ALCMI-011: Study of Plasma Next Generation Sequencing for Assessment, Characterization, Evaluation of Patients With ALK Resistance (SPACEWALK)
Conditions: Non-Small Cell Lung Cancer
Sponsor: Addario Lung Cancer Medical Institute

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
1 of 33 
Version: v1.7 
CONFIDENTIAL 
 
DF/HCC Protocol # 
17-683  
STUDY NUMBER 
ALCMI-011 
STUDY TITLE 
Title:  Study of Plasma Next Generation Sequencing for Remote 
Assessment, Characterization, Evaluation of Patients With ALK 
Drug Resistance (SPACEWALK). 
PROTOCOL V1.0 (ORIGINAL) DATE 
PROTOCOL v1.1 DATE 
PROTOCOL v1.2 DATE 
PROTOCOL v1.3 DATE 
PROTOCOL V1.4 DATE 
PROTOCOL V1.5 DATE 
PROTOCOL V1.6 DATE 
PROTOCOL V1.7 DATE 
17NOV2017 
28NOV2018 
13FEB2019 
18MAR2019 
12SEP2019 
19JUN2020 
19JAN2021 
15APR2021 
CURRENT VERSION 
V1.7 
COORDINATING CENTER 
Dana-Farber Cancer Institute 
SPONSOR 
Addario Lung Cancer Medical Institute (ALCMI) 
1100 Industrial Road, Suite 1 
San Carlos, California 94070 
PRINCIPAL INVESTIGATOR 
Mark Awad, MD, PhD 
Lowe Center for Thoracic Oncology 
Dana-Farber Cancer Institute 
450 Brookline Ave.  
Boston, Massachusetts 02215 
Phone: (617) 632-3468  
Fax: (617) 632-5786  
Mark_Awad@dfci.harvard.edu 
STUDY STATISTICIAN 
Suzanne Dahlberg, PhD 
Biostatistics and Computational Biology 
Dana-Farber Cancer Institute 
Phone: (617) 632-5580 
Email: dahlberg@jimmy.harvard.edu  
STUDY PROJECT MANAGER 
Addario Lung Cancer Medical Institute (ALCMI) 
Allison Harper, PharmD, RPh 
Phone: 704-996-6579 
Email: aharper@alcmi.net 
 
 
 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
2 of 33 
Version: v1.7 
CONFIDENTIAL 
 
1 TABLE OF CONTENTS 
2 
Protocol Revisions .................................................................................................................................... 5 
3 
Definitions ................................................................................................................................................ 6 
4 
Abstract .................................................................................................................................................... 7 
4.1 
Study Schema ................................................................................................................................... 8 
5 
Background & Rationale .......................................................................................................................... 8 
5.1 
ALK TKIs ............................................................................................................................................ 8 
5.2 
Resistance mechanisms to ALK TKIs ................................................................................................ 9 
5.3 
Plasma next-generation gene sequencing (NGS) ............................................................................ 9 
5.4 
Remote consent & enrollment ...................................................................................................... 10 
5.5 
Plasma response ............................................................................................................................ 11 
6 
Collaborators .......................................................................................................................................... 12 
6.1 
Addario Lung Cancer Medical Institute ......................................................................................... 12 
6.1.1 
ALCMI Biorepository .............................................................................................................. 13 
6.1.2 
ALCMI Data Repository .......................................................................................................... 13 
6.2 
Resolution Biosciences .................................................................................................................. 14 
6.3 
Study Roles of Supporting Laboratories & Service Providers ....................................................... 15 
7 
Objectives ............................................................................................................................................... 15 
7.1 
Primary Objectives ......................................................................................................................... 15 
7.2 
Secondary Objectives .................................................................................................................... 15 
8 
Study Design ........................................................................................................................................... 16 
8.1 
Remote Consent & Plasma NGS .................................................................................................... 16 
8.2 
Correlative Studies ......................................................................................................................... 16 
9 
Study Population .................................................................................................................................... 17 
9.1 
Inclusion Criteria ............................................................................................................................ 17 
9.2 
Exclusion Criteria ........................................................................................................................... 17 
9.3 
Inclusion of Women & Minorities ................................................................................................. 17 
10 
Study Procedures ............................................................................................................................... 17 
10.1 
Study Website ................................................................................................................................ 17 
10.2 
Informed Consent Process ............................................................................................................. 17 
10.2.1 
Study Hotline ......................................................................................................................... 18 
10.2.2 
Intake Form & Medical Record Release Form ....................................................................... 19 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
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Version: v1.7 
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10.2.3 
Subject Unique Identification Process .................................................................................. 19 
10.2.4 
Confirmation of Enrollment ................................................................................................... 19 
10.2.5 
California-based Subjects ...................................................................................................... 19 
10.3 
Baseline Plasma Collection ............................................................................................................ 19 
10.3.1 
Baseline Plasma NGS ............................................................................................................. 20 
10.4 
Study Questionnaire ...................................................................................................................... 20 
10.5 
Clinical Data Collection .................................................................................................................. 20 
10.6 
Radiology Image Collection & Analysis .......................................................................................... 21 
10.7 
Archival Tissue Collection .............................................................................................................. 21 
10.8 
Follow-up ....................................................................................................................................... 21 
10.9 
Optional Response Plasma Collection ........................................................................................... 21 
10.10 
Optional Progression Plasma Collection ................................................................................... 22 
10.11 
Study Calendar ........................................................................................................................... 23 
11 
Compensation .................................................................................................................................... 24 
12 
Statistical Considerations ................................................................................................................... 24 
12.1 
Study Design & Endpoints ............................................................................................................. 24 
12.2 
Sample Size, Accrual Rate & Study Duration ................................................................................. 25 
13 
Data Collection and Analysis .............................................................................................................. 26 
13.1 
Case Report Forms ......................................................................................................................... 26 
13.2 
Source Documents ......................................................................................................................... 26 
13.3 
Monitoring ..................................................................................................................................... 26 
13.4 
Interim Analysis Plan ...................................................................................................................... 27 
13.5 
Data & Safety Monitoring .............................................................................................................. 27 
13.6 
Publication Plan ............................................................................................................................. 27 
14 
Study Management ........................................................................................................................... 27 
14.1 
Study Responsibilities .................................................................................................................... 27 
14.2 
Regulatory ...................................................................................................................................... 28 
14.2.1 
IRB Approval ........................................................................................................................... 28 
14.2.2 
Recruitment Material & Subject Correspondence ................................................................. 28 
14.2.3 
Study Initiation ....................................................................................................................... 29 
14.2.4 
Protocol Deviations, Event & Amendment Reporting ........................................................... 29 
14.2.5 
Continuing Review and Final Report ...................................................................................... 29 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
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Version: v1.7 
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14.2.6 
Patient Safety ......................................................................................................................... 29 
14.2.7 
Study Withdrawal Process ..................................................................................................... 29 
14.2.8 
Benefits of Research Participation ......................................................................................... 30 
14.2.9 
Risks Associated with Participation ....................................................................................... 30 
14.2.10 
Regulatory Binder .............................................................................................................. 30 
14.2.11 
Data Privacy and Safety Monitoring ................................................................................. 30 
14.2.12 
Record Retention ............................................................................................................... 31 
15 
Appendices ......................................................................................................................................... 31 
A. 
Introduction Letter ........................................................................................................................ 31 
16 
References ......................................................................................................................................... 32 
 
 
 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
5 of 33 
Version: v1.7 
CONFIDENTIAL 
 
2 
PROTOCOL REVISIONS 
Amendment Number 
Approval Date 
Modification 
Amendment #1 
06SEP2018 
Reflects a change in study staff.   
No modifications to the protocol or consent form. 
Amendment #2 
05OCT2018 
Congruency review for NIH grants.   
No modifications to the protocol or consent form. 
Amendment #3 
18DEC2018 
Created protocol v1.1 dated 28NOV2018 
• ALCMI’s biorepository location modified 
• ALCMI’s data repository vendor modified 
• Remote informed consent form process modifications 
• Minor modifications to the subject’s experience 
• Informed consent form modifications 
Amendment #4 
20DEC2018 
Study opened to enrollment; funding resolved.  
No modifications to the protocol.   
Consent form modified to reflect date study open to enrollment.   
Amendment #5 
19FEB2019 
Minor modifications to the Blood Collection & Handling Instructions.   
No modifications to the protocol or consent form. 
Amendment #6 
19FEB2019 
Created protocol v1.2 dated 13FEB2019. 
• Reflects Administrative Clarification 1.02112019 – change from 
QConsent to OpenMedNet online consent platform.   
Amendment #7 
18MAR2019 
Modifications to consent form.   
No modifications to the protocol. 
Amendment #8 
25APR2019 
Created protocol v1.3 dated 18MAR2019. 
• Administrative Clarification 2.03072019 – nurse hotline. 
Amendment #9 
15MAY2019 
Administrative Clarification 3.04292019 – inclusion criteria clarification.  
No modifications to protocol or consent form.   
Amendment #10 
26SEP2019 
Marketing material – Webpage video  
Amendment #11 
02NOV2019 
Created protocol v1.4 dated 12SEP2019 
• Protocol modified to reflect all prior amendments 
• Protocol Revisions section added 
• Follow-Up language modified 
• Archival tissue collection added 
• Document formatting corrected 
Amendment #12 
03AUG2020 
Created protocol v1.5 dated 19JUN2020 
• 
Change of PI 
• 
Administrative Clarification v1.06192020 acknowledging change 
of PI 
Amendment #13 
26JAN2021 
Created protocol v1.6 dated 21JAN2021 
• 
Modified online consent platform language as result of vendor 
change from OpenMedNet to RedCap  
• 
Modified hotline language given change in personnel 
• 
Modified language to allow for remote monitoring visits 
Amendment #14 
Pending 
Created protocol v1.7 dated 03FEB2021 
• 
Modified schematic to match follow-up language which was 
approved in Protocol v1.4 dated 12 SEP2019 (Section 10.11, 
Study Calendar) 
• 
Added visit windows to each follow-up visit (Section 10.11, 
Study Calendar) 
 
 
 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
6 of 33 
Version: v1.7 
CONFIDENTIAL 
 
3 
DEFINITIONS 
Investigator: 
 
Individual responsible for the study at the site. 
Site: 
 
 
Tertiary center where study is performed by the Investigator. 
Study Manager:  
Qualified and trained collaborator acting as the point of contact. 
 
Abbreviation 
Definition 
ALCF 
Addario Lung Cancer Foundation 
ALCMI 
Addario Lung Cancer Medicine Institute 
ALK 
Anaplastic Lymphoma Kinase 
cfDNA 
Circulating cell-free deoxyribonucleic acid 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
CRF 
Case Report Form 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CTMS 
Clinical trials management system 
DF/HCC 
Dana-Farber/Harvard Cancer Center 
DNA 
Deoxyribonucleic acid 
DSMP 
Data Safety Monitoring Plan 
EGFR 
Epidermal growth factor receptor 
FDA 
US Food and Drug Administration  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GoYLC 
Genomics of Young Lung Cancer study 
HIPAA 
Health Insurance Portability and Accountability Act 
INHERIT 
Investigating Hereditary Risk from T790M study 
IRB 
Institutional Review Board 
m 
Month 
MCA 
Master Collaboration Agreement 
NGS 
Next generation sequencing 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
PFS 
Progression-free survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
RR 
Response rates 
SLB 
Scientific Leadership Board 
SOP 
Standard Operating Procedures 
TKI 
Tyrosine-kinase inhibitor 
TTD 
Time to treatment discontinuation 
US 
United States 
 
 
 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
7 of 33 
Version: v1.7 
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4 
ABSTRACT 
Patients with advanced anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) gain 
tremendous benefit from treatment with ALK-targeted tyrosine kinase inhibitors (TKI)1. Crizotinib, the first 
ALK TKI entering the clinic, has remained a standard of care for the last six years. Resistant mechanisms 
arising after crizotinib failure include secondary ALK resistance mutations, activation of bypass track 
pathways and drug-specific pharmacodynamic issues such as low blood brain barrier penetration.  
More potent next generation ALK TKIs such as ceritinib, alectinib, brigatinib and lorlatinib are under 
development, with some currently commercially available in parts of the world. With the expected median 
overall survival (OS) for metastatic ALK positive lung cancer patients now over two years and the expected 
widespread availability of several new ALK TKIs, most of those patients will receive multiple lines of different 
ALK inhibitors. When given after progression on crizotinib, those next generation agents yield response 
rates (RR) of 40-60% and progression free survival (PFS) times around 6-10 months(m)2,3. But little is known 
about the resistance mechanisms arising after failure to a next generation ALK TKI or about crossed 
resistance between different next generation ALK TKIs.  
The largest study to date addressing ALK TKI resistance mechanisms was a single-center study of tumor 
specimens from 83 patients, but only 48 of them had resistance after treatment with a next generation ALK 
TKI4. This study found that ALK resistance mutations were more common after progression on next 
generation ALK TKIs than after progression on crizotinib (56% vs 20%, respectively). A wide range of 
different ALK resistance mutations was identified and while numbers were small, results suggested a link 
between different ALK TKIs and specific resistance mutations. Furthermore, this and other emerging data 
also indicates that drug resistance mediated by some secondary ALK mutations can be overcome by using 
specific alternate ALK targeted therapies5.  
Tumor genotyping is now used in lung cancer patients with advanced disease and adenocarcinoma 
histology to decide the best first-line treatment. For those lung cancer patients whose tumor harbor an 
EGFR mutation or an ALK rearrangement treatment with specific TKIs is the best treatment option. 
Additionally, further tumor genotyping after tumor resistance has also demonstrated to improve outcomes 
in TKI-resistant EGFR-mutant NSCLC patients. The secondary EGFR T790M mutation accounts for resistance 
in 50% of the patients with EGFR-mutant lung cancer and tumor progression while on a first-generation 
EGFR TKI6. In those T790M positive patients, continuing EGFR inhibition with osimertinib, a third-generation 
EGFR TKI, has demonstrated to be superior to chemotherapy7. Until recently sequential tumor genotyping 
required patients to undergo new invasive procedures. With the availability of plasma-based genotyping 
technologies it is now feasible to characterize tumor genomics in cancer patients by analyzing the tumor 
DNA present in patients’ blood8. Circulating tumor DNA found among patients’ circulating free DNA (cfDNA) 
is shed into the bloodstream from lysed tumor cells. In EGFR-mutant NSCLC patients and resistance to first-
generation EGFR TKI the detection of the secondary EGFR T790M mutation using a plasma-based assay has 
demonstrated to be as effective as genotyping from tumor specimens7. Additionally, some plasma-based 
next-generation sequencing (NGS) platforms are now able to test a range of tumor mutations within a 
single analysis. These NGS assays are technically validated and clinically available, but are often not being 
studied in a systematic way.  

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
8 of 33 
Version: v1.7 
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In the present study, we plan to investigate resistance mechanisms arising in ALK-positive NSCLC patients 
after progression while on a next generation ALK TKI using a plasma-based NGS platform. We will monitor 
the next treatment line received by those patients to assess the benefit derived from immediate access to 
subsequent lines of therapy based on the specific genomic profile identified by baseline plasma NGS. We 
plan to use a commercially available, CLIA certified, plasma NGS platform to offer noninvasive testing of 
the cfDNA to characterize the resistant tumor profile. Plasma NGS results will be returned to subjects and 
their provider to inform of the tumor genomics and possible sensitivities of any detected resistance 
mutations to available ALK TKIs.  
Because it is now possible for patients to send plasma samples directly to central laboratories for NGS 
analysis, we will leverage a remote consent and participation approach to open enrollment to all 
nationwide patients with metastatic ALK-positive NSCLC. Our overarching hypothesis is that we can conduct 
a remote consent study using plasma NGS to characterize ALK resistance mechanisms arising at progression 
to a next-generation ALK TKIs, and predict the chance of response to different ALK TKIs according to the 
plasma NGS results. 
4.1 STUDY SCHEMA 
5 
BACKGROUND & RATIONALE 
5.1 ALK TKIS 
ALK-rearrangements are the second most common targetable genotype among patients with non-small 
cell lung cancer. Patients with advanced ALK-positive NSCLC gain tremendous benefit from treatment with 
ALK TKI’s1. Crizotinib, the first ALK TKI entering the clinic, has remained as the preferred first line treatment 
option for the last six years. When compared with a standard first line platinum-based chemotherapy, 
crizotinib yielded superior RR and PFS (74% vs 45% and 10.9 m vs 7.0 m, respectively)9. New potent next-
generation ALK TKIs such as ceritinib, alectinib, brigatinib or lorlatinib are under development, with some 
being commercially available in parts of the world. When given after progression on crizotinib, these second 
generation agents yield RR of 40-60% and PFS times around 6-10 m2,3. In the only available Phase III trial 
using chemotherapy or a next generation ALK TKI (ceritinib) after progression to crizotinib and 
Consent: 
 
 
Subject 
consents 
remotely 
 
 
 
 
Screening: 
Subject 
provides key 
medical 
records; 
reviewed to 
confirm 
advanced 
ALK + NSCLC 
& systemic 
progression 
on next-gen 
ALK TKI 
Plasma 
NGS:  
 
NGS of ALK 
and related 
genes in CLIA 
laboratory 
 
 
 
Enrollment, 
blood 
collection: 
(1) Kit sent 
directly to 
subject 
(2) blood 
draw locally 
and shipped 
directly to 
lab 
 
Follow-up: 
 
 
CRC follows 
treatment 
decisions and 
outcomes 
(record 
review & 
direct 
contact with 
subject)  
 
Result 
reporting:  
 
Report with 
results 
(including TKI 
sensitivity) 
sent to 
subject, 
treating MD 
& study team 
 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
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Version: v1.7 
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chemotherapy, ceritinib demonstrated that maintained ALK inhibition was superior to a standard second 
line chemotherapy (docetaxel or pemetrexed) in overall RR (39% vs 6.9%) and PFS (5.4months vs 
1.6months)10. With the average expected median OS now beyond 2 years for metastatic ALK-positive NSCLC 
patients, it is expected that most patients will receive several lines of therapy with different ALK TKIs.  
5.2 RESISTANCE MECHANISMS TO ALK TKIS 
Despite initial durable responses to ALK TKIs the emergence of drug resistance is inevitable. Some 
potential mechanisms of resistance to crizotinib are as follows: ALK dominant resistance, (such as 
secondary mutations), activation of bypass signaling pathways (including EGFR, KRAS, KIT, MET, and IGF-
1R) and some crizotinib specific pharmacodynamics providing low central nervous system (CNS) exposure 
11,12,13. The use of next generation ALK TKIs has demonstrated activity in this setting, probably due to their 
activity against some of the ALK resistance mutations and/or an optimal CNS exposure.  But again, it is 
known that those patients ultimately acquire resistance to those next generation ALK inhibitors. The 
largest study to date addressing resistance mechanisms to new ALK TKIs was a single-center study of tumor 
specimens from 83 patients, but only 48 of them had resistance to a next generation ALK TKI4. This study 
found that ALK resistance mutations were more common after progression on next-generation ALK TKIs 
than on progression to crizotinib (56% vs 20%, respectively). A myriad of different resistant mutations was 
identified and while numbers were small, a link between different ALK TKIs and specific resistance 
mutations was suggested. Furthermore, preclinical data suggests that drug resistance mediated by some 
ALK resistant mutations can be overcome by using specific alternate ALK targeted therapies. Importantly, 
this kind of molecularly-guided resistance therapy is now standard in EGFR-mutant NSCLC, where 
osimertinib is used to overcome TKI resistance mediated by the resistant mutation EGFR T790M14.  
5.3 PLASMA NEXT-GENERATION GENE SEQUENCING (NGS) 
Biopsies are the standard method for diagnosis of cancer, allowing the histological definition and molecular 
characterization of the disease.1 Nevertheless, patients often have limited tissue for molecular studies, 
particularly when the diagnosis is obtained from fine needle aspiration. Furthermore, the information 
obtained from a single biopsy provides only a limited view of a tumor, preventing an evaluation of its 
heterogeneity. Apoptotic or necrotic cancer cells in the tumor including metastatic sites as well as 
circulating tumor cells, released tumor DNA into the blood circulation as part of the total cfDNA. Therefore, 
in cancer patients cfDNA carries tumor-related gene abnormalities relevant for tumor development, 
progression, and resistance to therapy. For that reason, cfDNA in the plasma or serum could be used as a 
“liquid biopsy,” capable of providing the genetic landscape of all tumor lesions shedding DNA into the blood 
circulation. Since tumors continue to evolve during the course of the disease, acquiring new mutations that 
may be associated with resistance to therapy, cfDNA could be used to track for resistance mechanisms 
avoiding repeated invasive biopsies. Several studies have now suggested that multiplexed genotyping 
assays like plasma NGS can detect the mutations present in a patient’s cancer from the cfDNA present in 
plasma allowing the characterization of multiple tumor mutations in one single test15,16,17,18.Another 
potential advantage of cfDNA is the monitoring of the disease. Because cfDNA is mostly of germline origin 
from ruptured benign cells, tumor-derived mutations are inherently present at a very low prevalence. The 
total amount of tumoral cfDNA present in plasma is also related to the extension of the tumor8, with those 
patients with advanced disease and systemic progression carrying a higher plasma cfDNA load. 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
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Version: v1.7 
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In lung cancer patients with acquired resistance to EGFR targeted therapies liquid biopsy for tumor 
genotyping has proven to be an invaluable biomarker for identifying subsets of patients with benefit from 
sustained alternative EGFR inhibition. Lung cancer patients harboring EGFR mutations treated with gefitinib 
or erlotinib and who develop a secondary EGFR T790M resistance mutation have been shown to benefit 
more from treatment with the third-generation EGFR TKI osimertinib than with chemotherapy14. In that 
study, EGFR T790M mutations identified in biopsies or in plasma rendered similar outcomes.  
Overall, the plasma NGS assay from Resolution Bioscience used in the present study has demonstrated a 
high sensitivity and specificity, 77% and 100% respectively, when compared to other widely used plasma 
tests19. For the purposes of the present study sample estimation we will consider a conservative sensitivity 
of 70% for the NGS assay, meaning that 30% of patients harboring an ALK resistance mutation will test 
negative with our sensitivity assumption. Here, the ability of the plasma NGS to detect the presence of the 
original ALK rearrangement will be used as a quality control. Patients without a secondary ALK resistance 
mutation by plasma NGS but with a detected ALK rearrangement will be considered a true negative. Those 
without an ALK rearrangement identified by plasma NGS assay will be considered unevaluable for the 
primary purposes of the present study even if an ALK resistance mutation is identified. Additionally, plasma 
NGS can provide information from a wide range of genes that can elucidate off target resistance 
mechanisms such as p53, KRAS, PI3K, IGFR or MET. That genomic information can be obtained within the 
same plasma test and an exploratory analysis on these genomic alterations is planned.  
5.4 REMOTE CONSENT & ENROLLMENT 
When studying resistance mechanisms arising in ALK positive lung cancer patients upon progression on ALK 
inhibitors, we are limited not only by the small amount of tumor tissue usually available for genomic testing 
but also by the tiny number of lung cancer patients harboring an ALK rearrangement, only a 4-7% of the 
total lung cancer population. To overcome this limitation, we plan to leverage a remote consent and 
participation approach to allow every metastatic ALK positive NSCLC patient across the nation to enroll in 
this study. The web-based consent form utilized will allow participants to be directed for help and ask 
questions during the consent process. Study coordinators will receive a notification and respond to the 
questions in a timely manner. By using a web-based remote consent process every ALK positive NSCLC 
patient living in the Continental US (including Alaska, Hawaii and US Territories), with disease progression 
while on a next generation ALK TKI will be considered a potential candidate.  
Our group (DFCI and ALCMI) has previous experience with a remote consent approach both web and paper-
based. In the Genomics of Young Lung Cancer study (GoYLC), DFCI co-led a web-based remote participation 
study for patients under the age of 40 diagnosed with lung cancer in the Investigating Hereditary Risk from 
T790M (INHERIT) study, DFCI led a paper-based remote consent process for patients and subjects harboring 
germline T790M mutation.  Those two populations, patients younger than 40 years old at diagnosis and 
those harboring a germline T790M, are extremely uncommon conditions20. However, by using a remote 
consent and participation approach, 136 patients over 36 months and 121 subjects over 60 months were 
included in the GOYL and INHERIT studies, respectively.  20. If we consider that for example, germline T790M 
is present in around 1/1.000 lung cancers the accrual rate achieved in INHERIT study underlines the 
incredible power of remote participation studies to study uncommon populations in a timely manner. By 
using the same approach to study ALK TKI resistance in ALK-positive lung cancer, a more prevalent condition 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
11 of 33 
Version: v1.7 
CONFIDENTIAL 
 
found in 3-5% of lung cancers, we consider we will be easily able to accrue at least 300 patients over 2 
years.  
Eligible participants who receive care at DFCI and are identified using 02-180, 17-000, or other thoracic 
oncology protocols will be referred to the study website to complete the enrollment process using the 
electronic consent form rather than using a paper version in clinic.  
5.5 PLASMA RESPONSE 
Plasma 
response 
can 
also 
be 
assessed 
quantitatively through serial measurement of 
plasma genotyping. This phenomenon has been 
better studied in patients with advanced EGFR-
mutant NSCLC. For example, a translational 
analysis assessing EGFR mutant copies in plasma 
ctDNA was done within the FASTACT-2 study. 
This was a randomized, double-blind, Phase III 
study of intercalated erlotinib or placebo with 
chemotherapy 
followed 
by 
maintenance 
erlotinib or placebo in previously untreated 
advanced NSCLC patients21 
 
In the subset of patients with EGFR mutations 
there was a strong correlation between the 
dynamics of EGFR mutations detected in cfDNA 
and the radiologic assessment performed at 
cycle 3 and at progression (Figure 1). The same 
approach is now feasible for ALK mutations with 
current available plasma NGS assays and could 
be now done in ALK positive NSCLC patients22. 
Furthermore, studies of plasma genotyping 
performed by Sacher and colleagues and as part 
of the AURA trial support that decreases in EGFR 
mutant clones in plasma ctDNA correlate with  
higher tumor responses while persistence or 
increase correlate with treatment failure (Figure 
2).23, 24  
Those changes can be found in plasma early after treatment initiation and before the first tumor 
assessment usually done after 6-8 weeks on treatment. In ALK-mutated lung cancers, we expect to observe 
a similar phenomenon in which levels of ALK mutant clones will decrease in lung cancers exhibiting higher 
tumor responses. 
 
Figure 1. Dynamic change in EGFR mutant cfDNA at baseline, cycle 3, and 
progression (PD). GC+E, erlotinib plus chemotherapy; GC+P, placebo plus 
chemotherapy. aCopy/mL 0.1 were undetectable21.  
Figure 2. PFS based on clearance or detection of EGFR mutations in 
plasma samples taken A) 3 weeks and B) 6 weeks post initiation of 
osimertinib. 23 

 DF/HCC Protocol #: [17-683] 
Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
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6 
COLLABORATORS 
6.1 ADDARIO LUNG CANCER MEDICAL INSTITUTE  
The Addario Lung Cancer Medical Institute (ALCMI, voiced as "Alchemy") was founded by advanced stage 
lung cancer survivor Bonnie Addario in 2008 as a 501(c) (3) non-profit organization.  Working in tandem 
with its "partner" foundation the Bonnie J. Addario Lung Cancer Foundation (ALCF), ALCMI and ALCF 
contribute resources and join together to power collaborative, patient-centric initiatives like this trial. 
ALCMI does not serve the role of a traditional advocacy organization (education, awareness, grant making-
-these are functions that ALCF takes on, plus much more) but instead is focused on patient-centric research 
advancements, directly facilitating and driving initiatives in genetic (molecular) testing, therapeutic 
discoveries, targeted treatments and early detection.  
ALCMI has offices in California and biorepositories in California and Massachusetts, along with mature data 
banks and study management systems.  ALCMI has built a one-of-a-kind lung cancer research consortium 
currently comprised of 24+ member institutions in the US, UK, and Europe, all working together as a team 
to catalyze and accelerate discovery, development and delivery of new, more effective lung cancer 
treatment options.  
To bring form to this consortium, ALCMI developed and executed a Master Collaboration Agreement 
(identical) among all Member Institutions, governing centralized study development, contracting and 
budgeting, control of biospecimens and data, publication of results, intellectual property, indemnification 
and much more.  Member Institutions are motivated to join the ALCMI consortium as it's a trusted, patient-
founded/-focused Site Management Organization ensuring both scientific and patient advancements.  
Investigators at ALCMI member institutions often contribute their time and effort to advance our 
investigator-initiated, collaborative research, and similarly indirect costs are capped in order to ensure that 
our philanthropic-sourced funding are maximally employed.  ALCMI develops the centralized systems and 
study management, while each of the participating Member Institutions may contribute their clinical and 
scientific resources for specific initiatives. 
By providing access to critical masses of patient stakeholders, academic, community and industry 
researchers, ALCMI is making progress towards its goal of transforming lung cancer into a chronically 
managed disease by 2023. 
ALCMI COLLABORATING INSTITUTIONS 
➢ Alta Bates Summit Medical Center (Oakland, CA) 
➢ Boca Raton Regional Hospital (Boca Raton, FL) 
➢ Catalan Institute of Oncology (Barcelona, Spain) 
➢ Dana-Farber Cancer Institute (Boston, MA) 
➢ El Camino Hospital (Mountain View, CA) 
➢ Hoag Hospital (Newport Beach, CA) 
➢ Institut Gustave Roussy (Paris, France) 
➢ LA County Hospital (Los Angeles, CA) 
➢ Lahey Hospital & Medical Center (Burlington, MA) 
➢ Memorial Health System (Hollywood, FL) 

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Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
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➢ New York University (New York, NY) 
➢ Northside Hospital System (Atlanta, GA)  
➢ The Ohio State University (Columbus, OH) 
➢ Palo Alto Medical Foundation (Palo Alto, CA) 
➢ Rush University Medical Center (Chicago, IL) 
➢ Tahoe Forest Cancer Center (Truckee, CA) 
➢ Vanderbilt University Medical, Center (Nashville, TN) 
➢ University of California at Davis (Sacramento, CA) 
➢ University of California, San Diego (San Diego, CA 
➢ University of California, San Francisco (San Francisco, CA) 
➢ University of Manchester (Manchester, United Kingdom) 
➢ University of Southern California (Los Angeles, CA) 
➢ University of Torino (Turin, Italy) 
6.1.1 ALCMI Biorepository 
Thousands of new cases of lung cancer are diagnosed annually in ALCMI’s academic and community 
institutions.  The resultant ALCMI Biorepository is comprised of high-quality, standardized, annotated 
biospecimens, and serve as an open resource to academic and community researchers in the US. It will also 
form a foundation for collaboration with the National Institutes of Health and the biopharmaceutical 
industry for target/agent discovery and validation, genomics and proteomics—thus bringing new and 
improved treatment options to lung cancer patients in need.  
The ALCMI Biorepository is structured as a single resource comprised of biospecimens from all ALCMI 
research projects.   
As outlined in detail in the ALCMI Master Collaboration Agreement executed by all collaborating 
institutions, the rights to control and use of these banked biospecimens remain solely with ALCMI, 
specifically under the scientific review and prioritization oversight of the Scientific Leadership Board (SLB) 
of ALCMI.  The SLB is comprised of representative scientists and clinicians from among the participating 
ALCMI Collaborating Institutions, plus a lay member appointed by ALCMI to bring the patient perspective 
to the deliberations.  
6.1.1.0 
Biospecimen Distribution 
The ALCMI Biorepository is designed to be an ongoing effort, and will facilitate certain to-be-defined 
research studies.  Specimens will be available to ALCMI investigators and outside collaborators upon formal 
application and approval. All proposals are reviewed and prioritized by the ALCMI SLB, employing a research 
request application and procedure by which requests are prioritized based on scientific merit, resource 
utilization, etc.   
6.1.2 ALCMI Data Repository 
The ALCMI Data Repository enables centralized biological specimen tracking from initial collections through 
the course of treatment/outcomes to comply with regulations (such as GCPs and GLPs), satisfy study 
subject consent requirements, enhance scientific accuracy, and improve development efficiency. 

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Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
Authors: Dr. Awad & ALCMI 
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The sites' research coordinators/tissue procurement staff/data managers enter biospecimen information, 
subject demographics, clinical and laboratory data into the ALCMI Data Repository.  ALCMI investigators 
and approved staff will have web-based access to this system, subject to user-level security privileges and 
compliance with applicable privacy regulations, including HIPAA as indicated below.  A primary objective of 
ALCMI is to maintain subject confidentiality and assurance of informed consent for each biospecimen and 
data element procured.  
The ALCMI Data Repository streamlines and optimizes lung cancer investigators’ collaborative research 
efforts by providing intricate chain of custody for biospecimen transfers, detailed location and shipment 
management of biospecimens, aliquot, derivative, and pooled specimen tracking, and electronic signature 
capture upon transfer and disposition of biospecimens. These functions ensure that the tissue and data 
repositories remain in compliance with regulatory requirements and thus help to ensure that biospecimens 
used in ALCMI research and discovery efforts are of the very highest quality.  
The ALCMI Data Repository and Biorepository enables researchers to collect, manage and access 
comprehensive (de-identified to all except the contributing investigator and their authorized institutional 
colleagues) clinical data, medical histories, and critical proteomic, genomic and phenotypic data associated 
with biospecimens in compliance with HIPAA and other regulatory requirements.  Access to the ALCMI Data 
Repository is regulated by role-based security, with no capability by ALCMI staff and/or investigators and/or 
their staff to directly access the underlying database, unless specific permission is required for study 
activities. 
ALCMI’s data repository was developed and is managed by ClinCapture, a private cloud-based and 
electronic Data Collection (eDC) and Data Management Repository system.   
6.2 RESOLUTION BIOSCIENCES 
The haploid human genome contains 3 billion bases. Some driving mutations are single nucleotide 
variations (SNVs), where a single base change has occurred. For example, an adenine (A) becomes a guanine 
(G). Some of the SNVs are heterozygous mutations, so instead of 1 in 3 billion, it's actually a mutation of 1 
in 6 billion bases. If trying to reach a detection limit of 0.1% of ctDNA in 99.9% background cfDNA, the 
problem becomes the ability to detect one molecule in 6 trillion bases. 
Complicating the analysis, the cfDNA is broken into millions of short fragments. The average length of cfDNA 
is only 165 bases. Purified cfDNA from plasma appears predominantly as monomeric, dimeric, and 
occasionally trimeric nucleosome-sized DNA fragments. These short fragments must be mapped against 
the human genome to find out what gene they belong to and if they contain mutations of clinical 
significance.  
Resolution starts with a standard blood draw — a liquid biopsy. The whole blood is spun down in a 
centrifuge to separate plasma from the buffy coat and red-blood cell fractions to eliminate leukocytes 
(white blood cells) as they contain DNA that if allowed to lyse, contribute greatly to the background noise. 
Variable amounts of high molecular weight genomic DNA found in the plasma, presumably derived from 
nucleated blood cells that lyse, are also observed and excluded. 

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Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
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The cfDNA is extracted from the plasma for analysis. Through a series of proprietary biochemical steps, we 
amplify the cfDNA and using very small probes, target and capture strands of ctDNA. Resolution’s novel 
chemistry allows for a very even and deep capture of DNA sequences, regardless of GC content. This ability 
has two benefits: Resolution can easily capture any area of the genome equally and they do not have to 
sequence deeply to gather enough information to make a variant call. Their on-target rate is incredibly 
high, yielding > 95% sensitivity and 100% specificity. The lower level of detection is a mere 0.1%. 
Unlike PCR-based methods, Resolution’s system can discover mutations. They do not need to "pre-
program" specific variant sequences prior to capture. The Resolution platform can find SNPs, insertion and 
deletions, copy number variations (CNVs) / amplifications, and fusions / translocations. Critically, we can 
find fusions without any prior knowledge of the fusion partner or specific breakpoint. 
The extreme efficiency of the Resolution Bio ctDx™ platform allows us to analyze multiple patient samples 
on a single desktop sequencer run. The resultant data is just a few GBs — up to 250x less than some other 
methods. The result is faster turnaround time and lower cost.  Resolution currently run assays within their 
CLIA lab. 
6.3  STUDY ROLES OF SUPPORTING LABORATORIES & SERVICE PROVIDERS 
a) Dana Farber Cancer Institute – Investigative site for this study 
b) ALCMI – Provide study management, ALCMI Biorepository (specimen collection kits creation and 
distribution) and ALCMI Data Repository 
c) Resolution Bioscience – Perform cfDNA testing on liquid biopsy specimens 
d) Laboratory for Computational Imaging Analysis at Columbia University – Analyze imaging results.  
7 
OBJECTIVES 
7.1 PRIMARY OBJECTIVES 
To study the relationship between specific ALK resistance mutations and specific next generation ALK TKI 
received before progression and/or the number of ALK TKIs received. 
7.2 SECONDARY OBJECTIVES 
• 
To study the feasibility, sensitivity, and turnaround time of plasma NGS in lung cancer patients with 
ALK TKI resistance. 
• 
To study the outcomes of patients with ALK TKI resistance depending upon resistance mechanism 
detected and subsequent therapy received. 
• 
To study the relationship between plasma NGS results from plasma specimens to advanced ALK 
positive NSCLC subjects on progression to a next generation ALK TKI and treatment decisions. 
• 
To explore the ability of plasma genotyping to identify novel ALK resistance mechanisms. 

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Protocol Version Date: V1.7 15APR2021  
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8 
STUDY DESIGN 
8.1 REMOTE CONSENT & PLASMA NGS  
Our overarching hypothesis is that we can conduct a remote consent study using plasma NGS to 
characterize ALK resistance mechanisms arising in ALK positive NSCLC patients with progression while on a 
next generation ALK TKI, and that the chances of response to further treatment with a different ALK TKI can 
be predicted using those plasma NGS results.  
This study will attempt to prospectively assess the resistance mechanisms detected by a plasma NGS assay 
in patients with advanced ALK positive NSCLC and systemic progression outside the brain using a web-based 
remote consent form process. Subjects will be sent blood collection kits with the necessary materials for 
local draws and those specimens will be sent directly by the subjects to the central laboratory (Resolution 
Bioscience) for plasma NGS.  Plasma NGS results will be returned to the subject, their treating physician 
and study team, aiming to be returned within 2 weeks by Resolution Bioscience. This will allow prospective 
characterization of ALK resistant mutations arising in subjects after progression on different specific ALK 
TKIs. In addition, subsequent treatments and radiologic assessments received by the subjects will be 
prospectively monitored. A correlation between the ALK resistance mechanisms present at baseline, 
treatments received before and after plasma NGS assessments and outcomes will be analyzed.  
We further propose here that plasma NGS could grant the ability to non-invasively detect specific ALK 
resistance mutations and, therefore, predict the sensitivity to different ALK TKIs and patients’ outcomes. 
However, prospective CT-based response assessment is not feasible with a remote participation approach. 
We will instead use time to treatment discontinuation (TTD) as an alternate outcome. In collaboration with 
the US Food and Drug Administration (FDA), we found that TTD closely correlates with PFS outcomes in 
patients with genomic-driven lung cancer treated targeted therapies (manuscript in development), and is 
thus, well suited for studies of real-world evidence like ours. As such, we propose to evaluate the next 
treatment received by the subjects using TTD as the a time endpoint to assess treatment benefit. We also 
plan to analyze if plasma NGS results have any impact on the treatment decision process and if alterations 
in other relevant genes can impact subjects’ outcomes. 
8.2 CORRELATIVE STUDIES 
In addition to ALK rearrangement and ALK mutation assessment, plasma NGS can provide dynamic 
information about treatment effect. Because it is now possible to have genomic information about a wide 
range of genes through the same plasma NGS assay, we will also explore the relationship between other 
genomic alterations (e.g. mutations in p53, KRAS, EGFR or MET) with ALK TKI resistance and subject 
outcomes. We propose to use additional optional plasma NGS assessments after (a) 2-3 weeks of the next 
therapy initiated after baseline plasma NGS and (b) at disease progression or treatment discontinuation to 
explore plasma NGS as a biomarker for tumor response.  
Role of archival tissue:  In order to better understand novel or conflicting liquid biopsy results, we may need 
to request prior biopsy tissue to perform somatic tumor sequencing. This is expected to be requested on a 
case by case basis. No additional biopsy will be necessary on study. Tumor specimens will be labelled with 
the Subject Identification Number and any genomic analysis will be considered investigational, with no 
results returned to the subject. 

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Protocol Version Date: V1.7 15APR2021  
Title:  Study of Plasma Next Generation Sequencing for Remote Assessment, 
Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
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9 
STUDY POPULATION 
9.1 INCLUSION CRITERIA  
• 
Men or women older than 18 years old at the time of consent or age of majority for residential 
state. 
• 
Demonstration of having advanced ALK positive NSCLC. 
• 
Systemic progression (not CNS only progression) within the past 30 days, having previously been 
treated with a next-generation ALK TKI. 
• 
Patient must not have started a new line of therapy before signing the informed consent form. 
• 
Willingness to provide a blood specimen prior to the initiation of a new line of treatment. 
• 
Willingness to provide clinical and medical information to the study team as required.  
• 
Ability to read, write and communicate in English. 
• 
Ability to sign a web-based informed consent form. 
9.2 EXCLUSION CRITERIA 
• 
Participants who are unable to provide informed consent. 
• 
Participants who are 18 years of age or younger or less than the age of majority for their state of 
residence. 
• 
Participants who are unable to comply with the study procedures. 
• 
Known existence of an uncontrolled intercurrent illness including, but not limited to, psychiatric 
illness or social situations that would impair compliance with study requirements. 
• 
Participants who have previously enrolled to the study.  
9.3 INCLUSION OF WOMEN & MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial. 
10 STUDY PROCEDURES 
10.1  STUDY WEBSITE 
Patients 
will 
find 
information 
about 
the 
study 
on 
the 
study-specific 
website 
https://www.alcmi.net/SPACEWALK. The website will include a description of the study, aims, how to 
participate, and details for contacting the study team.  The trial will also be posted on www.clinicaltrials.gov.  
Physicians and advocacy groups are invited to refer interested patients to the study website.   
10.2  INFORMED CONSENT PROCESS 
To consent, the potential participant will fill out a Contact Form on the website or call the study-specific 
phone number.  The study team will then send potentially eligible participants a link to view the consent 
form that is hosted on Vanderbilt Institute for Clinical and Translational Research’s RedCap platform.  The 

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study team can provide potential participants a copy of the consent form via mail or email to review, 
however, consent is obtained through electronic signature on the RedCap platform. Study staff will be 
available by phone to assist with any questions that arise during the consent process.   
RedCap is an electronic informed consent tool available through a secure cloud-based portal that can be 
accessed from most devices that have an internet connection (e.g. tablet or desktop computer).  RedCap 
takes the Word version of the IRB-approved informed consent document and builds an electronic form that 
is viewed within the portal.  The electronic form has controls placed to capture signatures, dates, names 
and choices using check boxes or radio buttons.   
This technology allows investigators and research staff to respect individual privacy and promote 
understanding by allowing potential participants to choose their preferred location when reviewing the 
consent materials and discussing those materials with family or their regular doctor.  Potential participants 
can pose questions to the study team via phone or email. 
RedCap ensures appropriate consent documentation.  After logging into the RedCap portal, which is 
accessed via specific URL and individual login credentials, the participant or signatory reviews the electronic 
consent form and may provide an electronic signature by signing their name with a mouse or their finger.  
This electronic signature is date stamped.  The consent form cannot be finalized until all required signatures 
are obtained.  Once the form is finalized, the portal dashboard displays the certified PDF of the signed 
consent form that is encrypted, password-protected, and cannot be altered.  Participants have immediate 
access to the signed form within the portal and may view, download, and print the form at any time.   
RedCap is in full compliance with HIPAA Security Rules (or HIPAA/HITECH).   
In the rare situation a potential participant is unable to sign the online consent (e.g. due to technical 
difficulties), the study team may mail a paper consent form to the potential participant and proceed with 
a paper-based process until the participant’s technical difficulties have resolved at which time, the online 
consent will also be signed. 
10.2.1  Study Hotline 
The sponsor has provided a study-specific phone number to facilitate the recruitment process. The phone 
number is 844-44SPACE (844-447-7223). The hotline is available 6am-11pm EST, 7 days per week to 
individuals interested in participating in the study. The Hotline staff are responsible for: 
• 
responding to unique patient calls on the day received 
• 
answering study-related questions 
• 
releasing online consent form to appropriate potential participants 
• 
being available to assist with technical issues related to the online consent platform 
• 
communicating each patient interaction to the DFCI study team via email 
The Hotline staff are not responsible for providing medical advice, consenting study participants or study-
related activities.  The Hotline staff will only respond to patient calls and will not make any unsolicited 
calls.  

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10.2.2  Intake Form & Medical Record Release Form 
After signing the consent form, study participants will be immediately presented with an electronic version 
of the Intake Form and Medical Record Release Form.  The subject can choose to electronically complete 
the forms or receive them email as described below. 
 
Participants can also receive a screening email (Appendix I) from the study team with an Intake Form 
(Appendix J) and Medical Record Release Form (Appendix D). The Intake Form collects the subject’s contact 
information, emergency contact information and the treating physician’s contact information.  Subjects will 
also be asked to provide pathology reports, medication information and progression information if 
available. The Medical Record Release Form is DFCI’s standard form for obtaining patients’ outside hospital 
medical records. 
 
Upon completing the Intake Form and Medical Record Release Form, subjects will be screened for eligibility 
by study staff.  If eligible, subjects will be registered into the ALCMI’s study-specific data repository and 
assigned a unique subject identification number (see Section 10.2.3).  Subjects will also be registered into 
DFCI’s Clinical Trials Management System (CTMS) as per the institution’s standard process.   
ALCMI’s data repository will release an email notification of a new subject to the appropriate study team 
members such as the study coordinator and Principal Investigator.   
10.2.3  Subject Unique Identification Process 
Each subject that signs a consent form is assigned a unique identification number by the ALCMI Data 
Repository.  An example of a unique identifier is as follows: 011-01-001.  The first number “011” is the 
ALCMI protocol number; the second number “011” is the site number; the third number “001” is the 
subject number.  This identifier will be used for the purposes of the study only, and will be distinct from the 
patient identification (e.g. medical records number) noted on any medical record. 
10.2.4  Confirmation of Enrollment 
Once inclusion/exclusion criteria are verified, the study coordinator will notify the subject of their 
enrollment into the study. Subjects will be provided a study packet through the mail that will include an 
introduction letter (Appendix A), a signed copy of the consent form, a study questionnaire (Appendix B) a 
blood collection kit, and blood collection and handling instructions (Appendix C). Additionally, the subject’s 
treating physician will be sent a letter (Appendix E) describing the study and informing them of their 
patient’s participation in the study. 
10.2.5  California-based Subjects 
Subjects residing in California will be required to sign the California Bill of Rights at the time of confirmation 
of study enrollment.  The study coordinator will provide the document during the initial introductory email.   
10.3  BASELINE PLASMA COLLECTION 
The study coordinator will coordinate the shipment of the plasma collection kit for the baseline draw within 
4 days of enrollment confirmation. The plasma collection kit consists of a box with the required collection 
tubes and instructions for adequate acquisition, handling and shipment (Appendix C). A total of forty (40) 
mLs of blood will be collected for CLIA testing and storage for research purposes. The specimen will be 

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either drawn at the time of other clinical blood work or a separate blood draw will be performed. Twenty 
(20) mLs of the collected blood specimens will be tested in a panel of somatic alterations in cfDNA by 
Resolution Bioscience. Twenty (20) mLs of the collected blood will be stored at the ALCMI Biorepository for 
future lung cancer research.  See the ALCMI-011 Laboratory Guidelines for details on biospecimen shipping 
and handling.    
10.3.1  Baseline Plasma NGS 
The forty (40) mLs of blood will be shipped directly to Resolution Bioscience’s CLIA certified laboratory for 
analysis as per the standard processes. Laboratory staff will be blinded as to the subject’s treatment history.  
The results of plasma genotyping will be reported to the subject and the subject’s primary treating 
physician. Resolution Bioscience will also release the results to the study team for inclusion in ALCMI’s data 
repository.  
The plasma NGS report will not include any specific treatment recommendations but will describe the 
presence of an ALK rearrangement, ALK resistance mutation, or other relevant mutations using language 
such as the following: 
• 
If plasma NGS assay is negative for ALK rearrangement and negative for an ALK resistance mutation, 
this suggests levels of tumor DNA which are inadequate for detection of resistance mechanisms.  
• 
If plasma NGS assay is positive for ALK rearrangement and negative for an ALK resistance mutation, 
this makes it difficult to predict sensitivity to alternate ALK inhibitors. 
• 
If plasma NGS assay is positive for an ALK resistance mutation, the expected sensitivity and 
resistance of this ALK mutation to alternate ALK inhibitors will be provided. For example, the ALK 
resistance mutation G1202R confers resistance to crizotinib, ceritinib and alectinib while is 
sensitive to lorlatinib and there are controversial results regarding brigatinib activity. These will be 
expressed in the report using language such as: Likely resistant to crizotinib, ceritinib and alectinib. 
Possible sensitivity to brigatinib. Likely sensitive to lorlatinib. Appropriate scientific references will 
be provided. 
  
10.4  STUDY QUESTIONNAIRE 
A study questionnaire (Appendix B) will be emailed to the subjects after enrollment to obtain information 
about the subjects’ demographics, current condition, cancer history, and exposure history. The purpose is 
to gain information about the subject that may or may not be included in their medical records, but will 
allow the study staff to obtain a more complete representation of the patients’ cancer history.  
10.5  CLINICAL DATA COLLECTION 
A brief interview with the subjects and a review of the medical records provided will be completed for those 
selected for entry into the study. Data will be entered on the appropriate CRF in the ALCMI Data Repository.  
A CRF must be completed for each subject who has been enrolled and has signed an informed consent, 
including those that fail the screening process or are discontinued from the study.  The following clinical 
data will be collected: 
 
• 
Demographic data: age at diagnosis, age at enrollment, race/ethnicity, smoking history 

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• 
Cancer characteristics: pathology, sites of metastatic disease, prior genotyping results 
• 
Cancer history: date of diagnosis, date of advanced disease 
• 
Treatment history: dates of previous surgery, radiotherapy, chemotherapy and targeted therapy 
 
10.6  RADIOLOGY IMAGE COLLECTION & ANALYSIS 
To characterize tumor response and study patient outcomes, CT images from subjects will be collected by 
the study staff and transferred to the Laboratory for Computational Imaging Analysis at Columbia 
University. This will be an exploratory analysis as we cannot control the quality and timing of these scans. 
This imaging analysis will complement the plasma response analysis. 
Study staff will assist in obtaining copies of CT scans. For study staff to request copies of CT scan, study 
participants will be asked to complete a release form allowing their records to be obtained.  The study staff 
will obtain the CT scans for all subjects and the release forms will be maintained in a locked filing cabinet.  
Up to 25 CT scans will be collected per subject, depending upon availability.  PHI embedded in the images 
will be de-identified by the Laboratory for Computational Imaging Analysis at Columbia University prior to 
analysis.  Using computer-aided-diagnosis software, each scan will be assessed.  When serial imaging is 
available, change in nodule size will be characterized.  Because each scan will already have undergone 
clinical review, no findings from the CT image analysis will be reported back to the subject.   
10.7 ARCHIVAL TISSUE COLLECTION 
On a case by case basis, the study team may seek archival tissue specimens from subjects to better 
understand novel or conflicting liquid biopsy results, we may need to request prior biopsy tissue to perform 
somatic tumor sequencing.  Subjects do not need a biopsy to participate in this study.  When available, ten 
(10) slides and one (1) H&E slide will be collected from an archived specimen stored at the subject’s treating 
institution.  Tumor specimens will be labelled with the Subject Identification Number and any genomic 
analysis will be considered investigational, with no results returned to the subject.   
10.8  FOLLOW-UP 
After enrolled into the study, the study coordinator will contact the subject weekly for 4 weeks, or as the 
study coordinator deems necessary per the subject’s treatment plan.  The purpose of the study-specific 
Follow-Up Visit is to document any new treatment initiation and to release the optional plasma collection 
kit (see section 10.9), if applicable.  It is expected that at least two but no more than four study-specific 
Follow-Up visits will occur in the first 12 weeks.        
Subjects will then be contacted every 3 months, from the date of enrollment, to obtain information about 
therapy outcome until treatment failure.  Treatment failure will be defined as either termination of the 
current treatment or initiation of a new systemic therapy.  Subjects will be followed every three months 
for a maximum of 2 years post enrollment or until death.  
10.9  OPTIONAL RESPONSE PLASMA COLLECTION 
An optional blood collection will be offered 1-3 weeks but no more than 8 weeks after initiation of the 
subject’s post-enrollment anticancer regimen. The subject will be asked to notify the study coordinator 
when they have initiated a treatment regimen. Upon notification, the study coordinator will coordinate the 

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shipment of the plasma collection kit and a letter (Appendix F) describing the purpose of the optional blood 
collection to the subject.   
The plasma collection kit consists of a box with the required collection tubes and instructions for adequate 
acquisition, handling and shipment (Appendix C).  The blood draw will occur at the subject’s next standard 
of care blood draw.  The collection time schema allows a window of +/- 2 weeks from the specified date.  A 
total of twenty (20) mLs of blood will be collected for research purposes. Specimens will be labeled with 
the subject’s unique identification (no PHI), shipped directly to the ALCMI Biorepository and stored for 
future research. See the ALCMI-011 Laboratory Guidelines for details on biospecimens shipping and 
handling.    
10.10 
  OPTIONAL PROGRESSION PLASMA COLLECTION 
An additional optional blood collection will be offered after progression on the subject’s post-enrollment 
antitumoral regimen. The subject will be asked to notify the study coordinator when they have progressed 
on their treatment regimen. Upon notification, the study coordinator will coordinate the shipment of the 
plasma collection kit and a letter (Appendix G) describing the purpose of the optional blood collection to 
the subject.  
The plasma collection kit consists of a box with the required collection tubes and instructions for adequate 
acquisition, handling and shipment (Appendix C).  The blood draw will occur at the subject’s next standard 
of care blood draw. The patient is eligible for a progression blood draw at any time after clinical 
determination of disease progression (by their treating physician) and before initiating a subsequent line 
of therapy. A total of twenty (20) mLs of blood will be collected for research purposes. Specimens will be 
labeled with the subject’s unique identification (no PHI), shipped directly to ALCMI’s biobank and stored 
for future research. See the ALCMI-011 Laboratory Guidelines for details on biospecimens shipping and 
handling. 
Up to two optional progression plasma specimens will be collected upon progression on two different lines 
of therapy. This allows us to explore sequential therapy in case an initial therapy is ineffective but a 
subsequent therapy is effective, both suited in the same patient.    
 
 

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Characterization, Evaluation of Patients With ALK Drug Resistance (SPACEWALK) 
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10.11 STUDY CALENDAR 
Table 1: Times showed are estimations and can be adjusted with Principal Investigator approval if needed pending 
specific subject circumstances.  
Visit Schedule 
Registration, Enrollment and 
Visit 1 - Blood Collection 
Follow-up 
Visits 2-5 
 
Follow-up            
Visits 6-12 
Visit 13/End 
of 
Study/Early 
Termination 
Test/procedure 
Screening1 
 
Blood 
Collection  
Up to 4 visits 
within 12 
week 
window4 
Every 3 months from 
Enrollment7 
Visit 6 (+1 month) 
Visits 7-12 ±1 Month 
Study end3  
24 months   
-1 Month7 
 
Informed consent 
x 
 
 
 
 
Registration 
x 
 
 
 
 
Review inclusion & 
exclusion criteria 
x 
 
 
 
 
Baseline blood 
collection kit  
 
x 
 
 
 
Request medical 
records & imaging 
results 
x 
 
 
x6 
 
Follow-up4 
 
 
x4 
x 
x 
Receive NGS report 
 
 
x5 
 
 
Send kit for optional 
blood draw 
 
 
x2 
x2 
x2 
1 Screening is permitted to extend as long as 30 days, if necessary.   
2 Optional blood specimens may be collected 1-3 weeks after initiation of a new therapy as well as when a subject’s 
disease progresses on that therapy, prior to initiating subsequent line of therapy.  
3 Subjects will be followed on study for a minimum of 8 months and for a maximum of 24 months if the study remains 
open or in follow-up, or until death. 
4 Subjects weekly for 4 weeks, or as necessary per the subject’s treatment plan. It is expected that at least two but 
no more than four study-specific Follow-Up visits will occur in the first 12 weeks.  
(Visit 2 Week 1 ±3 days, Visit 3 Week 2 ±3 days, Visit 4 Week 3 ±3 days, Visit 5 Weeks 4-12)        
5 The NGS Report is only received once during the 12 week follow-up, typically within 14 days. 
6 Medical records & imaging results are only requested if attempts to reach the subject for follow-up have been 
unsuccessful, otherwise, data captured on disease progression and treatment changes are subject-reported. 
7 3 month visit windows include Visit 6 (3 months +1 month), Visits 7-12 (6,9,12,15,18,21 months ±1 month), Visit 13 
(24 months -1 month) 

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11 COMPENSATION 
There will be no compensation or incentives offered to the subject.  
Research blood draws will be performed with standard of care laboratories whenever possible. Subjects 
will be reimbursed for reasonable costs associated with research-only blood draws upon receipt of an 
invoice.   
12 STATISTICAL CONSIDERATIONS 
12.1  STUDY DESIGN & ENDPOINTS 
A total of 300 subjects will be enrolled. Of those, we assume approximately 53% of the subjects (n=160) 
will have DNA shed and detectable ALK rearrangements, and will have progressed on either alectinib or 
ceritinib. Of the 160 subjects, we assume 80 subjects will have progressed on alectinib and 80 subjects will 
have progressed on ceritinib. Table 1 below shows the expected distribution of resistance mutations among 
these subjects.  
 
Table 1: Expected distribution of resistance mutations 
ALK mutation 
Frequency after 
ceritinib 
Frequency after 
alectinib 
C1156Y 
5% 
0% 
F1174X 
15% 
0% 
I1171X 
0% 
10% 
L1196M 
0% 
5% 
G1202R 
20% 
30% 
G1202del 
5% 
5% 
D1203N 
2% 
0% 
L1198F 
5% 
0% 
C1156Y + L1198F 
2% 
2% 
F1245C 
0% 
2% 
No mutation 
46% 
46% 
 
 
We will focus on two key mutational differences, F1174X and I1171X. With a type I error of 0.10, we have 
99.8% power to detect the shown difference in acquiring the F1174X mutation, and 95.3% power to detect 
the shown difference in acquiring the I1171X mutation.  
We will investigate response and time to treatment discontinuation (TTD) of those patients who have 
acquired an ALK mutation on their respective potential targeted therapy.  
Table 2 below summarizes the maximum width of a 90% exact binomial confidence interval for response 
(CR+PR) to potential targeted therapy, per ALK mutation status.  
 
 

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Table 2: Max Width of 90% Exact Binomial Confidence Interval 
 
 
 
 
 
 
 
 
TTD is defined as the time from treatment start to treatment discontinuation for any reason, including 
disease progression, unacceptable toxicity, or death. For subjects who are alive without discontinuation, 
follow-up will be censored on the date of last adequate disease assessment. Table 3 below summarizes the 
intended TTD hazard ratios, median TTD improvement from 5 months, assuming exponential event time, 
power, and number of TTD events at full information with a Type I error of 0.10, for a total sample size of 
10 or 20 subjects. TTD will be estimated using the Kaplan-Meier method and Cox proportional hazards 
models will be used to estimate hazard ratios. Comparisons of groups will be made using the log-rank test 
and Cox modeling. 
Table 3: Time to Treatment Discontinuation 
 
Total 
Sample Size 
Number of 
events 
Hazard 
Ratio 
Median 
Survival 
Median Survival 
After Therapy 
1-Sided Type I 
Error Rate 
Power 
10 
6 
0.45 
5 Months 
12.5 Months  
0.10 
83% 
20 
14 
0.50 
5 Months 
10 Months 
0.10 
89% 
12.2    SAMPLE SIZE, ACCRUAL RATE & STUDY DURATION  
The study duration will be 32 months: 24 months of accrual, and a minimum of 8 months of follow-up on 
the last subject enrolled, though subjects will be followed for a maximum of 24 months if the study remains 
enrolling or in follow-up. In Table 4 are reflected the expected ethnic and racial distribution of the 
population to be included in the study. 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic/Latino 
20 
10 
30 
Not Hispanic/ Latino 
180 
90 
270 
ALK mutation 
Total Sample Size 
Number of Responses 
Max Width of 90% CI 
C1156Y 
4 
2 
0.8043 
F1174X 
12 
6 
0.5093 
I1171X 
8 
4 
0.6143 
L1196M 
4 
2 
0.8043 
G1202R 
40 
20 
0.2779 
G1202del 
8 
4 
0.6143 
D1203N 
2 
1 
0.9491 
L1198F 
4 
2 
0.8043 
C1156Y + L1198F 
4 
2 
0.8043 
F1245C 
2 
1 
0.9491 

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Ethnic Category: Total  
200 
100 
300 
Racial Category 
American Indian/Alaskan  
10 
5 
15 
Asian 
30 
15 
45 
African American 
10 
5 
15 
Hawaiian/ Pacific Islander 
4 
2 
6 
White 
146 
73 
219 
Racial Category: Total  
200 
100 
300 
Table 4. Expected ethnic and racial population distribution 
 
13 DATA COLLECTION AND ANALYSIS 
The Principal Investigator is responsible for assuring the accuracy, completeness and timeliness of all study 
documentation.   
13.1   CASE REPORT FORMS 
See section 10.5 for a description of clinical data to be collected and maintained within the ALCMI Data 
Repository.   
13.2   SOURCE DOCUMENTS 
Source documents are considered to be original subject records that may be in the form of lab, pathology 
or imaging reports.  Source documents are considered to be adequate when they are presented in final 
form; documents which are unsigned by hand or electronically are considered to be preliminary.  
 
All PHI is to be redacted from all source documents, such as histopathology or imaging reports.  Subject 
identifiers will be inserted onto the required source documents entered into the ALCMI Data Repository.  
13.3   MONITORING 
The Principal Investigator is responsible for the overall conduct of the study and other tasks detailed in 
section 14.1.   

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Once the study is initiated, the ALCMI Study Manager or designee will maintain regular contact with the 
Investigator and the site’s assigned study staff by periodic on-site or remote visits, telephone calls, letters, 
e-mails and FAX transmissions.  The purpose of this communication is to: confirm IRB approval of the study, 
track study enrollment, occasionally assess adherence to the study protocol and act as a resource to the 
study staff.  Any enrollment, specimen collection or shipment issues should immediately be reported to the 
Study Manager or designee. The Study Manager or designee will work with the site and ALCMI’s bio- and 
data repository staff to make any arrangements required to evaluate and correct problems.   
 
If the study requires, quality assurance monitoring visits from ALCMI or an ALCMI representative may be 
carried out to review study plan compliance, compare entries of the electronic case report forms with 
individual subjects’ medical records, and perform accounting of study material.  Site personnel should 
ensure ample time is scheduled to review data clarifications, protocol questions, and/or any data issues 
that may have surfaced prior to or during study conduct.  
 
13.4  INTERIM ANALYSIS PLAN 
An interim analysis of the study will be performed after 50, 100, and 200 subjects are enrolled.  The analysis 
will include a review of the study’s feasibility, enrollment rate, detection rate in the study population and 
to update our understanding of drug resistance reporting strategies. The analysis will include DFCI 
members, ALCMI representatives and may involve a steering committee of ALCMI investigators as needed. 
13.5  DATA & SAFETY MONITORING 
We will conduct data and safety monitoring, as is outlined within DFCI’s overall Data Safety Monitoring Plan 
(DSMP). The Principal Investigator and study staff are familiar with and will adhere to steps outlined within 
the DSMP. All research conducted for this study will undergo human subject’s review at DFCI. Clinical 
research coordinators or other staff members will be assigned to the study as needed. The responsibilities 
of the site staff include study compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, biospecimen kit shipment, and coordination of the 
activities of the study team.  
13.6    PUBLICATION PLAN 
The results should be made public within 24 months of reaching the end of the study.  The end of the study 
is the time point at which the last data items are to be reported, or after the outcome data are sufficiently 
mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration.  If a report 
is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that 
meets the requirements of the International Committee of Medical Journal Editors. A full report of the 
outcomes should be made public no later than 3 years after the end of the study.  
14 STUDY MANAGEMENT 
14.1   STUDY RESPONSIBILITIES  
ALCMI will be responsible for the following: 

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• 
Online informed consent, subject registration, data and biospecimen collection and tracking 
systems; 
• 
Centralized biospecimen and data storage; 
• 
Act as a resource to the study staff; 
• 
Facilitating cross-institutional collaboration processes within the ALCMI consortium. 
Investigator will be responsible for the following: 
• 
Ethical and safety considerations; 
• 
Ensure IRB review and approval are obtained and maintained; 
• 
Ensure that any reviewing IRB is promptly informed of significant new information about the 
investigation; 
• 
Conducting study in accordance with Good Clinical Practices and with applicable regulatory 
requirements; 
• 
Study staff’s adherence to protocol requirements; 
• 
Collection of sufficient quality and quantities of biospecimens; 
• 
Accurate and timely completion of case report forms; 
14.2   REGULATORY 
14.2.1   IRB Approval 
Before study initiation, the DF/HCC IRB must approve the study if required by the Institution.  It is the 
responsibility of the Investigator to provide the IRB with a packet of information necessary to satisfy the 
Institution’s requirements.  The Investigator shall provide a copy of the IRB approval to ALCMI prior to study 
initiation. If IRB approval is not required, a memo or waiver on the Institution’s letterhead indicating such 
a review is not applicable must be provided to ALCMI prior to study initiation. 
The Investigator will be responsible for writing the following reports: 
1) Withdrawal of IRB approval (must be reported to ALCMI within 5 working days); 
2) Deviations from the clinical protocol; 
3) Additional material that must be submitted to the IRB. 
14.2.2   Recruitment Material & Subject Correspondence 
A remote informed consent form process requires numerous communications with potential and enrolled 
subjects.  The follow recruitment materials and correspondence will be submitted to DF/HCC IRB for 
approval prior to implementation.  The Investigator shall provide a copy of the IRB approval of the 
materials prior to implementation. 
• 
Study website 
• 
Intake form 
• 
Introductory email 
• 
Introductory letter to primary physician 
• 
Blood draw cover letter 
• 
Any additional recruitment material designed in the future 

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14.2.3    Study Initiation 
The Investigator is responsible for ensuring study staff is adequately trained on the study.  ALCMI Study 
Manager will assist and participate in site initiation visit.  Study initiation will be performed prior to the 
onset of any study procedures and will include the following: 
• 
GCPs review; 
• 
Protocol review; 
• 
ALCMI Data Repository training; 
• 
Specimen collection, storage and shipment guidelines; 
• 
CRF completion guidelines review; 
• 
Investigator’s responsibilities; 
• 
Completion of other study documentation. 
Documentation of Study Initiation will be kept in the Regulatory Binder. 
14.2.4 Protocol Deviations, Event & Amendment Reporting 
All protocol deviations will be reported to the DF/HCC IRB during regular review. Amendments to this 
protocol will similarly be submitted to the DF/HCC for approval prior to implementation. As this is a 
correlative biomarker study, no significant study related adverse events are anticipated. Should any 
significant unanticipated adverse events occur, they will be promptly reported to the DF/HCC IRB followed 
by a complete written report.  
14.2.5  Continuing Review and Final Report 
Continuing review of this study will be conducted by the DF/HCC IRB as per standard institutional 
procedures.  
14.2.6   Patient Safety 
In the best interest of each patient participating in the study, each will be required to electronically sign an 
Informed Consent Form prior to participation in compliance with 21CFR50 Subpart B.  All patients will be 
provided a copy of the electronically signed informed consent.   
Patients must be told of the purpose of the study in clear laymen’s terms.  They must be informed of their 
rights as subjects, and understand that their participation is voluntary.  Participation in the study will not 
impact on the clinical care patients receive.  The consent form will notify patients that the optional 
biospecimens will be stored for the purpose of conducting future lung cancer research.   
The consent form must also specify whom to contact if there are injuries as a result of the study, and whom 
to contact with general questions about the study.  The consent form must specify that representatives of 
ALCMI, the IRB and employees of federal agencies may review medical records of the patient.  
14.2.7  Study Withdrawal Process 
Subjects may be removed from the study without their consent.  The criteria for terminating a subject’s 
participation include: 
• 
Intercurrent illness that prevents further follow-up. 
• 
Participant demonstrates an inability or unwillingness to comply with the procedures and/or 

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documentation requirements. 
• 
Lost to follow-up. 
• 
General or specific changes in the subject’s condition rendering them unacceptable for further 
follow-up in the judgment of the Principal Investigator. 
 
If a study subject wishes to be withdrawn from the study, this can be done in writing by sending a letter to 
the Principal Investigator.  The subjects must also be notified that if they choose to withdraw from the 
study at any time, the specimens stored for future research will be destroyed, if requested.  If a study 
subject decides to withdraw from the study and have their specimens destroyed, specimens that have not 
yet left the ALCMI’s biorepository will not be used in new studies and any remaining portions of specimens 
that have not been used for research will be destroyed. For specimens already shipped out from the 
biorepository, it may not be possible to locate the specimens or stop already ongoing research. Such 
specimens would have name and personal identifiers removed during the collection process and may be 
distributed with the subject and/or specimen identification number. The consent states that it will not be 
possible to stop the use of such specimens in already ongoing research. This withdrawal will be documented 
in the ALCMI Data Repository.  In addition, an off-study form will be completed per DFCI’s standard 
procedures. 
14.2.8   Benefits of Research Participation 
The ability of plasma NGS to assess ALK TKI resistance and to guide treatment upon progression to ALK TKIs 
remains unknown. This study addresses those question and, therefore, at this point no benefit for such 
approach has been described. Additionally, it is unlikely that the research using banked biospecimens will 
be of any medical benefit to study subjects. Neither the study subject nor the treating physician (unless 
he/she is an identified investigator in the ALCMI-010 study) will be told of the results of any research 
performed on the biospecimens stored for future research. Research using these biospecimens could lead 
to medical and scientific products that could improve prevention, diagnosis and treatment of disease. 
14.2.9    Risks Associated with Participation 
This is a low risk, non-intervention, non-treatment protocol.   
 
The potential risks associated with this study are minor. The multiple blood draws involved in this study are 
routine although they may be associated with minor bleeding, bruising or pain. The type of plasma 
genotyping involved in this study is not designed to detect germline genetic mutations associated with 
familial cancer syndromes.  No additional biopsies or imaging will be involved in this study aside from those 
organized by each subject’s primary oncologist as required for regular clinical care.  
14.2.10 Regulatory Binder 
DFCI will be provided a binder in which to store the required administrative information for the study.  
These documents will be verified prior to initiating the study, throughout the study and at the conclusion 
of the study.  Refer to CFR Section 812.140(a) for a list of the minimum required documents. 
14.2.11 Data Privacy and Safety Monitoring 
All subject information remains confidential and will be maintained in the following manner: 
• 
Access to subject data will only be permitted to necessary personnel; 

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• 
All subject identifiers will be removed and study-specific identifiers will be assigned and 
maintained; 
• 
The subject’s personal identity will not be used in reports that are written about the research.  
Blood specimens collected for analysis by Resolution Biosciences will be labeled with the subject’s name 
and date of birth, as this will be necessary for rigorous CLIA-level genetic testing.   
All optional blood collections will be labeled with the subject’s unique identification number.   
Following completion of the genetic analyses on this protocol, all specimens will be stored (including 
plasma, cfDNA and banked CT images) without any PHI labels and will only be labeled with the subject’s 
unique identification number. 
The results of any research using the stored blood will not be placed in the subject’s medical record. 
In the case of subject reimbursement for research-specific blood draws, ALCMI will be provided with the 
subject’s name and address for the purposes of reimbursement only.   
ALCMI, the Principal Investigator, and all other individuals involved in the research study shall comply with 
all applicable HIPAA Privacy Requirements.  The “HIPAA Privacy Requirements” refer collectively to the 
applicable provisions of the Administrative Simplification section of HIPAA-the Health Insurance Portability 
and Accountability Act of 1996 (as codified at 42 U.S.C. § 1320d – d-8) and any regulations promulgated 
hereunder, including without limitation, the federal privacy regulations (45 CFR Part 164) and the federal 
security standards (45 CFR Part 142).  
“PHI” refers to “protected health information” as defined in 45 CFR 164.504, and De-Identify shall be as 
defined in 45 CFR 164.514. 
14.2.12 Record Retention 
The Investigator must maintain complete, accurate and current study records for inspection by ALCMI, IRB 
or FDA representatives.  Records will be retained indefinitely unless the subject withdraws consent. 
15    APPENDICES 
A. Introduction Letter 
B. Study Questionnaire 
C1. Blood Collection and Handling Instructions 
C2. Blood Collection and Handling Instructions (Optional) 
D. Medical Record Release Form  
E. Letter Treating Physician  
F. Optional Blood Collection Letter (New Therapy) 
G. Optional Blood Collection Letter (Progression) 
H. Study Flyer 

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I. 
Screening Email 
J. 
Intake Form 
16 REFERENCES 
 
1.  
Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response 
to gefitinib therapy. Science. 2004;304(5676):1497-1500. doi:10.1126/science.1099314. 
2.  
Kim DW, Mehra R, Tan DSW, et al. Activity and safety of ceritinib in patients with ALK-rearranged 
non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 
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Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell 
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Gainor JF, Dardaei L, Yoda S, et al. Molecular Mechanisms of Resistance to First- and Second-
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Shaw AT, Friboulet L, Leshchiner I, et al. Resensitization to Crizotinib by the Lorlatinib ALK 
Resistance Mutation L1198F. N Engl J Med. 2015;374(1):54-61. doi:10.1056/NEJMoa1508887. 
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Sequist L V, Waltman B a, Dias-Santagata D, et al. Genotypic and histological evolution of lung 
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7.  
Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of 
treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol. 
2016;34(28):3375-3382. doi:10.1200/JCO.2016.66.7162. 
8.  
Bettegowda C, Sausen M, Leary RJ, et al. Detection of Circulating Tumor DNA in Early- and Late-
Stage Human Malignancies. Sci Transl Med. 2014;6(224):224ra24-224ra24. 
doi:10.1126/scitranslmed.3007094. 
9.  
Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung 
cancer. N Engl J Med. 2014;371(23):2167-2177. doi:10.1056/NEJMoa1408440. 
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G. Scagliotti, T.M. Kim, L. Crinò, G. Liu, C. Gridelli, S. Novello, K. Kiura, A. Bearz, O. Gautschi, E. 
Felip, M. Nishio, D.R. Spigel, T. Mok, P. Urban, S. Deudon, C. Zheng ATS. Ceritinib vs chemotherapy 
(CT) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-
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Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK 
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Katayama R, Shaw  a. T, Khan TM, Mino-Kenudson M, Iafrate AJ, Engelman J a. Mechanisms of 

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acquired crizotinib resistance in ALK-rearranged lung cancers. Cancer Res. 2012;72(8 
Supplement):5593-5593. doi:10.1158/1538-7445.AM2012-5593. 
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