug safety information site: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202570s017lbl.
pdf  
 
Investigators will adhere to labeling contraindications, warnings, and 
concomitant medication, herbal warnings as listed in the FDA labeling. 
 
Toxicities and Dosing Delays:  
Any patient who receives treatment on this protocol will be evaluable for 
toxicity.  Each patient will be assessed periodically for the development of 
any adverse event during the duration of the study. Adverse events will be 
assessed according to the NCI CTCAE v4.03, or if not in the CTCAE v4.03 
the best description of the medical condition in the opinion of the 
investigator, from the time of informed consent until 7 days (for non-serious 
AEs) or 30 days (for SAEs) after the last dose of study medication.  
 
Unless otherwise noted in the tables below, treatment may be delayed ≤ 3 
weeks from the expected day of the next treatment for any reason.  If 
treatment is delayed ≤ 1 week, subjects will proceed with the next day of 
treatment at the dose level recommended. If treatment is delayed >3 weeks, 
then the patient should be discontinued from protocol-mandated therapy. 
 
Missed doses of crizotinib are not to be made up.  In the event that 
crizotinib dosing is interrupted, the duration of cycle/treatment will not be 
extended.   
 
Dose Modifications: as per FDA labeling41 
Reduce dose as below, if 1 or more dose reductions are necessary due to 
adverse reactions of Grade 3 or 4 severity, as defined by National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.0:  
• 
First dose reduction: crizotinib 200 mg taken orally twice daily  
• 
Second dose reduction: crizotinib 250 mg taken orally once daily  
• 
Permanently discontinue if unable to tolerate crizotinib 250 mg taken 
orally once daily  
Table 1. Crizotinib Dose Modification – Hematologic Toxicitiesa  
Grade  
Crizotinib Dosing  
Grade 3  
Withhold until recovery to Grade 2 or less, then 
resume at the same dose schedule  
Grade 4  
Withhold until recovery to Grade 2 or less, then 
resume at next lower dose  
• 
a Except lymphopenia (unless associated with clinical 
events, e.g., opportunistic infections).  
• 
 


C O MI R B N u m b er : 1 6-2 0 2 5  
St u d y R ef er e n c e N u m b er : Pfi z er # W 1 2 1 6 2 4 7  
PI:  Dr. P atil   
Pr ot o c ol V er si o n D at e: 1 0/ 2 0 / 2 02 0  
 
A R M T ri al  
P a g e 1 4  of 3 3  
 
 
N o st arti n g d o s e a dj u st m e nt i s n e e d e d f or p ati e nt s wit h mil d ( 6 0 ≤ cr e ati ni n e 
cl e ar a n c e [ C L cr] < 9 0 m L/ mi n) or m o d er at e ( 3 0 ≤ C L cr < 6 0 m L/ mi n) r e n al 
i m p air m e nt, si n c e t h e p o p ul ati o n p h ar m a c o ki n eti c a n al y si s i n di c at e d n o 
cli ni c all y m e a ni n gf ul c h a n g e s i n st e a d y -st at e cri z oti ni b e x p o s ur e i n t h e s e 
p ati e nt s. Cri z oti ni b pl a s m a c o n c e ntr ati o n s m a y b e i n cr e a s e d i n p ati e nts wit h 
s e v er e r e n al i m p air m e nt ( C L cr < 3 0 m L/ mi n) T h e cri z oti ni b d o s e s h o ul d b e 
a dj u st e d t o 2 5 0 m g t a k e n or all y o n c e d ail y f or p ati e nt s wit h s e v er e r e n al 
i m p air m e nt n ot r e q uiri n g p erit o n e al di al y si s or h e m o di al y si s. T h e d o s e m a y 
b e i n cr e a s e d t o 2 0 0 m g t wi c e d ail y b a s e d o n i n di vi d u al s af et y a n d 
t ol er a bilit y aft er at l e a st 4 w e e k s of tr e at m e nt. 
 
 
Cri z o ti ni b i s e xt e n si v el y m et a b oli z e d i n t h e li v er. Tr e at m e nt wit h cri z oti ni b 
s h o ul d b e u s e d wit h c a uti o n i n p ati e nt s wit h h e p ati c i m p air m e nt. A cli ni c al 
st u d y w a s c o n d u ct e d i n p ati e nt s wit h a d v a n c e d c a n c er a n d v ar yi n g d e gr e es 
of h e p ati c i m p air m e nt ( b a s e d o n N ati o n al C a n c er I n stit ut e [ N CI] 
cl a s sifi c ati o n), w h o r e c ei v e d m ulti pl e d o s e s of cri z oti ni b t o e v al u at e t h e 
eff e ct of h e p ati c i m p air m e nt o n t h e p h ar m a c o ki n eti c s a n d s af et y of 
cri z oti ni b. N o st arti n g d o s e a dj u st m e nt of cri z oti ni b i s r e c o m m e n d e d f or 
p ati e nt s wit h mil d h e p ati c i m p air m e nt ( eit h er A S T > U p p er Li mit of N or m al 
( U L N) a n d t ot al bilir u bi n ≤U L N or a n y A S T a n d t ot al bilir u bi n > U L N b ut i s 
r e c o m m e n d e d f or cri z oti ni b e x p o s ur e w a s c o m p ar a bl e t o t h at  
fr o m p ati e nt s wit h n or m al h e p ati c f u n cti o n ( b ot h gr o u p s r e c ei v e d 2 5 0 m g 
t wi c e d ail y). T h e st arti n g cri z oti ni b d o s e f or p ati e nt s wit h m o d er at e h e p ati c 
i m p air m e nt ( a n y A S T a n d t ot al bilir u bi n > 1. 5 × U L N a n d 3 × U L N)  i s 
r e c o m m e n d e d t o b e 2 0 0 m g t wi c e d ail y. T h e st arti n g cri z oti ni b d o s e f or 
p ati e nt s wit h s e v er e h e p ati c i m p air m e nt ( a n y A S T a n d t ot al bilir u bi n 
> 3 × U L N) i s r e c o m m e n d e d t o b e 2 5 0 m g o n c e d ail y  a s cri z oti ni b d o s e s 
gr e at er t h a n 2 5 0 m g o n c e d ail y m a y r e s ult i n i n cr e a s e s of s y st e mi c 
cri z oti ni b e x p o s ur e t o s u pr a -t h era p e uti c l e v el s.  
 
 
 
T a b l e 2. Cri z oti ni b  D o s e M o difi c ati o n – N o n -H e m at ol o gi c T o xi citi e s  
Crit e ri a  
Cri z oti ni b  D o si n g  
Al a ni n e a mi n otr a n sf er as e ( A L T) 
or a s p art at e a mi n otr a nsf er a s e 
( A S T) el e v ati o n gr e at er t h a n 5 
ti m e s u p p er li mit of n or m al ( U L N) 
wit h t ot al bilir u bi n l e s s t h a n or 
e q u al t o 1. 5 ti m e s U L N  
Wit h h ol d u ntil r e c o v er y t o b a s eli n e or l e s s 
t h a n or e q u al t o 3 ti m e s U L N, t h e n r e s u m e 
at r e d u c e d d o s e.  
A L T or A S T el e v ati o n gr e at er 
t h a n 3 ti m e s U L N wit h c o n c urr e nt 
t ot al bilir u bi n el e v ati o n gr e at er 
t h a n 1. 5 ti m e s U L N  (i n t h e 
P er m a n e ntl y di s c o nti n u e.  


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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absence of cholestasis or 
hemolysis)  
Any grade drug-related interstitial 
lung disease/pneumonitis  
Permanently discontinue.  
QT corrected for heart rate (QTc) 
greater than 500 ms on at least 2 
separate electrocardiograms 
(ECGs)  
Withhold until recovery to baseline or to a 
QTc less than 481 ms, then resume at 
reduced dose.  
QTc greater than 500 ms or 
greater than or equal to 60 ms 
change from baseline with 
Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia  
Permanently discontinue.  
Bradycardia (symptomatic, may 
be severe and medically 
significant, medical intervention 
indicated)  
Withhold until recovery to asymptomatic 
bradycardia or to a heart rate of 60 bpm or 
above.  
  
Evaluate concomitant medications known to 
cause bradycardia, as well as 
antihypertensive medications.  
  
If contributing concomitant medication is 
identified and discontinued, or its dose is 
adjusted, resume at previous dose upon 
recovery to asymptomatic bradycardia or to 
a heart rate of 60 bpm or above.  
  
If no contributing concomitant medication is 
identified, or if contributing concomitant 
medications are not discontinued or dose 
modified, resume at reduced dose upon 
recovery to asymptomatic bradycardia or to 
a heart rate of 60 bpm or above.  
  
Bradycardia (life-threatening 
consequences, urgent 
intervention indicated)  
Permanently discontinue if no contributing 
concomitant medication is identified.  
  
If contributing concomitant medication is 
identified and discontinued, or its dose is 
adjusted, resume at 250 mg once daily upon 
recovery to asymptomatic bradycardia or to 
a heart rate of 60 bpm or above, with 
frequent monitoring.  
  
Visual Loss (Grade 4 Ocular 
Disorder)  
Discontinue during evaluation of severe 
vision loss.  


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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a Heart rate less than 60 beats per minute (bpm). b Permanently discontinue for recurrence.  
 
Monitor complete blood counts including differential white blood cell counts 
monthly and as clinically indicated, with more frequent repeat testing if 
Grade 3 or 4 abnormalities are observed, or if fever or infection occurs.  
 
Supplier, Storage, and Stability:  
Crizotinib will be supplied by Pfizer for this study as a 250mg capsule at no 
cost to the study patient. Pfizer will ship the drug to the main study center 
and study drug will be distributed by the main study center pharmacy. Store 
at room temperature 20° to 25°C (68° to 77°F); excursions permitted 
between 15° to 30°C (59° to 86°F) [see USP Controlled Room 
Temperature].  
 
Handling and Disposal:  
Crizotinib should be handled as per manufacturer recommendations. It 
should only be dispensed from an official study site by authorized personnel 
according to local regulations and stored in a secure area according to local 
regulations. The study pharmacist or designee at the site will be responsible 
for handling and dispensing study drug and completing associated 
documentation. The site must use an appropriate dispensing log/ 
accountability form. 
All used and unused bottles or blister packs of study drug must be returned 
to study site where their return will be recorded. Returned supplies will not 
be re-dispensed to participants. 
 
2. Duration of Treatment 
(a) Duration of Therapy:  6 weeks, +/- 1 week, with the last day of dosing 
on morning of surgical resection 
(b) Duration of Follow up: 5 years, this will be via chart review. 
(c) Follow up Treatments: Treatment after completion of 6 weeks of 
crizotinib and surgical resection is at the discretion of the patient’s 
treating physician. This may include adjuvant chemotherapy and or 
radiation dependent on pathologic analysis of resection specimen. 
 
 
3. Outcome measures 
(a) Objective Response Rate: participants’ response to treatment will be 
compared from initial/pretreatment scan to 6-week scan using RECIST 
1.1 
(b) Pathologic response rate: We apply a three-tiered categorization to report 
pathologic response: complete response (0% viable tumor present), 
<10% viable tumor present and, < 50% viable tumor present histologically 
in the resected tumor specimen.  The standard pathologic response rate 
reported is <50% viable tumor however, we wish to increase granularity 


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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Page 17 of 33 
 
and thus will be reporting additional cutoffs. 
(c) Metabolic Response: for participants in whom their initial staging scan 
was a PET scan will receive a follow-up PET at 6 weeks of treatment 
when available to compare metabolic pre-and post-induction therapy 
response as per PERCIST criteria. 
(d) Disease Free Survival at 5 years. 
(e) Progression Free Survival at 5 years. 
 
F. 
Study Calendar 
Procedure 
Screening 
(Day -28 to 
-1) 
D1 
to 
D42 
D21 (+/- 
4 days) 
D42 
(+/- 4 
days) 
Surgical 
Resection 
D43-49 
(+/- 7 
days) 
Standard of 
care follow -
up 
Informed Consent 
X 
 
 
 
 
 
History and Physical exam 
(including performance status 
assessment.(see appendix D) 
X 
 
X 
X 
 
X4 
Adverse Event Assessment 
 
 
X 
X 
 
 
Concomitant Medication 
Review  
X 
 
X 
X 
 
 
Lab Draw : CBC, CMP, serum 
pregnancy test1 
X 
 
X 
X 
 
 
ECG 
X 
 
X 
 
 
 
Molecular Testing of 
diagnostic biopsy sample ** 
X 
 
 
 
 
 
Further Molecular testing of 
surgical specimen 
 
 
 
 
X (w ith 
resection 
specimen) 
 
Plasma sample for tumor DNA 
evaluation (paid for by 
Guardant) 
X 
 
 
X 
 
X 
(optional)*** 
Crizotinib 250mg BID2 
 
X 
 
 
 
 
PET scan 
X3 
 
 
X (+/-5 
days, but 
before 
surgery) 
 
 
MRI Brain (optional based on 
treating physician) 
X3 
 
 
 
 
 
* Pre-surgical biopsy not required for plasma collection, but histological confirmation required 
prior to molecular testing. 
** Molecular screening to be done by Pfizer, University of California-San Francisco, or University 
of Colorado, no molecular screening cost to patient 
*** Patients have option of repeated Guardant blood draw  w ith each follow -up imaging study 
1CMP to include amylase and lipase at study entry only.  Screening CBC, CMP, and pregnancy 
test must be completed w ithin 14 days of Day 1.  Serum pregnancy test is only required at 
screening 
2Pt to continue 250mg BID crizotinib through morning of surgery (if allow ed by local anesthesia 
guidelines, otherw ise final dose should be evening before surgery), including cases w here 
surgery occurs later than day 43 as allow ed by surgical w indow  (of +/-7 days) due to scheduling 
or other issues. 
3 Must be completed w ithin four w eeks of signing consent and 6 w eeks of Day 1. 


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PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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4 Follow -up for 5 years by chart review .  Patients should receive scans, per standard of care.  
Scans should occur at 6-month intervals, at least from the time of surgical resection for the first 2 
years, then annually for three years.  Performance status not required. 
 
G. Laboratory Procedures and/or Other Assays for Research 
1. Blood and Tissue Handling 
(a) Tissue will be handled in accordance with routine clinical practice 
requirements in the University of Colorado Pathology Department and the 
University of Colorado Molecular Correlates Laboratory.  
(b) When performed at the University of Colorado the diagnostic biopsy 
specimen will undergo routine pathologic evaluation and once confirmed 
to be lung adenocarcinoma will undergo adequacy assessment by the 
study designated UCH pathologist prior to release to University of 
Colorado or Pfizer for additional testing. If sufficient tissue is available, 
1-2 cores of the diagnostic biopsy will remain at the University of 
Colorado for future correlative analysis. This tissue will be labeled and 
stored as per standard procedure. Biopsy specimens will be immediately 
released to University of Colorado or Pfizer once confirmed to be 
adenocarcinoma. Shipping costs to be covered by the trial. Molecular 
screening will occur at the University of Colorado, the University of 
California-San Francisco, or Pfizer as described above with an 
anticipated turnaround time of 2 weeks. 
(c) When available, the diagnostic H&E slide, on which molecular testing 
was performed and eligibility of the patient for the protocol was 
determined, will be obtained by the staff and scanned to a project 
specific image file utilizing University of Colorado Cancer Center 
(UCCC) imaging core Aperio scanner.  This imaging file will be made 
available to project-associated investigators via password-protected 
access. 
(d) Plasma circulating tumor DNA testing will be done via Guardant Health. 
This is not considered standard of care and will be covered by Guardant 
Health. For this testing, 4 additional tubes of blood will be drawn (Streck 
tubes, approximately 10 mL per tube). Samples will be designated for 
research use and sent to Guardant Health. Samples will be sent on 
screened patients as well as enrolled patients, on day 42 visit, and 
optionally with each post-treatment follow-up CT scan. 
 
(e) If additional study sites are added and tissue molecular screening is 
performed at participating institutions this is not included in study cost. 
and should be billed as standard of care.  
 
2. Post-Treatment Resection Specimen Handling 
(a) When surgical resection is performed at UCH, at least thirty minutes 
prior to surgical resection, the designated pathology personnel will be 
notified of the impending tissue collection and given the room number in 
which the procedure will take place.  The designee will attend the 


COMIRB Number: 16-2025 
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PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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procedure and immediately snap freeze tissue sample OCT containing 
cryomolds by submersion in liquid nitrogen (N2).  Following the 
procedure, the tissue will be delivered to the pathology department or 
CMOCO laboratory by the designee attending the procedure.  Utilizing 
the study ID generated by the study coordinator at the time of consent, 
the case will be linked to a specific pathology accession number (PYY-
XXX).  These frozen blocks will be stored in a designated location within 
a CMOCO liquid N2 storage unit until processed for histologic evaluation 
and collection of RNA for study related RNA analyses. If processed 
immediately, interim storage may not be required. 
(b) Histopathologic evaluation of surgical resection specimens will be 
performed within 24-36 hours of collection unless weekends or holidays 
prevent this (processing will take place on next working day when 
conflicts are encountered).  Each tissue sample will be sectioned on a 
cryostat and an H&E slide will be prepared and reviewed at the time of 
frozen section by a designated UCH pathologist.  Presence of tumor, 
percentage of necrosis and overall estimated tumor/stromal cellularity 
will be recorded for each specimen, and this information will be stored 
(OnCore).  The H&E slides will be barcoded, entered into the OnCore 
database, and subsequently stored in the archives.   
 
3. Additional analyses 
(a) Tissue preparation is outlined in Appendix A.  
Additional testing may include but is not limited to direct sequencing of 
oncogenes, immunohistochemistry, proximity ligation assay (PLA) and 
RT-PCR for oncogenic fusions.   
(b) Immunohistochemistry of tumor samples: 
IHC will be completed on post resection samples by the research 
histology core for tissue microenvironment characterization as well as 
determination of evidence of epithelial to mesenchymal transition. 
Proteins to be evaluated include but are not limited to e-cadherin, 
vimentin, fibronectin, CD4, CD8, CD14, CD16, CD206, PDL1, and 
CSF1R.  
(c) Proximity Ligation Assay of tumor resection samples:  
PLA to be performed to determine the level of signal inhibition by 
crizotinib of each oncogenic driver. Assays will be performed in 
laboratory of the Principal Investigator. They will be performed as 
previously described using assay modifications specific from ALK, 
ROS1, and MET.42 
(d) RNAseq evaluation of tumor samples:  
RNA seq procedures outlines in Appendix B and C. Genetic mutations 
and expression changes will be evaluated with RNAseq. This will assist 
with identification of new markers of disease response/ survival as well 
as identification of possible targets of combination therapy. These 


COMIRB Number: 16-2025 
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PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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experiments will be done within the University of Colorado Core facility 
and the data analysis and interpretation will be done with the study 
designated bioinformatics faculty member.  
 
IV. 
Assessment of Safety 
A. Definition of Adverse Event (AE) 
Adverse event means any untoward medical occurrence associated with the use of 
an intervention in humans, whether or not considered intervention-related (21 CFR 
312.32 (a)). 
 
B. Definition of Serious Adverse Event (SAE) 
An SAE or serious suspected adverse reaction. An AE or suspected adverse 
reaction is considered “serious” if, in the view of either the investigator or Pfizer, it 
results in any of the following outcomes:  
• 
death,  
• 
is life-threatening (i.e., causes an immediate risk of death),  
• 
requires inpatient hospitalization or prolongation of existing hospitalization,  
• 
results in a persistent or significant disability or incapacity (i.e., substantial 
disruption of the ability to conduct normal life functions), results in a 
congenital anomaly/ birth defect, or  
• 
is considered to be an important medical event.   
An important medical event may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this SAE 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
 
C. Definition of an Unanticipated Problem Involving Risks to Participants 
or Others (UAP) 
This study will use the definition of an Unanticipated Problem Involving Risks to 
Participants or Others (UAP) which is any event that was unforeseen and indicates 
that the research procedures caused harm (including physical, psychological, 
economic or social harm) to the participants or others, or indicates that participants 
or others are at increased risk of harm than was previously known or recognized. 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as 
the IRB-approved research protocol and informed consent document; and 
(b) the characteristics of the participant population being studied; 


COMIRB Number: 16-2025 
Study Reference Number: Pfizer #W1216247 
PI:  Dr. Patil  
Protocol Version Date: 10/20/2020 
 
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Page 21 of 33 
 
• 
Related or possibly related to participation in the research (“possibly 
related” means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved 
in the research); and 
• 
Suggests that the research places participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
D. Classification of an Adverse Event 
1. Severity of Event 
For AEs not included in CTCAE v4.03, the following guidelines will be used to 
describe severity. 
• 
Mild (grade 1)– Events require minimal or no treatment and do not 
interfere with the participant’s daily activities. 
• 
Moderate (grade 2)– Events result in a low level of inconvenience or 
concern with the therapeutic measures. Moderate events may cause 
some interference with functioning. 
• 
Severe (grade 3)– Events significantly interrupt a participant’s usual 
daily activity despite systemic drug therapy or other treatment.  
• 
Life-Threatening (grade 4)- The patient is at immediate risk of death. 
• 
Death (grade 5)- The patient dies as a direct result of the complication 
or condition induced by the AE. 
2. Relationship to the Study Agent 
The clinician’s assessment of an AE’s relationship to study agent (drug, biologic, 
device) is part of the documentation process, but it is not a factor in determining 
what is or is not reported in the study. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. All AEs must have their 
relationship to the study agent assessed. In a clinical trial, the study product must 
always be suspect. To help assess, the following guidelines are used.  
• 
Related – The AE is known to occur with the study agent, there is a 
reasonable possibility that the study agent caused the AE, or there is a 
temporal relationship between the study agent and event. Reasonable 
possibility means that there is evidence to suggest a causal relationship 
between the study agent and the AE. 
• 
Not Related – There is not a reasonable possibility that the 
administration of the study agent caused the event, there is no temporal 
relationship between the study agent and event onset, or an alternate 
etiology has been established. 


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PI:  Dr. Patil  
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3. Expectedness 
The PI will be responsible for determining whether an SAE is expected or 
unexpected. An SAE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously 
described for the study agent. 
E. Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits and interviews of a study participant presenting for medical care, or upon 
review by a study monitor. All AEs including local and systemic reactions not meeting 
the criteria for SAEs will be captured on the appropriate CRF. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority 
to make a diagnosis), and time of resolution/ stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will 
be considered as baseline and not reported as an AE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as 
an AE. UAPs will be recorded in the data collection system throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after 
the last dose of study medication. At each study visit, the investigator will inquire 
about the occurrence of AE/ SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
 
F. Reporting Procedures 
1. Adverse Event Reporting 
AEs will be reported in accordance with the UCCC DSMC and COMIRB policies. 
2. Serious Adverse Event Reporting 
SAEs will be reported in accordance with Pfizer’s SAE Form Completion Guide, 
the UCCC DSMC and COMIRB policies.  SAEs will also be reported in 
accordance with the United States Food and Drug Administration (FDA) 
requirements, as applicable, under IND or IND Exemption.  
All SAEs will be followed until satisfactory resolution or until the PI deems the 
event to be chronic or the adherence to be stable.  


COMIRB Number: 16-2025 
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PI:  Dr. Patil  
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3. Unanticipated Problems Reporting 
Reportable UAPs will be submitted to the UCCC DSMC, and to COMIRB per their 
policy. Promptly reportable events will be submitted within 5 working days of the 
event or knowledge of the event. 
4. Procedures in Case of Pregnancy 
There is no available date on the use of the study agent during pregnancy. 
Female participants of reproductive potential will be advised to use effective 
contraception during treatment with study agent and for at least 45 days after 
receiving the final dose. Male participants with female partners of reproductive 
potential will be advised to use condoms during treatment with the study agent 
and for at least 90 days after receiving the final dose. 
Any unexpected pregnancy will be reported and procedures followed, in 
accordance with Pfizer’s Safety Reporting Reference Manual and the 
exposure during pregnancy form will be completed. 
 
V. 
Ethics / Protection of Human Subjects 
A. Ethical Standard 
The PI will ensure that this study is conducted in full conformity with regulations for 
the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56. ICH E6 may also be followed to the extent it has been 
adopted by and is in accordance with FDA regulations. 
 
B. Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject 
materials will be submitted to the Colorado Multiple Institutional Review Board 
(COMIRB) for review and approval. Approval of both the protocol and the consent 
form must be obtained before any subject is enrolled. Any amendment to the protocol 
will require review and approval by COMIRB before the changes are implemented to 
the study. All changes to the consent form will COMIRB approved; a determination 
will be made regarding whether previously consented participants need to be re-
consented. 
 
C. Informed Consent Process 
1. Informed Consent Procedure 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in study related procedures. Consent will be obtained in a quiet setting 
and the subject will be given ample time to consider the consent form and ask 
questions.  Every effort will be made to ensure that the patient has an 


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understanding of the consent form based upon his/her verbal responses. The 
consent form must be signed and dated by the participant or the participant’s 
legally authorized representative, and by the person obtaining the consent. The 
participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical 
record or research file. Participants enrolled in this study will consent to the 
following procedures: 
 
(a) Pre-treatment tumor biopsy and/ or liquid biopsy (optional) 
(b) Treatment with crizotinib for 6 weeks  
(c) Standard of care imaging at diagnosis as well as 1 additional imaging 
study (PET scan (preferred) or CT scan) which will be done after 6 weeks 
of neoadjuvant treatment and prior to surgical resection. 
(d) Surgical resection of tumor sample 
(e) Clinical and follow-up data will be collected on the patient 
(f) New molecular tests developed in the future may be performed on this 
tissue. 
(g) Participants will be educated that aside from the portion of the specimen 
used for diagnostic pathology, the residual samples to be obtained are for 
research purposes, and that they may derive no benefit from their 
participation. The determinants for any further treatment guided by the 
molecular testing will be defined by the enrollment criteria of alternate 
studies.  
 
2. Protected Health Information (PHI) 
This project will require the use of PHI for research purposes.  A HIPAA 
authorization form will be provided to the subject at the time of consent.  This 
authorization will designate the specific health information that will be required 
to be released.  This authorization form is provided by COMIRB as part of the 
consent form. The signed and dated authorization will be collected by the 
clinical research coordinator at the same time the subject is consented.  The 
authorization describes in detail what information will be collected and for what 
purposes it will be used. 
 
Participant confidentiality will be strictly held in trust by the PI and any study 
personnel, or research entity that may see or receive PHI under this study. This 
confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the 
Sponsor-PI. 
 
The study monitor, other authorized representatives of the sponsor, 
representatives of the IRB, or pharmaceutical company supplying study agent 


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may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each 
clinical site for internal use during the study. At the end of the study, all records 
will continue to be kept in a secure location for as long a period as dictated by 
local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and 
scientific reporting, will be transmitted to and stored at the University of 
Colorado Cancer Center. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data 
will be identified by a unique study identification number. The study data entry 
and study management systems used by the University of Colorado Cancer 
Center research site staff will be secured and password protected. At the end of 
the study, all study databases will be de-identified and archived according to 
the University of Colorado Cancer Center policies. 
 
VI. 
Study Monitoring and Oversight 
A. Data Safety Monitoring Committee (DSMC) Oversight 
The sponsor investigator will be responsible for monitoring the trial per the trial 
monitoring plan, in addition to overseeing the safety and efficacy of the trial 
including any specimens collected, executing the data and safety monitoring (DSM) 
plan, and complying with all reporting requirements to local and federal authorities. 
This oversight will be accomplished through additional oversight from the Data and 
Safety Monitoring Committee (DSMC) at the University of Colorado Cancer Center 
(CU Cancer Center). The DSMC is responsible for ensuring data quality and study 
participant safety for all clinical studies at the CU Cancer Center, which is the 
coordinating institution of this trial. A summary of the DSMC’s activities is as 
follows:  
 
• 
Conduct of internal audits  
• 
Ongoing review of all serious adverse events (SAEs) and unanticipated 
problems (UAPs)  
• 
Has the authority to suspend trials for safety or trial conduct issues  
• 
May submit recommendations for corrective actions to the CU Cancer 
Center’s Executive Committee  
 
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are reported to 
the DSMC, IRB and the sponsor investigator per protocol. All SAEs and UAPs are 
to be reported to the DSMC within 7 (for fatal or life-threatening events) or 15 (non-
life-threatening events) calendar days of the sponsor investigator receiving 
notification of the occurrence. 
 


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Each subject’s treatment outcomes will be discussed by the site PI and appropriate 
staff at regularly scheduled meetings. Data regarding number of subjects, 
significant toxicities, dose modifications, and treatment responses will be discussed 
and documented in the meeting’s minutes.  
 
The sponsor investigator is responsible for organizing and conducting regularly 
scheduled teleconferences with all participating sites. The sponsor investigator will 
also be responsible for including data from all the participating sites to include the 
minutes from these regularly scheduled teleconferences between the sponsor 
investigator and the sites within the overall trial’s DSM progress report.  
 
The sponsor investigator will provide a DSM progress report to the CU Cancer 
Center DSMC on a recurring basis (either every six or twelve months based on 
DSMC vote). The DSM report will include a protocol summary, current enrollment 
numbers, summary of toxicity data to include specific SAEs, UAPs and AEs, any 
dose modifications, all protocol deviations, and protocol amendments. The DSM 
report submitted to the DSMC will also include, if applicable, the results of any 
efficacy data analysis conducted. Results and recommendations from the review of 
this progress report by the DSMC will then be provided to the sponsor investigator 
in a DSMC review letter. The sponsor investigator is then responsible for ensuring 
this letter is submitted to the site’s IRB of record at the time of IRB continuing 
review. 
 
B. Quality Control and Quality Assurance 
1. Clinical Site Monitoring.  Site monitoring visits will be performed by the for this 
study will be performed by CU Cancer Center Clinical Monitor on a regular basis, 
pursuant to the Clinical Monitoring Plan (CMP), incorporated herein by reference. 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and 
the distribution of the monitoring reports. During these visits, information 
recorded on the CRFs will be verified against source documents.  Additional 
computer programs that identify selected protocol deviations, out-of-range data, 
and other data errors within the electronic data entry may also be used to help 
monitor the study.  As necessary, requests for data clarification or correction will 
be sent to the appropriate site PI. 
2. Audits.  Independent auditors from the sponsor investigator’s authorized 
representative will be allowed by the site’s PI to audit.  In addition, audits may be 
conducted at any time by appropriate regulatory authorities and/or the IRB. 
 
VII. Data Collection and Handling: 
Data Storage Method. Participant data will be entered and stored in REDCAP.  This 
database is a secure system with audit capabilities.  Study related data will only be made 
available to personnel involved in the study through the use of access privileges and 
passwords.  
 


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VIII. Statistical Considerations 
 
General considerations: Data collected in this study will be presented using summary  
tables, patient data listings, and figures. Disease evaluations will be performed by  
investigators per the RECIST 1.1 criteria.  26 evaluable subjects are planned for this  
study.  
 
Analysis populations: Patients who received at least 3 weeks of crizotinib treatment in   
neoadjuvant setting will be included in the efficacy analyses.  
 
Analysis methods: Summary statistics will be used for the primary outcome objective 
response rate. Objective response rate is defined as the proportion of subjects with 
complete response or partial response evaluated before the surgery.  95% exact 
confidence interval will be provided. Pathologic response and Metabolic Response will 
be summarized and reported similarly. Kaplan-Meier survival curves will be used to 
display disease free survival and progression free survival. Median survival times will 
be calculated and reported. For the translational endpoints, we will use t-test, chi-
square test, or logistic regression, as appropriate, to assess if there is any difference 
between samples with incomplete response with samples with complete response in 
measurements obtained using genetic, proteomic, and cell imaging techniques to 
understand mechanisms leading to incomplete tumor response. 
 
Determination of sample size: We use ORR as the efficacy outcome to power the study. With 
35% as the historical ORR for chemotherapy and 60% as the desirable rate, 26 subjects will 
provide 80% power to detect this 25% difference with a type I error rate of 0.05 using a single 
stage design. Subjects with a minimum of 3 weeks of crizotinib treatment in the 
neoadjuvant setting will be included in the efficacy evaluation. It is estimated that at  
maximum 10% of subjects might not be eligible to be included due to shorter period of  
treatment duration or lost to follow-up. Thus, the study will recruit 29 subjects at  
maximum to account for the potential 10% loss in evaluable subjects.  We estimate that the 
cumulative percentage of patients that will have ALK, ROS1, or MET activating alterations will 
be approximately 10%, therefore, we will need to screen ~260 patients to obtain 26 evaluable 
participants. 
 
 
IX. 
Potential Scientific Problems:   
A. Low accrual- If we find that screening and accrual are not meeting targets by 3 
months into trial we will plan to discuss expansion of the clinical trial to additional 
locations 
B. Inability to detect target activating mutations - This is a concern due to the low 
prevalence of these alterations, may ultimately require larger screening population 
and validation of screening modality. Samples in which no oncogenic mutations are 
found may be subject to additional testing methods for validation. 
C. Delays in surgical scheduling resulting in large variations in treatment times. 
Disease response to neoadjuvant treatment will be standardized to evaluation with 


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6-week scan. We hope to be able to ensure timely surgical excision with a 1-week 
window for surgery and for patient enrollment at time of surgical evaluation. 
Participants will continue on crizotinib treatment until the day or surgery. 
 
X. 
Summarize Knowledge to be Gained:   
This study will generate knowledge regarding molecular mechanisms of the development 
of resistance to therapies for thoracic cancers using early stage non-small cell lung 
cancer as a model.  This knowledge to could lead to improved treatment modalities and 
survival for patients with all stages of non-small cell lung cancer. 
 
XI. 
References: 
 
1. 
Hata AN, Niederst MJ, Archibald HL, et al. Tumor cells can follow distinct evolutionary paths to 
become resistant to epidermal growth factor receptor inhibition. Nat Med. Mar 2016;22(3):262-
269. 
2. 
Awad MM, Katayama R, McTigue M, et al. Acquired resistance to crizotinib from a mutation in 
CD74-ROS1. N Engl J Med. Jun 20 2013;368(25):2395-2401. 
3. 
Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with 
ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. Mar 1 2012;18(5):1472-
1482. 
4. 
Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or 
erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. Mar 
2005;2(3):e73. 
5. 
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung 
cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. Mar 23 2011;3(75):75ra26. 
6. 
Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired 
resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer 
Res. Apr 15 2013;19(8):2240-2247. 
7. 
Kazandjian D, Blumenthal G, Zhang L, et al. Exploratory responder analyses of greatest depth 
of response (DepOR) and survival in patients with metastatic non-small cell lung cancer 
(mNSCLC) treated with a targeted therapy or immunotherapy. J Clin Oncol. 2016;J Clin Oncol 
34, 2016 (suppl; abstr 2590). 
8. 
Group NM-aC. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review 
and meta-analysis of individual participant data. Lancet. May 3 2014;383(9928):1561-1571. 
9. 
Kappers I, Klomp HM, Burgers JA, Van Zandwijk N, Haas RL, van Pel R. Neoadjuvant 
(induction) erlotinib response in stage IIIA non-small-cell lung cancer. J Clin Oncol. Sep 1 
2008;26(25):4205-4207. 
10. 
Schaake EE, Kappers I, Codrington HE, et al. Tumor response and toxicity of neoadjuvant 
erlotinib in patients with early-stage non-small-cell lung cancer. J Clin Oncol. Aug 1 
2012;30(22):2731-2738. 
11. 
Lara-Guerra H, Waddell TK, Salvarrey MA, et al. Phase II study of preoperative gefitinib in 
clinical stage I non-small-cell lung cancer. J Clin Oncol. Dec 20 2009;27(36):6229-6236. 
12. 
S. L, Yang Y. Neoadjuvant Crizotinib and Surgical Resection of Two Stage IIIA Lung 
Adenocarcinomas with Anaplastic Lymphoma Kinase Gene Rearrangement. J Thorac Oncol. 
2015;WCLC 2015 P2.01-028.3150. 
13. 
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in 
non-small-cell lung cancer. Nature. Aug 2 2007;448(7153):561-566. 
14. 
Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 
Mar 2012;18(3):378-381. 


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15. 
Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung 
cancers to select targeted drugs. JAMA. May 21 2014;311(19):1998-2006. 
16. 
Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with 
non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. Sep 10 2009;27(26):4247-
4253. 
17. 
Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung 
adenocarcinoma. Nature. Jul 31 2014;511(7511):543-550. 
18. 
Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of 
lung cancers. J Clin Oncol. Mar 10 2012;30(8):863-870. 
19. 
Davies KD, Le AT, Theodoro MF, et al. Identifying and targeting ROS1 gene fusions in non-
small cell lung cancer. Clin Cancer Res. Sep 1 2012;18(17):4570-4579. 
20. 
Birchmeier C, Birnbaum D, Waitches G, Fasano O, Wigler M. Characterization of an activated 
human ros gene. Mol Cell Biol. Sep 1986;6(9):3109-3116. 
21. 
Davies KD, Doebele RC. Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer 
Res. Aug 1 2013;19(15):4040-4045. 
22. 
Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in 
EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U 
S A. Dec 26 2007;104(52):20932-20937. 
23. 
Awad MM, Oxnard GR, Jackman DM, et al. MET Exon 14 Mutations in Non-Small-Cell Lung 
Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification 
and c-Met Overexpression. J Clin Oncol. Mar 1 2016;34(7):721-730. 
24. 
Paik PK, Drilon AE, Yu HA, et al. Response to crizotinib and cabozantinib in stage IV lung 
adenocarcinoma patients with mutations that cause MET exon 14 skipping. J Clin Oncol. 
2015;33((suppl; abstr 8021)). 
25. 
Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in 
cancer. Nat Commun. 2014;5:4846. 
26. 
Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-
positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. Oct 
2012;13(10):1011-1019. 
27. 
Camidge DR, Ou SH, Shapiro G, et al. Efficacy and safety of crizotinib in patients with 
advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol. 
2014;32(5s):(suppl; abstr 8001). 
28. 
Ou SH, Bang YJ, Camidge DR, et al. Efficacy and safety of crizotinib in patients with advanced 
ROS1-rearranged non-small cell lung cancer (NSCLC). J Clin Oncol. 2013 2013;31(Supple; 
Abstr 8032). 
29. 
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive 
lung cancer. N Engl J Med. Dec 4 2014;371(23):2167-2177. 
30. 
Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N 
Engl J Med. Nov 20 2014;371(21):1963-1971. 
31. 
Paik PK, Drilon A, Fan PD, et al. Response to MET Inhibitors in Patients with Stage IV Lung 
Adenocarcinomas Harboring MET Mutations Causing Exon 14 Skipping. Cancer Discov. Aug 
2015;5(8):842-849. 
32. 
Davies KD, Mahale S, Astling DP, et al. Resistance to ROS1 inhibition mediated by EGFR 
pathway activation in non-small cell lung cancer. PLoS One. 2013;8(12):e82236. 
33. 
Cargnelutti M, Corso S, Pergolizzi M, et al. Activation of RAS family members confers 
resistance to ROS1 targeting drugs. Oncotarget. Mar 10 2015;6(7):5182-5194. 
34. 
Dziadziuszko R, Le R, Aisner DL, Wrona A, R.C. D. ROS1 Resistance to Crizotinib Is Mediated 
by an Activating Mutation in c-KIT. 16th World Conference on Lung Cancer. 2015;MINI30.08 
(Abtract ID 2244). 
35. 
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell 
lung cancer to gefitinib. N Engl J Med. Feb 24 2005;352(8):786-792. 
36. 
McCoach C, Le A, D. A, et al. Resistance mechanisms to targeted therapies in ROS1+ and 
ALK+ non-small cell lung cancer. J Clin Oncol.34, 2016 (suppl; abstr 9065). 


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37. 
Gainor JF, Dardaei L, Yoda S, et al. Molecular Mechanisms of Resistance to First- and Second-
Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov. Jul 18 2016. 
38. 
Dziadziuszko R, Le AT, Wrona A, et al. An Activating KIT Mutation Induces Crizotinib 
Resistance in ROS1-Positive Lung Cancer. J Thorac Oncol. Apr 9 2016. 
39. 
Heist RS, Sequist LV, Borger D, et al. Acquired Resistance to Crizotinib in NSCLC with MET 
Exon 14 Skipping. J Thorac Oncol. Aug 2016;11(8):1242-1245. 
40. 
Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated 
data-mining platform. Neoplasia. Jan-Feb 2004;6(1):1-6. 
41. 
US Food and Drug Administration. Crizotinib (Xalkori). 2016; 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202570s017lbl.pdf. Accessed 
9/10/16. 
42. 
Smith MA, Hall R, Fisher K, et al. Annotation of human cancers with EGFR signaling-associated 
protein complexes using proximity ligation assays. Sci Signal. Jan 13 2015;8(359):ra4. 
43. 
Keysar SB, Astling DP, Anderson RT, et al. A patient tumor transplant model of squamous cell 
cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins. Mol Oncol. 
Aug 2013;7(4):776-790. 
44. 
Kleczko EK, Kim J, Keysar SB, et al. An Inducible TGF-beta2-TGFbetaR Pathway Modulates 
the Sensitivity of HNSCC Cells to Tyrosine Kinase Inhibitors Targeting Dominant Receptor 
Tyrosine Kinases. PLoS One. 2015;10(5):e0123600. 
45. 
Hart SN, Therneau TM, Zhang Y, Poland GA, Kocher JP. Calculating sample size estimates for 
RNA sequencing data. J Comput Biol. Dec 2013;20(12):970-978. 
46. 
Liu Y, Zhou J, White KP. RNA-seq differential expression studies: more sequence or more 
replication? Bioinformatics. Feb 1 2014;30(3):301-304. 
47. 
Wu H, Wang C, Wu Z. PROPER: comprehensive power evaluation for differential expression 
using RNA-seq. Bioinformatics. Jan 15 2015;31(2):233-241. 
 
 


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APPENDIX 
A. Tissue preparation for additional analysis: 
Tissue will be microdissected for RNA extraction with a goal of obtaining at least 500 tumor 
cells to facilitate optimal RNA sequencing.  The H&E slide will be utilized to demarcate 
areas for desired tissue collection and this area will be macroscopically dissected from 
other tissue (non-tumor, necrotic tissue, etc.) and placed in RNeasy. If any frozen biopsies 
remain after collection of tissue for RNA extraction and IHC, these blocks will be barcoded 
and stored in liquid N2 archives for future use. 
 
Tissue transferred to RNeasy will undergo RNA extraction by pathology staff and the 
barcoded RNA specimen will then be transferred to the Genomics core for assessment of 
quality metrics and subsequent sequence analysis.  The research histology core will be 
responsible for formalin fixed tissue processing and paraffin embedding.  The block will be 
sectioned to generate 16 slides with single tissue sections on each.  The first will be 
stained with H&E, barcoded and archived in CMOCO.  The remaining 15 sections will be 
prepared on plus slides and stored as barcoded, unstained immunoblanks in the archive.  
Immunohistochemistry including development and optimization of new antibodies, should 
that be required for immunohistochemistry (IHC), can be provided by the research 
histology core. 
 
A research surgical pathology report will be generated for each tissue sample under an 
accession number as described above.  This report will give a single diagnosis based on 
histologic review of all frozen and formalin-fixed paraffin embedded (FFPE) H&E sections 
generated during processing.  If unexpected histopathologic features (i.e. histology 
inconsistent with a prior diagnostic/screening biopsy) are found on review of frozen or 
FFPE generated H&E slides, tissue will be held for any ancillary testing, such as IHC, that 
is deemed necessary by the pathologist for establishing an accurate diagnosis. 
 
All residual material after the above-described tissue processing and testing will be stored 
in the archives. 
 
When surgery is performed at other institutions, tumor samples will be collected and flash 
frozen for transport to the University of Colorado for processing. 
 
B. RNAseq assay.  
Sequencing Library will be constructed using 1µg total RNA following Illumina TruSeq RNA 
Sample Preparation v2 Guide. The poly-A containing mRNA molecules will be purified 
using poly-T oligo-attached magnetic beads. Following purification, the mRNA will be 
fragmented into small pieces using divalent cations under elevated temperature. The 
cleaved RNA fragments will be converted into first strand cDNA using reverse 
transcriptase and random primers. This will be followed by second strand cDNA synthesis 
using DNA Polymerase I and RNase H. These cDNA fragments will go through an end 
repair process, the addition of a single “A” base, and then ligation of the adapters. The 
products will be purified and enriched with PCR to create the final cDNA library. The cDNA 
library will be validated on the Agilent 2100 Bioanalyzer using DNA-1000 chip. Cluster 
generation will be performed on the Illumina cBot using a Single Read Flow Cell with a 
Single Read cBot reagent plate (TruSeq SR Cluster Kit). Sequencing of the clustered flow 
cell will be performed on the Illumina HiSeq 2000 using TruSeq SBS v4 reagents for 


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1x125bp. Sequencing images will be generated through the sequencing platform (Illumina 
HiSeq 2000). The raw data will be analyzed in four steps: image analysis, base calling, 
sequence alignment, and variant analysis and counting.  
 
C. RNAseq Data Analysis. 
RNAseq obtained from participants will be analyzed as previously described.32,43,44 We 
plan to sequence 60-80 million 1x125bp reads per samples, which based on our previous 
and published papers on RNAseq power calculation and sample size estimation, with 5-7 
samples per group, these sequencing reads should be enough to detect 2-fold differentially 
expressed genes with 80% power with 0.05 type I error.32,43-47 Data analysis: Sequencing 
reads that passed quality control will be mapped against the human genome using 
Tophat2 workflow. We will use the NCBI reference annotation (build 37.2) as a guide, and 
allowing 3 mismatches for the initial alignment and 2 mismatches per segment with 25 bp 
segments. Next, we will employ Cufflinks to assemble the transcripts using the RefSeq 
annotation as the guide, allowing for novel isoform discovery in each sample. Isoforms 
were ignored if the number of supporting reads was less than 30 and if the isoform fraction 
was less than 10% for the gene. Following data fragment bias correction, multi-read 
correction, and normalized by the total number of reads. The transcript assemblies for 
each sample will be merged using cuffmerge. To estimate individual samples transcript 
expressions, we will compute the transcripts’ FPKM values by rerunning Cufflinks using the 
merged assembly as the guide. The final output of this analysis step is a P x N matrix, 
where P is the number of samples and N is the number of transcripts, respectively. As the 
primary discovery in this aim is to identify genes and pathways that are differentially 
expressed in the pre-vs-early-treatment, we will summarize gene expression for individual 
sample by summing the FPKM values of multiple transcripts that represent the same gene. 
Subsequent data analyses of RNAseq will be performed on this matrix. Significant genes 
will be identified using the R package LIMMA. Significant genes will be identified using the 
lmFit, eBayes, and decide Tests functions (FDR < 0.05 and fold change > 2). The statistics 
will be moderated using empirical Bayes shrinkage (via the eBayes function), global 
multiple testing strategy, and Benjamini & Hochberg adjustment. For Gene Set Enrichment 
Analysis (GSEA), we will use the human pathways obtained from KEGG as genesets. 
Enriched pathways will be identified by running GSEA using 1000 permutations as a stand-
along java app (version 2.07). 
 
 


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D. ECOG performance scale 
 
 
 

ICF_002.pdf: 
Consent and Authorization Form
Page 1 of 16
Principal Investigator:
Tejas Patil, MD
COMIRB No:
16-2025
Version Date:
     October 20, 2020
Study Title:
ARM Study: A phase II trial to evaluate crizotinib in the 
neoadjuvant setting in non-small cell lung cancer patients with 
surgically resectable, ALK, ROS1, or MET-oncogene positive
non-small cell lung cancer
You are being asked to be in a research study.  This form provides you with information 
about the study. A member of the research team will describe this study to you and answer 
all of your questions. Please read the information below and ask questions about anything 
you do not understand before deciding whether or not to take part. 
Why is this study being done?
This study plans to learn more about non-small cell lung cancer (NSCLC) by testing blood 
and tumor tissue samples. We will be studying a chemotherapy drug called crizotinib, 
which is already used to treat certain types of NSCLC, but we are trying to learn if patients 
who are given this treatment before they have surgery (neoadjuvant) to remove their tumor 
tissue may respond better to this treatment. We will collect plasma and tumor tissue 
samples before you start the treatment with crizotinib, at the time of surgery, and after your 
surgery. Evaluation of tumor tissue early in treatment will allow us to study early cancer 
cell activity
You are being asked to be in this research study because you have been newly diagnosed 
with NSCLC with the specific gene mutations ALK, ROS1 or MET mutation that your 
doctor believes meets the requirements to be in the study. 
Crizotinib (Xalkori ®) will be called “the study drug” throughout the rest of this consent
form.
Other people in this study
Up to 260 people from your area will participate in the study. 
Up to 260 people around the country will be in the study. 
What happens if I join this study?
If you join the study, you will be asked to sign this consent form before you receive any 
study related tests or procedures. You will be given a copy to keep and the original form 
will be kept at the clinic. You can withdraw from the study at any time and without giving a 
reason. This will not affect the standard medical care you receive. 
COMIRB
APPROVED
For Use
24-Nov-2020
04-Feb-2021


Consent and Authorization Form
COMIRB 16-2025
PI:  Tejas Patil, MD
Version Date:  10.20.2020
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There are three parts to this study:
1. Before starting the study (Screening) 
2. During the Study (Treatment)
3. Completion of Study (After Treatment Follow-up)
This next section is an overview of what will be expected of you, and what you can expect 
if you take part in this study. 
Study Procedures: 
Some procedures you receive while taking part in this study are “standard care 
procedures” for treatment of your disease. Some procedures are required only for this 
study and are called “research” procedures. All procedures that will take place during 
this study are described below. The time points when these study procedures will take 
place are specified in the next section called “Study Visits”.

Informed Consent  
Before any study required procedure takes place, this informed consent 
document will be discussed with you and you will be given a copy of this 
document.

Medical and Cancer History
Before you start the study, we will record your date of birth, race, ethnicity, 
complete medical history. This history will look at the background and progress 
of your cancer and the prior therapies you have received for your disease. 

Physical Examination
A physical examination will be completed as part of your standard of care. We 
will also look at whether the study drug is affecting your body functions including 
lungs, heart, abdomen, extremities, skin, head (eyes, ears, noses, hair, etc.), 
and neurologically.

Blood samples  
These tests are sometimes referred to as safety labs so the study doctor can be 
sure it is safe for you to take part in this study and to be given the study drugs. 
o
Serum pregnancy tests will be performed in women who are able to become 
pregnant. A positive pregnancy test prior to being given the study drugs, will 
exclude you from starting or continuing to take part in the study. 
o
Complete blood count (CBC)
o
Comprehensive metabolic panel (CMP)


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o
Tumor DNA testing. The cost of this test is paid for by this study.

Tumor tissue biopsy 
When you have a biopsy a sample of your tumor tissue is removed from your body. 
Some of this tissue will undergo routine pathologic evaluation, but some tissue will 
be leftover and normally discarded. For this research, we will test some of the 
leftover tissue. The cost of this test will be paid for by this study. There will be two 
time points where we will test your tumor tissue for this research, once at the 
beginning of the study to see if you are eligible to take part in the study, and then to 
compare after surgical removal of the tumor tissue. If you had a previous biopsy we 
will ask to use some of the tumor tissue that was leftover (archived tumor tissue), or 
we will use the leftover tumor tissue from the biopsy that will be performed before 
your surgery. 

Electrocardiogram (ECG)
An ECG is a test that records the electrical activity of the heart. 
 

Positron emission tomography (PET)
A PET scan is a radiation or nuclear medicine image that will show 3-dimensional, 
color images of your body.

Brain MRI scan 
An MRI is a scan that uses radio waves and a strong magnetic field to provide 
images of internal organs and tissues.

Vital Signs 
We will take your blood pressure, heart rate, respiratory rate, body temperature and 
weight.  Height will be measured only during screening.

Performance Status  
We will assess how well you are performing your daily activities.

Other Medications
Your study doctor will let you know which other medications you can and cannot 
take while taking part in this study.  From the time you first receive the study drugs 
through 30 days after the last dose, we will record other medications you may be 
taking. 


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
Review Adverse Events
Some risks have been identified because of the disease process or through 
use of the study drugs. These are commonly called side effects and will be 
followed very closely by your doctor and the study staff. More information 
about these will be provided in the Risk section of this consent form. 
Study Visits: 
1.  SCREENING

Sign Informed Consent

Medical history and physical exam 

Performance status assessments

Review of medications

Blood draws – about 1-2 Tablespoons of blood will be drawn
o
CBC
o
CMP
o
Pregnancy test (for women of childbearing potential)
o
Tumor DNA evaluation – research 

ECG 

Molecular testing on diagnostic biopsy

PET scan

Brain MRI – if clinically indicated
2.  TREATMENT
Day 1 to Day 42

Crizotinib 250mg is taken by mouth two times per day from Day 1 to Day 
42 – research 
Day 21 (+/- 4 days)

History and physical exam 

Performance status assessments

Review of medications

Review of adverse events

Blood draws  - about 1 Tablespoon of blood will be drawn
o
CBC
o
CMP

ECG


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Version Date:  10.20.2020
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Day 42 (+/- 4 days, but before surgery)

History and physical exam

Performance status assessments

Review of medications

Review of adverse events

Blood draws - about 1 Tablespoon of blood will be drawn
o
CBC
o
CMP
o
circulating tumor DNA evaluation - research

PET scan
Day 43-49 

Surgery to remove tumor

Molecular testing of tissue – research 
3.  AFTER TREATMENT FOLLOW-UP

Standard of care visits with your physician, including routine surveillance 
scans, medical history and physical exam.

You will have the option to participate in additional blood draws for further 
circulating tumor DNA evaluation after your routine scans. This is an 
optional research procedure.
How long will I be on the study?
You will receive treatment with the study drug for 42 days before your surgery to remove 
your tumor tissue.  Any treatment you receive after your surgery will not be part of this study.  
However, we will continue to follow your progress for up to 5 years by reviewing your 
medical chart.  
What are the possible discomforts or risks?
Risks from the Study Drug – crizotinib 
As with any study drug, side effects may occur when taking this study drug. While 
taking part in this study, and being treated with the study drugs, you will be watched 
carefully for any side effects. Some side effects may go away after you stop taking 
the study drug. Some side effects can be long lasting and may never go away or 
may even lead to death. 


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Version Date:  10.20.2020
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You should talk to your study doctor about any side effects or discomfort you may 
have. The study doctor may give you some medicine that will help with some side 
effects. The study doctor may also interrupt or discontinue the study drug. 
You will be notified by your study doctor of any new side effects seen in other 
patients that occur during the time you are on the study. This may affect you 
wanting to continue in this research study. 
Based on animal studies and/or other studies with similar types of drugs, side 
effects or discomforts you may experience while in this study include:
Common Side Effects

Changed or blurry vision

Nausea

Feeling tired or fatigued

Diarrhea

Constipation

Abdominal pain

Low white blood cell count, which may increase your risk of infection

Low heart rate or longer than normal recharge of heart between beats

Dizziness

Vomiting

Loss of appetite

Swelling in arms or legs

Change in taste

Numbness or tingling of arms and legs

Elevated liver enzymes
Uncommon Side Effects

Low red blood cell count (anemia), which may make you feel tired or 
fatigued

Upset stomach or indigestion

Stomach/throat ulcers

Flu-like symptoms

Muscle spasms

Headache

Skin rash

Interstitial lung disease or pneumonitis

Liver damage


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Version Date:  10.20.2020
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Risks of Having Blood Taken
In this study we will need to get about 3 tablespoons of blood from you. We will get 
blood by putting a needle into one of your veins and letting the blood flow into a glass 
tube.  You may feel some pain when the needle goes into your vein.  A day or two later, 
you may have a small bruise where the needle went under the skin. 
Risks of having an ECG
An electrocardiogram (ECG) is a test that records the electrical activity of the heart.  
Skin irritation is rare but could occur during an ECG from the electrodes or gel that is 
used.
Risks of having a PET Scan
PET stands for positron emission tomography, which uses radiation. The machine 
detects pairs of gamma rays that are emitted indirectly by a tracer (positron-emitting 
radionuclide), which is placed in the body on a biologically active molecule. The images 
are reconstructed by computer analysis. These are not painful but if a patient is 
uncomfortable with small confined spaces or noise sensitive, they should alert their 
physician. There may be related procedures that might be uncomfortable.
Risks of Having an MRI 
In this study we will take Magnetic Resonance Images (MRI’s) of your head. The MRI 
machine uses powerful magnetic waves to take pictures inside the body. The waves 
themselves are not harmful, but they can cause metal to heat up and electronics to 
stop working. 
You should NOT have an MRI if you have metal or electronic devices inside your 
body. Heart pacemakers and insulin pumps are examples of electronic devices.
 
The MRI machine is a small round tube. It might make you uncomfortable if you do not 
like tight spaces.
The most common side effect of having an MRI is flashing lights in the eyes. This is 
caused by the magnetic waves and is not harmful. Some people also experience 
warmth and reddening of the skin. This usually goes away after a few minutes.
 
Risks of loss of confidentiality
There is a risk that people outside of the research team will see your research 
information.  We will do all that we can to protect your information, but it cannot be 
guaranteed.


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Version Date:  10.20.2020
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Risks of pregnancy and breastfeeding
Women of childbearing potential should avoid becoming pregnant while taking the 
study drug. Women of childbearing potential who are receiving the study drug, or 
partners of women of childbearing potential receiving the study drug, should use 
adequate contraceptive methods during use of the study drug and for at least 90 days 
after receiving the last dose of the study drug. 
There are no adequate and well-controlled studies in pregnant women using the study 
drug, but based on animal studies such exposure to the study drug can cause harm to 
a fetus.  It also is not known whether the study drug is excreted in breast milk, but 
many drugs are excreted in breast milk, and can cause harm to nursing infants.  If you 
are breastfeeding, you should not take part in this study.
Female participants who breastfeed or become pregnant, and male participants who 
impregnate a female partner, while taking the study drug need to tell your study doctor 
immediately so it can be reported to the study drug manufacturer. If you become 
pregnant while taking part in this study, you will need to withdraw from the study, but 
we will need to follow-up with you throughout the pregnancy and report to the study 
drug manufacturer the outcome of your pregnancy.  
The study may include risks that are unknown at this time. 
What are the possible benefits of the study?
This study is designed for the researcher to learn more about Crizotinib.  However, there is 
no guarantee that your health will improve if you join this study.  Also, there could be risks 
to being in this study.  If there are risks, these are described in the section describing the 
discomforts or risks.
Are there alternative treatments? 
There may be other ways of treating your stage IA-IIIA non-small cell lung cancer.  These 
other ways include: 

You may choose to receive treatment with another experimental therapy.

You may choose to receive treatment with another approved therapy.

You may choose to receive comfort/palliative care.

You could also choose to get no treatment at all.
You should talk to your doctor about your choices.  Make sure you understand all of your 
choices before you decide to take part in this study.  You may leave this study and still 
have these other choices available to you. 


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Version Date:  10.20.2020
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Who is paying for this study? 
This research is being conducted by Tejas Patil, MD, with funding support by Pfizer, Inc. 
who is also providing the study drug, and paying for the tumor DNA test. 
The sponsor will only pay for procedures not considered standard of care as detailed 
below.
Will I be paid for being in the study?  
You will not be paid to be in the study. 
Will I have to pay for anything?
It will not cost you anything to be in the study.
You and/or your health insurance may be billed for the costs of medical care during this 
study, if these expenses would have happened even if you were not in the study, or if your 
insurance agrees in advance to pay. If you have health insurance, the cost of these 
services will be billed to your insurance company. If your insurance does not cover these 
costs, or if you do not have insurance, these costs will be your responsibility.
Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in this 
study.  If you choose to take part, you have the right to stop at any time.  If you refuse or 
decide to withdraw later, you will not lose any benefits or rights to which you are entitled. 
If you leave this study, you will still receive your normal medical care.  The only medical 
care that you will lose is the medical care you are getting as part of this study.  You might 
be able to get that same kind of medical care outside of the study.  Ask your study doctor. 
If there are any new findings during the study that may affect whether you want to continue 
to take part, you will be told about them.


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Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the study 
doctor thinks that being in the study may cause you harm, or for any other reason. Also, 
the sponsor may stop the study at any time 
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Tejas Patil, MD 
immediately. His phone number is 720-848-9264. 
We will arrange to get you medical care if you have an injury that is caused by this research.  
However, you or your insurance company will have to pay for that care. 
Who do I call if I have questions?
The researcher carrying out this study is Tejas Patil, MD, you may ask any questions you 
have now. If you have questions, concerns, or complaints later, you may call Tejas Patil, 
MD at 720-848-9264. You will be given a copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Tejas 
Patil, MD with questions. You can also call the responsible Institutional Review Board 
(COMIRB). You can call them at 303-724-1055. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov/. This Web 
site will not include information that can identify you. You can search this Web site at any 
time.
Optional Study Procedures
Here are the optional parts of this study. Remember, no matter what you decide to do 
about these optional parts of the study, you may still take part in the main study. If 
you decide to withdraw your consent for the optional parts, you can continue to take part in 
the main study, unless you withdraw your consent for the main study as well. 
Following each optional procedure is a statement asking if you want to participate in the 
optional procedure. Please read the statement and think about your choice. After reading 
the sentence, please check “Yes” or “No” and initial next to your choice. If you have any 
questions, please talk to your doctor or nurse.
1. Optional Consent for Additional Blood Draws
As a participant at the University of Colorado, you are being asked if you would like 
to participate in optional blood draws during the follow-up phase of this study. If 


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Version Date:  10.20.2020
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you agree to participate, you will have blood drawn after each routine scan during 
the follow-up phase. Your sample will be analyzed for circulating tumor DNA. This is 
a research procedure and is paid for by the study.
I give my permission additional blood draws after each routine follow-up 
scan.
   Yes
   No
_________Initials
2. Optional Consent for Data and Specimen Banking for Future Research
Dr. Patil would like to keep some of the data, blood and tissue that is taken during 
the study but is not used for other tests. If you agree, the data and samples will be 
kept and may be used in future research to learn more about non-small cell lung 
cancer. The research that is done with your data and samples is not designed to 
specifically help you. It might help people who have non-small cell lung cancer and 
other diseases in the future. Reports about research done with your data and 
samples will not be given to you or your doctor. These reports will not be put in your 
health records. The research using your data and samples will not affect your care.
The choice to let Dr. Patil keep the data and samples for future research is up to 
you. No matter what you decide to do, it will not affect the care that you will receive 
as part of the study. If you decide now that your data and samples can be kept for 
research, you can change your mind at any time and contact your study doctor to let 
him or her know that you do not want Dr. Patil to use your data and samples any 
longer, and they will no longer be used for research. Otherwise, they may be kept 
until they are used up, or until Dr. Patil decides to destroy them. 
When your data and samples are given to other researchers in the future, Dr. Patil 
will not give them your name, address, phone number or any other information that 
will let the researchers know who you are. 
Sometimes data and samples are used for genetic research (about diseases that 
are passed on in families). Even if your data and samples are used for this kind of 
research, the results will not be told to you and will not be put in your health records. 
Your data and samples will only be used for research and will not be sold. The 
research done with your data and samples may help to develop new products in the 
future, but there is no plan for you to be paid.
The possible benefits of research from your data and samples include learning 
more about what causes non-small cell lung cancer and other diseases, how to 
prevent them and how to treat them. The greatest risk to you is the release of your 
private information. Dr. Patil will protect your records so that your name, address 


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Version Date:  10.20.2020
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and phone number will be kept private. The chance that this information will be 
given to someone else is very small. There will be no cost to you for any data or 
sample collection and storage by Dr. Patil.
Please read each sentence below and think about your choice. After reading each 
sentence, circle “yes” or “no.” If you have questions, please talk to your doctor or 
nurse. Remember, no matter what you decide to do about the storage and future 
use of your data and samples, you may still take part in the study.
I give my permission for my data, blood and tissue to be stored in a central tissue 
bank at University of Colorado Biorepository for future use by the study 
investigators:
1. I give my permissions for my data, blood and tissue samples to be kept by 
Dr. Patil for use in future research to learn more about how to prevent, 
detect, or treat lung cancer.
   Yes
   No
_________Initials
2. I give my permissions for my data, blood and tissue samples to be used for 
research about other health problems (for example: causes of heart disease, 
osteoporosis, diabetes).
   Yes
   No
_________Initials
3. I give my permission for my archived tumor tissue, if available, to be used for 
future research.
   Yes
   No
_________Initials
4. I give my permission for my study doctor (or someone he or she chooses) to 
contact me in the future to ask me to take part in more research.
   Yes
   No
_________Initials
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to protect 
information about you.  Federal and state laws including the Health Insurance Portability 
and Accountability Act (HIPAA) also protect your privacy.   This part of the consent form 
tells you what information about you may be collected in this study and who might see or 
use it.  


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Version Date:  10.20.2020
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The institutions involved in this study include: 
University of Colorado Denver
University of Colorado Hospital
We cannot do this study without your permission to see, use and give out your information.  
You do not have to give us this permission.  If you do not, then you may not join this study.  
We will see, use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside the UCD and its affiliate hospitals 
may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information 
but confidentiality cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Principal Investigator (PI), at the name and address listed below.  If you do cancel your 
permission to use and disclose your information, your part in this study will end and no 
further information about you will be collected.  Your cancellation would not affect 
information already collected in this study.  
Tejas Patil, MD
University of Colorado Denver, Anschutz Medical Campus
Division of Medical Oncology
Mail Stop 8113 HSC
12631 E. 17th Avenue
Academic Office One (AO1), Room 8515
Aurora, CO   80045
Both the research records that identify you and the consent form signed by you may be 
looked at by others who have a legal right to see that information, such as:
  

Federal offices such as the Food and Drug Administration (FDA) and the Office of 
Human Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

Pfizer, Inc. who is the company providing funding support and study drug Crizotinib 
for this research study.

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow all 
of the rules for research.


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We might talk about this research study at meetings.  We might also print the results of this 
research study in relevant journals, but we will always keep the names of the research 
subjects, like you, private. 
You have the right to request access to your personal health information from the 
Investigator. 
The investigator (or staff acting on behalf of the investigator) will use your 
information for the research outlined in this consent form. They will also make all or 
some of the following health information about you collected in this study available 
to:   Guardant Health (the company analyzing the tumor DNA in your blood), and other 
participating sites in this study.
Some of the research procedures involve genetic testing or the use of your genetic 
information.  Your genetic information will not be released to others.
  
Genetic Information Nondiscrimination Act (GINA)
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. This law generally will protect 
you in the following ways: 

Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 

Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 

Employers with 15 or more employees may not use your genetic information that we 
get from this research when making a decision to hire, promote, or fire you or when 
setting the terms of your employment. 
All health insurance companies and group health plans must follow this law by May 21, 
2010. All employers with 15 or more employees must follow this law as of November 21, 
2009. 
Be aware that this new Federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance.
Information about you that will be seen, collected, used and disclosed in this study: 

Name and Demographic Information (age, sex, ethnicity, address, phone number, 
etc.)


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
Portions of your previous and current Medical Records that are relevant to this 
study, including but not limited to Diagnosis(es), History and Physical, laboratory or 
tissue studies, radiology studies, procedure results

Research Visit and Research Test records

Tissue samples and the data with the samples. 

Billing or financial information
What happens to Data, Tissue, Blood and Specimens that are collected in this 
study? 
Scientists at the University of Colorado Denver and the hospitals involved in this study 
work to find the causes and cures of disease.  The data, tissue, blood and specimens 
collected from you during this study are important to this study and to future research.  If 
you join this study:

The data, tissue, blood, or other specimens given by you to the investigators for 
this research no longer belong to you.  

Both the investigators and any sponsor of this research may study your data, 
tissue, blood, or other specimens collected from you.

If data, tissue, blood, or other specimens are in a form that identifies you, UCD 
or the hospitals involved in this study may use them for future research only with 
your consent or Institutional Review Board (IRB) approval.

Any product or idea created by the researchers working on this study will not 
belong to you.

There is no plan for you to receive any financial benefit from the creation, use or 
sale of such a product or idea. 
HIPAA Authorization for Optional Additional Study Procedures 
In this form, you were given the option to agree to additional, optional research 
procedures.  You must also give us your permission, under HIPAA rules, to use and 
disclose the information collected from these optional procedures, as described above.  
Some of these optional procedures may involve genetic testing or the use of your genetic 
information.  Your genetic information will not be released to others.  
If you decline to give us permission to use and disclose your information, you cannot take 
part in these optional procedures, but you can still participate in the main study.  Please 
initial next to your choice:
_____ I give permission for my information, from the optional procedures I have agreed 
to above, to be used and disclosed as described in this section.


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_____ I do not give permission for my information for any optional procedures to be 
used and disclosed; I understand that I will not participate in any optional 
procedures.
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me.  I understand the possible risks 
and benefits of this study.  I understand and authorize the access, use and disclosure of 
my information as stated in this form.  I know that being in this study is voluntary.  I choose 
to be in this study: I will get a signed and dated copy of this consent form.
Signature: 
Date: 
Print Name: 
Consent form explained by: 
Date: 
Print Name: 
A signature line for a witness is required for consent of
non-reading subjects and consent using a short form.
Witness Signature: 
Date: 
Witness Print Name:  
Witness of Signature

Witness of consent process