A Biomarker-Driven Master Protocol for Previously Treated Squamous Cell Lung Cancer (Lung-Map)
Conditions: Recurrent Squamous Cell Lung Carcinoma, Stage IV Squamous Cell Lung Carcinoma AJCC v7
Sponsor: SWOG Cancer Research Network

 
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PRIVILEGED COMMUNICATION 
Distribution IRB Review Only 5/28/14 
FOR INVESTIGATIONAL USE ONLY 
 
 
 
 
     
Activated June 16, 2014 
 
SWOG 
 
A BIOMARKER-DRIVEN MASTER PROTOCOL FOR PREVIOUSLYTREATED  
SQUAMOUS CELL LUNG CANCER (LUNG-MAP) 
 
NCT #02154490 
TITLE 
This is a potential FDA registration study. There will be additional centralized and on-site monitoring conducted in 
addition to routine audits. Sites must also maintain a study specific Trial Master File for this study 
(https://swog.org/Visitors/QA/Index.asp). 
 
STUDY CHAIRS: 
CURRENT STUDY AGENTS: 
Roy S. Herbst, M.D., Ph.D. 
Available from Commercial Sources 
  (Steering Committee/Targeted Agent Selection  
Docetaxel ** (Taxotere®)(RP56976) (NSC 628503) 
Committee Co-Chair) 
Erlotinib * (OSI-774, Tarceva) (NSC 718781) 
Yale Cancer Center 
 
Section of Medical Oncology 
Available from Pharmaceutical Collaborators: 
333 Cedar Street, WWW221 
SWOG Held INDs  
New Haven, CT 
AZD4547 (NSC 765338) (IND-119672) 
Phone: 203/785-4116 
GDC-0032 (Taselisib) (NSC 778795) (IND-119672) 
FAX: 203/785/4116 
Ipilimumab (NSC 732442) (IND-119672) 
E-mail: roy.herbst@yale.edu  
MEDI4736 (NSC 778709) (IND-119672) 
 
Nivolumab (NSC 748726) (IND-119672)  
Fred R. Hirsch, M.D., Ph.D. (Translational Medicine) 
Palbociclib (PD-0332991) (NSC 772256) (IND-119672) 
University of Colorado Cancer Center 
Talazoparib (BMN 673) (NSC 771561) (IND-119672) 
P.O. Box 6511, MS 8117 
Tremelimumab (NSC 744483) (IND-119672) 
Aurora, CO 80045 
 
Phone:  303/724-3858 
STUDY CHAIRS (contd.): 
E-mail:  fred.hirsch@ucdenver.edu  
 
 
David R. Gandara, M.D. (SWOG, Lung-MAP Co-Chair) 
Philip C. Mack, Ph.D. (Translational Medicine) 
UC Davis Cancer Center 
UC Davis Cancer Center 
Division of Hematology/Oncology 
Division of Hematology/Oncology 
4501 X Street 
4501 X Street 
Sacramento, CA 95817 
Sacramento, CA 95817 
Phone:  916/734-3772 
Phone:  916/734-8022 
FAX:  916/734-7946 
FAX:  916/734-2361 
E-mail: drgandara@ucdavis.edu  
E-mail:  pcmack@ucdavis.edu  
 
 
BIOSTATISTICIANS: 
 
Lawrence H. Schwartz, M.D. (Imaging) 
Mary Redman, Ph.D. 
Jieling Miao, M.S. 
Columbia University Medical College 
Shannon McDonough, M.S. 
James Moon, M.S. 
180 Fort Washington Avenue, HP-3-320 
Katherine Griffin, M.S. 
New York, NY 10032 
SWOG Statistical Center 
Phone:  212/305-8994 
1100 Fairview Ave N, M3-C102 
FAX:   212/305-4835 
P.O. Box 19024 
E-mail:  lhs2120@cumc.columbia.edu.  
Seattle, WA 98109-1024 
 
Phone: 206/667-4623 
* Erlotinib is not a current study agent effective 11/25/2014. 
FAX: 206/667-4408 
** Docetaxel is not a current study agent effective12/18/2015. 
E-mail: mredman@fredhutch.org  
 
E-mail: smcdonou@fredhutch.org  
 
E-mail: kgriffin@fredhutch.org  
 
E-mail: jmiao@fredhutch.org  
 
E-mail: jmoon@fredhutch.org  
 
 
 

 
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ALLIANCE STUDY CHAIR: 
 
 
Everett Vokes, M.D. 
 
University of Chicago Medical Center 
E-mail:  evokes@medicine.bsd.uchicago.edu  
 
 
ECOG-ACRIN STUDY CHAIR: 
 
 
Suresh Ramalingam, M.D. 
 
Emory University 
 
E-mail:  suresh.ramalingam@emoryhealthcare.org  
 
 
CCTG STUDY CHAIR: 
 
Natasha Leighl, BSc, MMSc, M.D.  
Univ. Health Network-Princess Margaret Hospital  
E-mail:  Natasha.leighl@uhn.ca  
 
NRG STUDY CHAIR: 
 
Jeff Bradley, M.D. 
Washington University School of Medicine 
E-mail:  jbradley@radonc.wustl.edu  
 
 
SWOG STUDY CHAIR: 
 
Karen Kelly, M.D. 
UC Davis Cancer Center 
E-mail: karkelly@ucdavis.edu  
 
 
 
PARTICIPANTS 
 
 
 
 
 
 
 
 
 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
CCTG/Canada CancerTrials Group 
NRG/NRG Oncology 
SWOG/SWOG 

 
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TABLE OF CONTENTS 
Page 
 
 
TITLE ERROR! BOOKMARK NOT DEFINED. 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective of the Master Protocol (S1400) .......................................................................... 7 
1.2 
Design #1: Phase II/III Design ......................................................................................................... 7 
1.3 
Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III) ................................. 8 
1.4 
Common Objectives for all sub-studies designs .............................................................................. 9 
2.0 
BACKGROUND ............................................................................................................................... 9 
2.1 
General Background ........................................................................................................................ 9 
2.2 
Choice of Disease Setting .............................................................................................................. 10 
2.3 
Study Design .................................................................................................................................. 11 
2.4 
SP44 anti-C-MET Immunohistochemistry (IHC) Assay ................................................................. 12 
2.5 
Inclusion of Women and Minorities ................................................................................................ 12 
3.0 
DRUG INFORMATION .................................................................................................................. 13 
4.0 
STAGING CRITERIA ..................................................................................................................... 14 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 15 
5.1 
Screening/Pre-Screening Registration ........................................................................................... 15 
5.2 
Sub-study Registration ................................................................................................................... 17 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 20 
7.0 
TREATMENT PLAN ...................................................................................................................... 20 
7.1 
Treatment ....................................................................................................................................... 20 
7.2 
Radiology Review .......................................................................................................................... 20 
7.3 
Discontinuation of Treatment ......................................................................................................... 20 
7.4 
Follow Up Period ............................................................................................................................ 20 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 20 
9.0 
STUDY CALENDAR ...................................................................................................................... 21 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 21 
10.1 
Measurability of Lesions................................................................................................................. 21 
10.2 
Objective Status at Each Disease Evaluation ................................................................................ 23 
10.3 
Best Response ............................................................................................................................... 25 
10.4 
Performance Status ....................................................................................................................... 25 
10.5 
Time to Death ................................................................................................................................. 26 
10.6 
Investigator-Assessed Progression-Free Survival ......................................................................... 26 
10.7 
Progression-Free Survival by Central Review ............................................................................... 26 
10.8 
Duration of Response (DoR) .......................................................................................................... 26 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 26 
11.1 
Design #1: Phase II/III Design ....................................................................................................... 27 
11.2 
Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III) ............................... 31 
11.3 
Blinded Independent Centralized Review (BICR) of PFS and/or ORR ......................................... 36 
11.4 
Accrual Information ........................................................................................................................ 37 
11.5 
Screening Success Rate Evaluation .............................................................................................. 38 
11.6 
Treatment Arm Randomization Acceptance Rate Evaluation ........................................................ 38 
11.7 
Data and Safety Monitoring ........................................................................................................... 38 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 39 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 39 
13.1 
Registration Timing ........................................................................................................................ 39 
13.2 
Investigator/Site Registration ......................................................................................................... 39 
13.3 
OPEN Registration Requirements ................................................................................................. 42 
13.4 
Registration Procedures................................................................................................................. 43 

 
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13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 44 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 44 
14.1 
Data Submission Requirements for Screening/Pre-Screening Registration ................................. 44 
14.2 
Master Forms ................................................................................................................................. 44 
14.3 
Data Submission Procedures ........................................................................................................ 44 
14.4 
Data Submission Overview and Timepoints for Screening/Pre-Screening Registration ............... 46 
14.5 
Data Submission FOR PATIENTS WHO WILL NOT BE REGISTERED TO ANY OF THE SUB-
STUDIES ........................................................................................................................................ 47 
14.6 
Data Submission FOR PATIENTS WHO HAVE PROGRESSED ON A SUB-STUDY AND WISH 
TO REGISTER TO A NEW SUB-STUDY ...................................................................................... 47 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 48 
15.1 
SWOG Specimen Tracking System (STS) .................................................................................... 48 
15.2  
Biomarker Profiling (Required) ....................................................................................................... 48 
15.3 
Correlative Studies and Banking  (Optional for Patients) .............................................................. 50 
15.4 
Radiology Review (Required for all Sub-studies) .......................................................................... 51 
15.5 
S1400GEN Survey Ancillary Study (Optional for Patient) ............................................................. 52 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 54 
16.1 
Adverse Event Reporting Requirements........................................................................................ 56 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 57 
18.0 
APPENDIX ..................................................................................................................................... 59 
18.1a 
Biomarker-Testing Algorithm and Clinical Assays ......................................................................... 60 
18.1b 
New York Heart Association Classification .................................................................................... 66 
18.1c 
Risk Based Monitoring Plan ........................................................................................................... 67 
18.1d 
Dose and Administration Schedules Overview .............................................................................. 74 
18.1e 
Specimen Flow Diagram ................................................................................................................ 76 
18.1f 
S1400GEN ..................................................................................................................................... 77 
18.2 
List of Sub-study Attachments ....................................................................................................... 86 
 
 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient 
enrollments: 
 
Submit study data directly to the Lead 
Cooperative Group unless otherwise 
specified in the protocol: 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal: 
 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately at 
1-866-651-2878 to receive 
further instruction and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
 
Please refer to the patient 
enrollment section of the 
protocol for instructions 
on using the Oncology 
Patient Enrollment 
Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPE
N_SYSTEM/ or  
https://OPEN.ctsu.org.  
 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com.  
 
Data collection for this study will be done 
exclusively through Medidata 
Rave.  Please see the data submission 
section of the protocol for further 
instructions.  
 
Other Tools and Reports: 
Institutions participating through the 
CTSU continue to have access to other 
tools and reports available to the SWOG 
Workbench.  Access this by using your 
active CTEP-IAM USER ID and 
password at the following url: 
https://crawb.crab.org/TXWB/ctsulogon.a
spx.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org.   Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires 
user log on with CTEP-IAM username and password. Permission to view and download this protocol and 
its supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
 
CTSU site should follow procedures outlined in the protocol for site registration.  Patient Enrollment 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For patient eligibility questions contact the SWOG Data Operations Center by phone or email: 
 
206-652-2267 
S1400question@crab.org  
 
For treatment or toxicity related questions contact S1400Medicalquery@swog.org. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
CTSU General Information Line: 
888-823-5923 
ctsucontact@westat.com  
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at https://www.ctsu.org 
  

 
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SCHEMA 
 
 
 
Pre-Screening Registration 
Screening Registration 
 
 
 
Common Broad Platform CLIA Biomarker Profiling Ω 
 
 
 
Progression 
 
 
 
 
 
 
 
 
Sub-study Assignment ¥ 
 
 
 
If known positive biomarker 
 
If not eligible for biomarker driven sub-studies 
S1400G 
(Active Phase II) 
Target HRRD 
S1400K 
(Active Phase II) 
Target C-MET 
S1400F 
(Active Phase II) 
Non-Match, Previously Treated 
Anti-PD-1/PD-L1 Resistant 
S1400I 
(Active Phase III) 
Anti-PD-L1/ Non-Match Agent 
Talazoparib Ø 
(BMN 673) 
ABBV-399 (Process II) Ø 
Cohort 1 
(acquired 
resistance) 
MEDI4736 
(Durvalumab) 
plus 
Tremelimumab 
Cohort 2 
(primary 
resistance) 
MEDI4736 
(Durvalumab) 
plus 
Tremelimumab 
Arm 1 
Nivolumab plus 
Ipilimumab 
Arm 2 
Nivolumab 
Ω 
Archival formalin-fixed paraffin-embedded (FFPE) tumor, fresh core needle biopsy if needed. 
¥ 
Sub-study assignment will be determined by the SWOG Statistics and Data Management Center (SDMC). Sub-study assignment will be 
determined based on randomization for patients eligible for multiple sub-studies (see Section 11.0 for details). 
Patients registered to the screening/pre-screening component, but not randomized to a treatment arm of any of the sub-studies will be 
followed until death or 3 years after screening/pre-screening registration, whichever comes first. 
Ø  
Upon progression (as defined in Section 10.2d in S1400), patients may be eligible for another sub-study. The new sub-study assignment will 
be determined by the SWOG SDMC. (see Section 14.6). 
 
 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective of the Master Protocol (S1400) 
 
The overarching goal for this protocol is to establish a National Clinical Trials Network 
(NCTN) mechanism for genomically screening large but homogeneous cancer populations 
and subsequently assigning and accruing simultaneously to a multi-sub-study “Master 
Protocol”.  Biomarker-driven sub-studies in this protocol will evaluate a targeted therapy 
(TT) or targeted therapy combination (TTC) based on designated therapeutic biomarker-
drug combinations, with the ultimate goal being approval of new targeted therapies in this 
setting.  In addition, the protocol includes at least one “non-match” sub-study which will 
include all screened patients not eligible for any of the biomarker-driven sub-studies.  This 
sub-study will evaluate a non-match therapy (NMT), also with the goal of approval.  For all 
sub-studies the investigational therapy arm will be referred to as the investigational therapy 
arm. We hypothesize that this Master Protocol mechanism will yield definable and 
measurable efficiencies in terms of improving genomic screening of cancer patients for 
clinical trial entry, and improved time lines for drug-biomarker testing allowing for inclusion 
of the maximum numbers of otherwise eligible patients in comparison with currently 
employed “single screen-single trial” approaches. 
 
This Protocol employs a “hybrid” master protocol in which the design for a given sub-study 
is chosen from a limited number of clinical trials designs based on the expected biomarker 
prevalence and background data.  The design options for the sub-studies include a Phase 
II/III design and a Single Arm Phase II followed by a Randomized Phase III (under specified 
conditions).  The objectives for each design are included in this section (Section 1.0) and 
the statistical considerations for each design are included in S1400 Section 11.0. 
 
1.2 
Design #1: Phase II/III Design 
 
a. 
Sub-study Primary Objectives 
 
1. 
Phase II Component 
 
The primary objective within the Phase II component is to evaluate if there 
is sufficient evidence to continue to the Phase III component of the sub-
study by comparing investigator-assessed progression-free survival (IA-
PFS) between investigational therapy versus standard therapy (SoC) in 
patients with advanced stage refractory squamous cell carcinoma (SCCA) 
of the lung. 
 
2. 
Phase III Component 
 
The co-primary objectives of the Phase III component are: 
 
i. 
To determine if there is both a statistically and clinically-
meaningful difference in IA-PFS among advanced stage 
refractory SCCA of the lung randomized to receive investigational 
therapy versus SoC. 
 
ii. 
To compare overall survival (OS) in patients with advanced stage 
refractory SCCA of the lung randomized to investigational therapy 
versus SoC. 
 
 

 
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b. 
Sub-study Secondary Objectives 
 
1. 
Phase II Component 
 
i. 
To compare response rates (confirmed and unconfirmed, 
complete and partial responses) among patients randomized to 
receive investigational therapy versus SoC. 
 
ii. 
To evaluate the frequency and severity of toxicities associated 
with investigational therapy versus SoC. 
 
iii. 
To evaluate the duration of response (DoR) among patients who 
achieve a CR or PR by RECIST 1.1 
 
2. 
Phase III Component 
 
i. 
To compare the response rates (confirmed and unconfirmed, 
complete and partial) among patients randomized to receive 
investigational therapy versus SoC. 
 
ii. 
To evaluate the frequency and severity of toxicities associated 
with investigational therapy versus SoC. 
 
c. 
Treatment Arm Randomization Acceptance Rate Objective 
 
To evaluate the treatment arm randomization acceptance rate (TARAR) within 
each treatment arm of each sub-study defined as the percentage of patients 
randomized to a treatment arm that receive any protocol treatment. 
 
1.3 
Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III) 
 
a. 
Sub-study Primary Objectives 
 
1. 
Phase II Component 
 
The primary objective within the Phase II component is to evaluate the 
objective response rate (confirmed and unconfirmed, complete and 
partial). 
 
2. 
Phase III Component 
 
The co-primary objectives of the Phase III component are: 
 
i. 
To determine if there is both a statistically and clinically-
meaningful difference in IA-PFS among advanced stage 
refractory SCCA of the lung randomized to receive investigational 
therapy versus SoC. 
 
ii. 
To compare overall survival (OS) in patients with advanced stage 
refractory SCCA of the lung randomized to investigational therapy 
versus SoC. 
 
 

 
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b. 
Sub-study Secondary Objectives 
 
1. 
Phase II component 
 
i. 
To evaluate PFS and OS with investigational therapy 
 
ii. 
To evaluate the duration of response (DoR) among patients who 
achieve a CR or PR (confirmed and unconfirmed) by RECIST 1.1 
 
c. 
To evaluate the frequency and severity of toxicities associated with investigational 
therapy. 
 
1. 
Phase III Component  
 
i. 
To compare the response rates (confirmed and unconfirmed, 
complete and partial) among patients randomized to receive 
investigational therapy versus SoC. 
 
ii. 
To evaluate the frequency and severity of toxicities associated 
with investigational therapy versus SoC. 
 
1.4 
Common Objectives for all sub-studies designs 
 
a. 
Screening Success Rate Objective 
 
To evaluate the screen success rate defined as the percentage of screened 
patients that register for a therapeutic sub-study. Screen success rates will be 
evaluated for the total screened population and by the subset of patients screened 
following progression on previous therapy or pre-screened on current therapy. 
 
b. 
Translational Medicine Objectives 
 
1. 
To identify additional predictive tumor/blood biomarkers that may modify 
response or define resistance to the TT/TTC beyond the chosen 
biomarker for biomarker-driven sub-studies. 
 
2. 
To evaluate potentially predictive biomarkers for NMT in the non-match 
studies. 
 
3. 
To identify potential resistance biomarkers at disease progression. 
 
4. 
To establish a tissue/ blood repository from patients with refractory 
squamous cell carcinoma (SCCA) of the lung. 
 
 
2.0 
BACKGROUND 
 
2.1 
General Background 
 
Despite several impressive therapeutic advances in recent years, cancer remains the 
second-leading cause of death in the United States and effective new therapies are still 
desperately needed.  Developing a potential therapy from the initial discovery stage 
through clinical testing and regulatory review is a complicated, expensive, and often 
inefficient process that can take up to 15 years.  Included among the many challenges of 
drug development are the difficulties in recruiting cancer patients to clinical trials, the 

 
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extensive bureaucratic processes required to initiate any clinical trial, and lengthy 
regulatory review.  Modernizing this process with innovative approaches and new clinical 
trial designs is of high importance. 
 
Although the advent of targeted therapies holds great promise for improved efficacy, this 
also means that many patients may need to be screened before enough patients harboring 
the necessary genomic alteration are available for the trial to be completed.  In order to 
address the expense and inefficiencies of the current drug development process and in 
hopes to identify promising compounds in selected populations, stakeholders began to 
develop and test innovative approaches for clinical trials, including development of 
algorithms for clinical trial designs facilitating early drug/biomarker co-development.  (1)  
Phase II screening trials such as BATTLE (Biomarker-integrated Approaches of Targeted 
Therapy for Lung Cancer Elimination) and I-SPY 2 TRIAL (Investigation of Serial Studies 
to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) are early 
trial examples using biomarker screening and facilitating addition of new drugs and 
biomarkers into the protocol on a “rolling” basis.  (2, 3)  Here we propose a Master Protocol 
for genomic screening and multi-sub-study testing of drug/biomarker combinations in a 
Phase II/III setting compatible with subsequent FDA approval.  Genomic screening of a 
large patient resource provided by sites participating in the NCI National Clinical Trials 
Network (NCTN) is designed to identify a series of molecular targets/biomarkers for which 
there will be a new drug match, leading to appropriate sub-study assignment and drug 
treatment.  Each molecular target included in S1400 will be represented by a biomarker for 
which there will be an analytically validated diagnostic assay.  This approach provides a 
basis for large-scale screening/clinical registration trial with the ability to screen patients, 
either through genomic analysis or immunohistochemistry based assays, with 
homogeneous eligibility criteria and direct them to a sub-study of the trial based on the 
results of screening diagnostic tests. 
 
There are multiple advantages to a multi-sub-study Master Protocol, compared to the 
traditional alternative of multiple 2-arm registration studies.  First, for drugs that have 
already shown promise in a biomarker-selected patient population, grouping these under 
a single trial, with a control (standard-of-care) arm will dramatically reduce the overall 
screen failure rate.  For example, with the biomarker prevalence rates anticipated for 
molecular targets in this protocol, and a minimum of 4 drug/biomarker trial sub-studies 
open at any one time, a “hit rate” of well over 60% can be achieved, making the screening 
process worthwhile for patients and physicians alike.  Second, there are processes and 
operational efficiencies gained by having a single master protocol, which could be 
amended as needed as drugs enter and exit the study.  A master protocol will also provide 
consistency, as every drug for the disease would be tested in the identical manner. 
Sponsors may be encouraged to include their drug in a master registration trial if there 
were assurances that if pre-specified efficacy and safety criteria were met during the Phase 
II/III process, the drug and accompanying companion diagnostic would be approved. 
Finally, by improving the overall efficiency of drug development in a specific disease 
setting, this trial offers the advantage of bringing safe and effective drugs to patients sooner 
than they might otherwise be available. 
 
2.2 
Choice of Disease Setting 
 
We have chosen to use lung cancer as the prototype disease for this Master Protocol.  
Lung cancer is the most common cancer today, with an estimated 228,190 new cases 
expected in the United States in 2013 alone.  (4)  Non-small cell lung cancer (NSCLC) is 
characterized by multiple and often independent mutations and potential therapeutic 
targets, and screening is rapidly becoming a part of treatment in some subtypes of lung 
cancer, such as adenocarcinoma, making it an excellent case study for a multi-sub-study 
biomarker driven Master Protocol. 
 
 

 
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Genomic characterization studies of lung adenocarcinomas conducted over the last 10 
years have revealed a number of therapeutically targetable alterations, many of which have 
received therapeutic validation.  This has led to a transformation of our standard of care 
approach for these patients that are now routinely molecularly genotyped in an attempt to 
pair the identified mutation with the appropriate targeted therapy.  Similar progress in 
genotyping is being made for squamous cell carcinoma of the lung (SCCA) primarily led 
by The Cancer Genome Atlas (TCGA) but also other sequencing efforts.  (5, 6)  A number 
of the alterations that have been identified are targetable but relatively uncommon, while 
others are more common but not as readily actionable.  (7)  Lung SCCA remains an 
“orphan” group where substantial developments in targeted therapeutics have yet to be 
seen and all the targeted therapies so far approved in NSCLC, are largely ineffective.  In 
hopes of identifying promising compounds in this setting, the selection of subgroups 
(genotype or phenotype-driven) is a strategy which is increasingly adopted in clinical trials.  
Thus, we are proposing a multi-sub-study Master Protocol combining Phase II and Phase 
III, where interim endpoints are met, in a disease setting representing a major unmet need 
in cancer therapy: SCCA.  This approach will provide the basis for FDA approval of new 
drugs with matching companion diagnostics.  If this multi-sub-study Master Protocol 
strategy is successful, this type of biomarker-driven umbrella protocol could be used for 
registration trials in other settings. The FDA recently approved the PD-1 checkpoint 
inhibitor nivolumab for the treatment of lung SCCA based on a Phase 3 trial of nivolumab 
versus docetaxel based on overall survival benefit and checkpoint inhibitor therapy is a 
major component of the Master protocol strategy. (8) 
 
2.3 
Study Design 
 
This is a prospective, multi-sub-study master registration protocol, in which patients with 
advanced stage lung SCCA (previously treated), are assigned to a biomarker-driven 
targeted therapy (TT) phase II study with the primary objective being overall response rate.  
If the objective response rate observed in the phase II study is judged sufficient the study 
will proceed into a Phase III trial in which patients will be randomized to biomarker-driven 
targeted therapy or SoC.  Each sub-study is defined by a genotypically defined alteration 
(biomarker) in the tumor and a drug (or drug combination) that targets it.  Each sub-study 
will function autonomously and will open and close independently of the other sub-studies.  
The candidate drugs must have demonstrated biologic activity against the target 
associated with a proposed predictive biomarker(s).  Drug combinations in the 
experimental arm will be allowed in appropriate settings and where appropriate the control 
arm may consist of FDA approved targeted therapy such as erlotinib.  Archival formalin-
fixed paraffin-embedded (FFPE) tumor will be screened by a broad analytically validated 
testing next generation sequencing (NGS) platform centrally to establish eligibility within 
10-14 days.  This platform will be supplemented by individual immune-histochemical (IHC) 
protein assays performed in a CLIA setting as necessitated by the specific experimental 
agent used.  Core needle biopsies for fresh tumor tissue may be necessary when archival 
tumor tissue is not available or on a drug-biomarker-specific basis. 
 
Patients with tumors that do not match one of the currently active drug-biomarker 
combinations (“non-match” patients) will be assigned to a specific “non-match” sub-study 
and randomized to either treatment with a designated “non-match” drug (anticipated to 
initially consist of an agent targeting PD-L1) or SoC.  This is a really important sub-study 
as it will serve as the anchor for S1400 and will provide access to an exciting new therapy 
approach for patients whose tumors do not harbor the genomic abnormalities targeted (or 
express the biomarker) in the other sub-studies, while ensuring that the screen failure rate 
will be low for the trial overall. 
 
 

 
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As described in preliminary discussions with the FDA, it is anticipated that the broad 
Foundation Medicine NGS testing platform may itself be suitable for registration purposes, 
while other methods may be required for companion diagnostic status for a given 
experimental agent/biomarker protocol sub-study.  (9)  In addition, it is expected that 
patients will be “pre-screened” in advance during first-line therapy in order to reduce delay 
in S1400 enrollment at the time of failure on first line therapy. Patients will be separately 
consented for screening and treatment randomization. 
 
The Foundation Medicine NGS Assay to be used for identification of genomic alterations 
in the subject tumor in the master protocol for previously treated squamous cell lung cancer 
S1400 will be based on Foundation Medicine’s T5 assay for cancer gene profiling. For this 
study, pre-specified classification rules will be applied to data generated by the T5 assay 
to place patients into biomarker defined groups. The laboratory process used for the 
Foundation Medicine NGS Assay is a robust, multi-step protocol to generate targeted deep 
sequence data from adaptor-ligated sequencing libraries of DNA extracted from FFPE 
tissue. The workflow is executed in a Clinical Laboratory Improvement Amendments 
(CLIA)-certified and College of American Pathologists (CAP) accredited laboratory and 
begins with sample receipt and accessioning into a laboratory information management 
system (LIMS), incorporates the generation of targeted sequencing data on an NGS 
platform, and culminates with a customized analysis pipeline capable of detecting genomic 
alterations with high accuracy. Multiple steps of the process are run on automated liquid 
handlers to ensure consistency/efficiency. The assay includes process-matched controls 
in each run, and defined quality control (QC) metrics are used throughout the process to 
monitor sample and assay performance.  
 
2.4 
SP44 anti-C-MET Immunohistochemistry (IHC) Assay 
 
c-Met overexpression has been reported in NSCLC, with varying prevalence depending on 
method of evaluation and scoring. For example, c-Met positivity has been reported in 
24.4%-29% of patients with squamous cell lung cancer. (10,11) Though c-Met protein 
overexpression is common in NSCLC, strategies thus far to select patients based on 
overexpression for treatment with anti-c-Met monoclonal antibodies and small molecule 
inhibitors of c-Met have failed to show clinical benefit in large randomized studies. ABBV-
399 (Process II) is a based on a different mechanism of action, i.e. to use the c-Met 
expression to deliver the toxin, and thus has a potential to improve the quality of life and 
outcome of patients with squamous cell lung cancer, based on its tolerability and 
preliminary efficacy.  
 
2.5 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  Accrual is expected to reach between 500 and 
800 patients per year. The minimum and maximum anticipated annual accrual in the 
ethnicity/race and sex categories are shown in the tables below.  
 
 

 
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Assuming 500 patients accrued in a year: 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
6 
9 
15 
Not Hispanic or Latino 
210 
275 
485 
Total Ethnic 
216 
284 
500 
Racial Category 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
4 
7 
11 
Black or African American 
16 
26 
42 
Native Hawaiian or other Pacific Islander 
2 
3 
5 
White 
193 
248 
441 
Racial Category: Total of all Subjects 
216 
284 
500 
 
Assuming 800 patients accrued in a year: 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
10 
14 
24 
Not Hispanic or Latino 
336 
440 
776 
Total Ethnic 
346 
454 
800 
Racial Category 
American Indian or Alaskan Native 
2 
0 
2 
Asian 
6 
11 
17 
Black or African American 
26 
42 
68 
Native Hawaiian or other Pacific Islander 
2 
3 
5 
White 
310 
398 
708 
Racial Category: Total of all Subjects 
346 
454 
800 
 
 
3.0 
DRUG INFORMATION 
 
Please see Section 18.2 for sub-study specific drug information and sub-study specific treatment 
plans.  
 
Investigator’s Brochures 
 
For information regarding Investigator’s Brochures, please refer to SWOG Policy 15. For S1400, 
the investigational drugs are being provided under an IND held by SWOG. For INDs filed by SWOG, 
the protocol serves as the Investigator Brochure for the performance of the protocol. In such 
instances submission of the protocol to the IRB should suffice for providing the IRB with information 
about the drug. However, in cases where the IRB insists on having the official Investigator Brochure 
from the company, requests may be submitted to the CTSU website by completing the CTSU 
Request for Clinical Brochure. 
 
 

 
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4.0 
STAGING CRITERIA 
 
Patients must have Stage IV disease as outlined below (AJCC Cancer Staging Manual, 7th Edition, 
2010): 
 
Stage IV 
Any T Any N M1a 
 
 
Any T Any N M1b 
 
Primary Tumor (T) 
 
TX 
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in 
sputum or bronchial washings but not visualized by imaging or bronchoscopy 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
T1 
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the 
main bronchus)* 
T1a 
Tumor 2 cm or less in greatest dimension 
T1b 
Tumor more than 2 cm but 3 cm or less in greatest dimension 
T2 
Tumor more than 3 cm but 7 cm or less or tumor with any of the following features (T2 
tumors with these features are classified T2a if 5 cm or less); Involves main bronchus, 2 
cm or more distal to the carina; Invades visceral pleura (PL1 or PL2); Associated with 
atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve 
the entire lung 
T2a 
Tumor more than 3 cm but 5 cm or less in greatest dimension 
T2b 
Tumor more than 5 cm but 7 cm or less in greatest dimension 
T3 
Tumor more than 7 cm or one that directly invades any of the following:  parietal pleural 
(PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal 
pleura, parietal pericardium; or tumor in the main bronchus (less than 2 cm distal to the 
carina* but without involvement of the carina; or associated atelectasis or obstructive 
pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe 
T4 
Tumor of any size that invades any of the following:  mediastinum, heart, great vessels, 
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor 
nodule(s) in a different ipsilateral lobe 
 
* 
The uncommon superficial spreading tumor of any size with its invasive component limited 
to the bronchial wall, which may extend proximally to the main bronchus, is also classified 
as T1a. 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastases 
N1 
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and 
intrapulmonary nodes, including involvement by direct extension 
N2 
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s) Distant Metastasis (M) 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
M1a 
Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant 
pleural (or pericardial) effusion ** 
M1b 
Distant metastasis 
 

 
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** 
Most pleural (and pericardial) effusions with lung cancer are due to tumor.  In a few 
patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are 
negative for tumor, and the fluid is non-bloody and is not an exudate.  Where these 
elements and clinical judgment dictate that the effusion is not related to the tumor, the 
effusion should be excluded as a staging element and the patient should be classified as 
M0. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following sections must be met in order for a patient to be considered 
eligible for the corresponding registration. Section 5.1 must be met prior to screening/pre-screening 
registration, while Section 5.2 must be met prior to sub-study registration. Use the spaces provided 
to confirm a patient's eligibility.  For each criterion requiring test results and dates, please record 
this information on the S1400 Onstudy Form and submit via Medidata Rave® (see Section 14.0).  
Any potential eligibility issues should be addressed to the Data Operations Center in Seattle at 
S1400question@crab.org prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28.  This allows for efficient patient scheduling without exceeding the guidelines.  
If Day 7, 14, 16, 28 or 42 falls on a weekend or holiday, the limit may be extended to the next 
working day. 
 
5.1 
Screening/Pre-Screening Registration  
 
a. 
Patients must have pathologically proven squamous cell carcinoma (SCCA) 
cancer of the lung confirmed by tumor biopsy and/or fine-needle aspiration.  
Disease must be Stage IV SCCA as defined in Section 4.0, or recurrent. The 
primary diagnosis of SCCA should be established using the current WHO/IASLC-
classification of Thoracic Malignancies.  (12)  The diagnosis is based on H&E 
stained slides with or without specific defined IHC characteristic (p40/p63 positive, 
TTF1 negative) if required for diagnosis.  Mixed histologies are not allowed. 
 
b. 
Patients must either be eligible to be screened at progression on prior treatment 
or to be pre-screened prior to progression on current treatment. Patients will either 
consent to the Screening consent or the Pre-Screening consent, not both. These 
criteria are: 
 
1. 
Screening at progression on prior treatment:  
To be eligible for screening at progression, patients must have received at 
least one line of systemic therapy for any stage of disease (Stages I-IV) 
and must have progressed during or following their most recent line of 
therapy. For patients whose prior systemic therapy was for Stage I-III 
disease only (i.e. patient has not received any treatment for Stage IV or 
recurrent disease), the prior systemic therapy must have been a platinum-
based chemotherapy regimen and disease progression on the platinum-
based chemotherapy must have occurred within one year from the last 
date that patient received that therapy. For patients whose prior therapy 
was for Stage IV or recurrent disease, the patient must have received at 
least one line of a platinum-based chemotherapy regimen or checkpoint 
inhibitor therapy (e.g. Nivolumab or Pembrolizumab).   
 
2. 
Pre-Screening prior to progression on current treatment:   
To be eligible for pre-screening, current treatment must be for Stage IV or 
recurrent disease and patient must have received at least one dose of the 

 
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current regimen. Patients must have previously received or currently be 
receiving a platinum-based chemotherapy regimen or checkpoint inhibitor 
therapy (e.g. Nivolumab or Pembrolizumab). Patients on first-line 
treatment are eligible upon receiving Cycle 1, Day 1 infusion.  Note:  
Patients will not receive their sub-study assignment until they 
progress and the S1400 Notice of Progression is submitted. 
 
c. 
Patients must have adequate tumor tissue available, defined as ≥ 20% tumor cells 
and ≥ 0.2 mm3 tumor volume.  
• 
The local interpreting pathologist must review the specimen.  
• 
The pathologist must sign the S1400 Local Pathology Review Form 
confirming tissue adequacy prior to screening/pre-screening registration.   
 
Patients must agree to have this tissue submitted to Foundation Medicine for 
common broad platform CLIA biomarker profiling and c-Met IHC (see Section 
15.1).  If archival tumor material is exhausted, then a new fresh tumor biopsy that 
is formalin-fixed and paraffin-embedded (FFPE) must be obtained.  A tumor block 
or FFPE slides 4-5 microns thick must be submitted. Bone biopsies are not 
allowed. If FFPE slides are to be submitted, at least 12 unstained slides plus an 
H&E stained slide, or 13 unstained slides must be submitted. However, it is 
strongly recommended that 20 FFPE slides be submitted. Note:  Previous next-
generation DNA sequencing (NGS) will be repeated if done outside this study for 
sub-study assignment. 
 
Patients must agree to have any tissue that remains after NGS testing retained for 
the use of the Translational Medicine (TM) studies (if such TM studies are defined) 
within any sub-study the patient is enrolled in. 
 
d. 
Patients must not have a known EGFR mutation, or ALK fusion.  EGFR/ALK 
testing is not required prior to registration and is included in the FMI testing for 
screening/prescreening. 
 
e. 
Patients must have Zubrod performance status 0-1 (see Section 10.4) documented 
within 28 days prior to screening/pre-screening registration. 
 
f. 
Patients must be ≥ 18 years of age. 
 
g. 
Patients must also be offered participation in banking for future use of specimens 
as described in Section 15.0. 
 
h. 
Patients must be willing to provide prior smoking history as required on the S1400 
Onstudy Form. 
 
i. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
j. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
k.  
U.S. patients who can complete the survey and the interview by telephone or email 
in English must be offered participation in the S1400GEN Survey Ancillary Study 
(see Sections 15.5 and 18.1f). NOTE: Patients enrolled to S1400 prior to Revision 
#12 are not eligible for the S1400GEN Survey Ancillary Study. Study physicians 

 
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will provide participants with a hard copy of the survey (at the time of informed 
consent) to improve tracking and comprehension during the interview. 
 
5.2 
Sub-study Registration  
 
For patients screened at progression on prior treatment, a sub-study assignment from the 
SWOG Statistical Center should be received within 16 days of tissue submission.  
 
For patients pre-screened prior to progression on current therapy, submission of the S1400 
Notice of Progression Form is required to receive a sub-study assignment. The sub-study 
assignment should be received from the SWOG Statistical Center within 1 day of 
submission of the S1400 Notice of Progression (provided at least 16 days have passed 
since tissue submission). Patients must then register to the assigned sub-study in order to 
receive their treatment assignment.  
 
After progression on an S1400 sub-study, the S1400 Request for New Sub-Study 
Assignment Form may be submitted to receive a new sub-study assignment (see Section 
14.6). The new sub-study assignment should be received from the SWOG Statistical 
Center within 1 day of submission of the S1400 Request for New Sub-Study Assignment 
Form. Patients must then register to the assigned sub-study to receive their treatment 
assignment. 
 
Patient must meet the eligibility criteria listed in Section 5.0 of the assigned sub-study.  The 
common eligibility criteria are included here.  For ease of reference, these common 
eligibility criteria have also been incorporated into Section 5.0 of each of the sub-studies.  
If patient does not meet the additional criteria listed in Section 5.0 of the assigned sub-
study, submit the S1400 Request for Sub-Study Reassignment Form.  (See Section 18.1a 
for biomarker reporting.) Any potential eligibility issues should be addressed to the Data 
Operations Center in Seattle at S1400question@crab.org prior to registration. 
 
a. 
Patients whose biomarker profiling results indicate the presence of an EGFR 
mutation or EML4/ALK fusion are not eligible. Due to existence of approved 
therapies the biomarker exclusion rules are as follows: 
 
Gene 
Alteration type 
Ineligible Alteration 
EGFR 
Substitution 
L858R, T790M, A289V, G719A, S768I, 
G719C, R108K, G598V, R222C, L62R, 
L861Q, P596L, V774M 
Indel 
non-frame shifting insertions or deletions 
between amino acids 740 and 780, in exons 
19 and 20, transcript NM_005228 
Fusion 
None 
Amplification 
None 
ALK 
Substitution 
None 
Indel 
None 
Fusion 
EML4-ALK, CLIP4-ALK, CLTC-ALK, KIF5B-
ALK, NPM1-ALK, RANB2-ALK, STRN-ALK, 
TFG-ALK 
Amplification 
None 
 

 
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b. 
Patients must have progressed (in the opinion of the treating investigator) following 
the most recent line of therapy. 
 
c. 
Patients must not have received any prior systemic therapy (systemic 
chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub-
study registration.  Patients must have recovered (≤ Grade 1) from any side effects 
of prior therapy.  Patients must not have received any radiation therapy within 14 
days prior to sub-study registration. (See 5.2e for criteria regarding therapy for 
CNS metastases). 
 
d. 
Patients must have measurable disease (see Section 10.1) documented by CT or 
MRI.  The CT from a combined PET/CT may be used to document only non-
measurable disease unless it is of diagnostic quality as defined in Section 10.1c.  
Measurable disease must be assessed within 28 days prior to sub-study 
registration.  Pleural effusions, ascites and laboratory parameters are not 
acceptable as the only evidence of disease.  Non-measurable disease must be 
assessed within 42 days prior to sub-study registration.  All disease must be 
assessed and documented on the Baseline Tumor Assessment Form.  Patients 
whose only measurable disease is within a previous radiation therapy port must 
demonstrate clearly progressive disease (in the opinion of the treating investigator) 
prior to registration. See Sections 15.0 and 18.1c for guidelines and submission 
instructions for required central radiology review. 
 
e. 
Patients must have a CT or MRI scan of the brain to evaluate for CNS disease 
within 42 days prior to sub-study registration.  Patient must not have 
leptomeningeal disease, spinal cord compression or brain metastases unless:  (1) 
metastases have been locally treated and have remained clinically controlled and 
asymptomatic for at least 14 days following treatment and prior to registration, AND 
(2) patient has no residual neurological dysfunction and has been off 
corticosteroids for at least 24 hours prior to sub-study registration. 
 
f. 
Patient must have fully recovered from the effects of surgery at least 14 days prior 
to sub-study registration. 
 
g. 
Patients must not be planning to receive any concurrent chemotherapy, 
immunotherapy, biologic or hormonal therapy for cancer treatment.  Concurrent 
use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and 
hormone replacement therapy) is acceptable. 
 
h. 
Patients must have an ANC ≥ 1,500 mcL, platelet count ≥ 100,000 mcL and 
hemoglobin ≥ 9 g/dL obtained within 28 days prior to sub-study registration. 
 
i. 
Patients must have adequate hepatic function as defined by serum bilirubin ≤ 
Institutional Upper Limit of Normal (IULN) and either ALT or AST ≤ 2 x IULN within 
28 days prior to sub-study registration (if both ALT and AST are done, both must 
be < 2 IULN).  For patients with liver metastases, bilirubin and either ALT or AST 
must be ≤ 5 x IULN (if both ALT and AST are done, both must be ≤ 5 x IULN). 
 
j. 
Patients must have a serum creatinine ≤ the IULN OR measured or calculated 
creatinine clearance ≥ 50 mL/min using the following Cockroft-Gault Formula: 
 
Calculated Creatinine Clearance = (140 - age) X (actual body weight in kg) † 
 
72 x serum creatinine* 
 
Multiply this number by 0.85 if the patient is a female. These tests must have been 
performed within 28 days prior to sub-study registration. 

 
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† The kilogram weight is the patient weight with an upper limit of 140% of the 
IBW. 
* Actual lab serum creatinine value with a minimum of 0.8 mg/dL. 
 
k. 
Patients must have Zubrod performance status 0-1 (see Section 10.4) documented 
within 28 days prior to sub-study registration.  
 
l. 
Patients must not have any Grade III/IV cardiac disease as defined by the New 
York Heart Association Criteria (i.e., patients with cardiac disease resulting in 
marked limitation of physical activity or resulting in inability to carry on any physical 
activity without discomfort), unstable angina pectoris, and myocardial infarction 
within 6 months, or serious uncontrolled cardiac arrhythmia (see Section 18.1b). 
 
m. 
Patients must not have documented evidence of acute hepatitis or have an active 
or uncontrolled infection. 
 
n. 
Patients with a known history of HIV seropositivity: 
 
1. 
Must have undetectable viral load using standard HIV assays in clinical 
practice. 
2. 
Must have CD4 count ≥ 400/mcL. 
3. 
Must not require prophylaxis for any opportunistic infections (i.e., fungal, 
mAC, or PCP prophylaxis). 
4. 
Must not be newly diagnosed within 12 months prior to sub-study 
registration.  
 
o. 
Prestudy history and physical exam must be obtained within 28 days prior to sub-
study registration. 
 
p. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 
Stage I or II cancer from which the patient is currently in complete remission, or 
any other cancer from which the patient has been disease free for five years. 
 
q. 
Patients must not be pregnant or nursing.  Women/men of reproductive potential 
must have agreed to use an effective contraceptive method.  A woman is 
considered to be of "reproductive potential" if she has had menses at any time in 
the preceding 12 consecutive months.  In addition to routine contraceptive 
methods, "effective contraception" also includes heterosexual celibacy and 
surgery intended to prevent pregnancy (or with a side-effect of pregnancy 
prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation.  However, if at any point a previously celibate patient chooses to become 
heterosexually active during the time period for use of contraceptive measures 
outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
r. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
 

 
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s. 
Patients with impaired decision-making capacity are eligible as long as their 
neurological or psychological condition does not preclude their safe participation 
in the study (e.g., tracking pill consumption and reporting adverse events to the 
investigator). 
 
t. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
 
6.0 
STRATIFICATION FACTORS 
 
For sub-studies employing Design #1, within each sub-study, patients will be randomized between 
sub-study treatment arms using block randomization.  See Section 6.0 in each sub-study for sub-
study specific stratification factors. 
 
 
7.0 
TREATMENT PLAN 
 
7.1 
Treatment 
 
See Section 18.2 for sub-study specific treatment information. 
 
7.2 
Radiology Review 
 
a. 
To ensure the highest standards and consistency between different centers, all 
scans for disease assessment (baseline, interim and end of treatment scans) must 
be submitted to the National Cancer Institute’s National Clinical Trials Network 
(NCTN) Imaging and RT Quality Assurance Service Core (IROC) in Ohio for 
centralized review (see Section 15.0). 
 
b. 
Centralized review will be performed by 3 radiology experts.  The scans will be 
submitted to IROC.  IROC will transmit the scans to the reviewers who will transmit 
the results to the SWOG Statistical Center. 
 
c. 
Details of submission of scans to IROC for centralized review and on the central 
review process are listed in Section 15.0 and 18.1c. 
 
7.3 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented on the Off Treatment 
Notice. 
 
7.4 
Follow Up Period 
 
Patients who have been registered to the pre-screening/screening component, but not 
registered/randomization to a treatment arm of any of the sub-studies will be followed until 
sub-study registration or death, whichever comes first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
See Section 18.2 for sub-study specific toxicities to be monitored and dose modifications. 
 

 
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9.0 
STUDY CALENDAR 
 
See Section 18.2 for sub-study specific study calendars. 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm 
with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters. 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease. Note:  Lymph nodes 
that have a short axis < 1.0 cm (10 mm) are considered non-pathological and 
should not be recorded or followed. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are considered non-
measurable as are previously radiated lesions that have not progressed. 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT. 
 
NOTE REGARDING DIAGNOSTIC QUALITY:   
 
CT – Computed Tomograph Imaging 
 

 
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In order for a CT to be of diagnostic quality to be used in determining 
measurable disease, the slice thickness needs to match the protocol 
Section 10.0. 
 
Recommended Scan mode: 
Multi-detector and/or helical 
Contrast Enhancement: 
IV and oral contrast unless contraindicated 
Slice Section thickness: 
maximum 5mm, preferable 2.5mm or less 
Slice Increment: 
continuous or overlapping sections; no gaps 
Imaging Region: 
Thoracic inlet through adrenal glands (and 
appropriate scans if disease exists elsewhere) 
Image Matrix size: 
512 × 512 or better 
Image Reconstruction / Filter
： 
Institutional standard 
 
If a CT scan is performed with a slice thickness greater than 5 mm 
then lesions must be twice the slice thickness. If any PET/Spiral CT 
is used at baseline where the CT is of diagnostic quality, follow-up 
scans can be done by a spiral CT.  
 
If any PET/Conventional CT is used at baseline where the CT is of 
diagnostic quality, follow-up scans can be done by conventional CT. 
 
Institutions will have to submit radiology reports documenting that 
the CT used in PET/CT is of diagnostic quality. No other methods of 
assessments are interchangeable. 
 
MRI – Magnetic Resonance Imaging  
MRI can be performed using a 1.5 or 3.0 T field strength. If a MRI is 
performed instead of a CT, the MRI can be performed according to 
institutions clinical standard of care protocols with slice thickness of no 
more than 5mm (in transverse).  
If an MRI scan is performed with a slice thickness greater than 5 mm, then 
lesions must be twice and above the slice thickness. 
 
PET/CT – Positron Emission Tomography with FDG  
When a FDG PET/CT is performed, the emission scans should be started 
in the range of 60 – 75 min after FDG injection, otherwise use your 
institution protocols. It is necessary for follow up scans that they are 
performed in an identical way to the baseline with the same PET/CT 
scanner and a variation in timing of no more than +/- 10 min. Preferably, 
schedule the patient for both baseline and follow-up scans at the same 
time of day (AM or PM) to improve reproducibility. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts. 
 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 

 
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10.2 
Objective Status at Each Disease Evaluation 
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease. 
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas. Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans. For study-specific imaging requirements, see the Study 
Calendar in the appropriate sub-study specific section. 
 
Disease evaluations for patients treated with MEDI4736 will also utilize an alternative 
system of immune-related response criteria (irRC) which is described in detail in S1400A. 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.   Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline. 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
d. 
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  Appearance of any new lesion/site.  Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see Section 10.2e). 
 
 
If a new lesion is equivocal, for example because of its small size, continued 
therapy and follow-up evaluation will clarify if it represents truly new disease. If 
repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm. 
 

 
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1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion. 
 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a confirmation 
by anatomical assessment (e.g. CT, MRI, x-ray) as new site of disease to 
be considered progressive disease.  In such a case, the date of 
progressive disease will be the date of the initial abnormal FDG-PET.  
e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
f. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician). 
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression. 
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed. 
 
5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression. However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter the size of the 
effusion. 
 

 
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7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate. 
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b. 
PR:  Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above. 
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
2 
Ambulatory and capable of self-care but unable to carry out 
anywork activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 

 
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10.5 
Time to Death 
 
From date of sub-study registration (or date of screening/pre-screening registration if 
patient never enrolls in a sub-study) to date of death due to any cause.  Patients last known 
to be alive are censored at date of last contact. 
 
10.6 
Investigator-Assessed Progression-Free Survival 
 
From date of sub-study registration to date of first documentation of progression assessed 
by local review or symptomatic deterioration (as defined above), or death due to any cause.  
Patients last known to be alive without report of progression are censored at date of last 
disease assessment. For patients with a missing scan (or consecutive missing scans) 
whose subsequent scan determines progression, the expected date of the first missing 
scan (as defined by the disease assessment schedule) will be used as the date of 
progression.  
 
10.7 
Progression-Free Survival by Central Review 
 
From date of sub-study registration to date of first documentation of progression assessed 
by central review or symptomatic deterioration (as defined above), or death due to any 
cause.  Patients last known to be alive without report of progression are censored at date 
of last disease assessment. For patients with a missing scan (or consecutive missing 
scans) whose subsequent scan determines progression, the expected date of the first 
missing scan (as defined by the disease assessment schedule) will be used as the date of 
progression.  
 
10.8 
Duration of Response (DoR) 
 
From date of first documentation of response (CR or PR) to date of first documentation of 
progression assessed by local review or symptomatic deterioration (as defined above), or 
death due to any cause among patients who achieve a response (CR or PR).  Patients last 
known to be alive without report of progression are censored at date of last disease 
assessment. For patients with a missing scan (or consecutive missing scans) whose 
subsequent scan determines progression, the expected date of the first missing scan (as 
defined by the disease assessment schedule) will be used as the date of progression. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
As stated above, the design of S1400 is multi-sub-study design.  The conduct of each sub-study 
proceeds independently of the other sub-studies with decisions at the interim and final analyses 
within one study having no impact on other sub-studies.   This Protocol employs a “hybrid” master 
protocol in which the design for a given sub-study is chosen from a limited number of clinical trials 
designs based on the expected biomarker prevalence and background data.  The design options 
for the sub-studies include Design #1 a Phase II/III design (see Section 11.1) and Design #2 a 
Single Arm Phase II followed by a Randomized Phase III (under specified conditions) (see Section 
11.2).  The objectives for each design are included in Section 1.0 and the statistical considerations 
for each design are included in this section. 
 
Sub-study eligibility will be based on the results of biomarker analysis at screening.  Patients with 
a single “positive” biomarker will be assigned to the associated sub-study.  Patients with no 
“positive” biomarkers will be assigned to the non-match sub-study.  Patients eligible for multiple 
sub-studies based on the results of the biomarker analysis will be randomized to sub-study 
assignment.  The randomization ratio will be the ratio of the prevalence of the biomarkers allowing 
for a greater likelihood of assignment to the study with the lower prevalence (e.g. for two markers 

 
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with 5% and 15% prevalence, the randomization ratio will be 3:1 in favor of the lower prevalence 
biomarker; for three biomarkers with 5%, 10% and 15% prevalence, the ratio will be 6:3:2, and so 
on).  However, the ratio will be bounded such that no biomarker sub-study has more than a 4-fold 
chance of assignment.  As sub-studies are closed or new sub-studies added the randomization 
ratio will be modified based on the sub-study biomarker prevalence for the actively accruing studies.  
Initial estimates of sub-study biomarker prevalence from sources outside this study will be used to 
determine the assumed prevalence of the sub-study biomarkers for determination of these sub-
study assignment randomization ratios.  If a specific sub-study biomarker prevalence estimate is 
substantially different from initial estimate, the prevalence estimates may be updated at most once 
during the conduct of the associated sub-study. 
 
11.1 
Design #1: Phase II/III Design 
 
a. 
Primary Endpoint 
 
Phase II Component:  The primary objective within the Phase II component is to 
compare investigator-assessed PFS (IA-PFS) between investigational therapy 
versus standard of care (SoC) in patients with advanced stage refractory 
squamous cell carcinoma (SCCA) of the lung.  The investigational therapy arm will 
be judged to have provided sufficient evidence to proceed to the Phase III 
component if the Phase II interim futility analysis at 55 progression events does 
not rule out the hypothesized improvement in median PFS (see Section 11.1c for 
details). 
 
Phase III Component: The Phase III design has two co-primary objectives:  an 
evaluation of IA-PFS and OS. 
 
1. 
The primary PFS objective within the Phase III component of each sub-
study is to rule out less than a 33% improvement (HR = 0.75) in median 
IA-PFS (or equivalently less than a one-month difference in medians) 
between investigational therapy and SoC in patients with advanced stage 
refractory squamous cell carcinoma (SCCA) of the lung. 
 
2. 
The primary OS objective within the Phase III component of each sub-
study is to compare overall survival (OS) in patients with advanced stage 
refractory SCCA of the lung randomized to receive investigational therapy 
versus SoC. 
 
b. 
Secondary Endpoints 
 
Phase II Component:  Secondary objectives of the Phase II interim analysis will be 
to compare response rate (RR; confirmed and unconfirmed) and toxicity 
frequencies between the two arms within each sub-study. 
 
Phase III Component:  Secondary objectives of the Phase III component will be to 
compare response rate (RR; confirmed and unconfirmed), IA-PFS, censoring 
patients with symptomatic deterioration (SD) at the time of SD, and toxicity 
frequencies between the two arms within each sub-study. 
 
c. 
Sample Size with Power Justification 
 
The total sample size for each independently conducted Phase II/III sub-study is 
determined based on the biomarker prevalence, with all other design parameters 
the same across sub-studies.  Details regarding the sample size for each sub-
study is included in the Statistical Considerations in the sub-study protocol for each 
sub-study.  (13) 

 
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Phase II Design:  The Phase II interim futility analysis within each sub-study is to 
occur upon the observation of 55 investigator-assessed progression events.  Sub-
studies will follow either Plan A or Plan B for this interim analysis.  Specification of 
plan for each sub-study is stated in the sub-study specific protocols (see Section 
18.0). 
 
Plan A:  The size is based on a design that targets a 2-fold increase in median IA-
PFS with investigational therapy (HR =0.5) with 90% power and a 10% 1-sided 
type I error rate.  The futility boundary will be crossed if the alternative hypothesis 
of a 2-fold increase (HR = 0.5) is rejected at the 1-sided 10% level.  This design 
has a 90% chance of stopping for futility under the null (1-α) and a 10% chance of 
falsely rejecting the alternative under a true 2-fold increase (1-Power).  The 
approximate threshold associated with these parameters for continuation of the 
study past the Phase II interim futility analysis is the observation of at least a 41% 
improvement in median PFS (HR = 0.71). 
 
Plan B:  The size is based on a design that targets a 2.5-fold increase in median 
IA-PFS with investigational therapy (HR =0.4) with 95% power and a 4% 1-sided 
type I error rate.  The futility boundary will be crossed if the alternative hypothesis 
of a 2.5-fold increase (HR=0.4) is rejected at the 1-sided 5% level.  This design 
has a 96% chance of stopping for futility under the null and a 5% chance of falsely 
rejecting the alternative under a true 2.5-fold increase.  The approximate threshold 
associated with these parameters for continuation of the study past the Phase II 
interim futility analysis is the observation of at least a 63% improvement in median 
PFS (HR=0.61). 
 
Phase III Design:  While a co-primary objective is the comparison of IA-PFS 
between the arms, the sample size for Phase III component of each sub-study is 
based on a design that targets a 50% improvement in median OS (HR=0.67) with 
90% power and a 2.5% 1-sided type I error rate.  This design requires 256 deaths.   
 
The primary analysis of IA-PFS will be based on ruling out the null hypothesis of 
less than or equal to a 33% improvement in median PFS (an HR of 0.75 or greater). 
Assuming the median PFS in the control arm is 3 months, then, this evaluation is 
ruling out a month or less difference between the arms.  The expected number of 
IA-PFS events by the observation of 256 deaths.  The final analysis for PFS will 
occur after completion of accrual, when either the 290 IA-PFS events have been 
observed or the maximum number of expected IA-PFS events has occurred if the 
sample size is less than 290 patients.  With 290 PFS events and under the design 
assumptions, testing the IA-PFS null hypothesis of a HR equal to 0.75 at the 0.014 
level has 90% power to detect HR of 0.5 (a 2-fold increase in median PFS).  The 
approximate threshold for determining PFS is both clinically and statistically 
significant is a 75% improvement in median PFS (HR = 0.57).  The 0.014 level for 
testing IA-PFS was chosen based on this desired level of clinical significance. 
 
d. 
Analysis Plan Including Plans for Formal Interim Analysis 
 
Primary analyses will be performed on an intent-to-treat basis.  Stratified (using 
randomization stratification factors) log-rank test will be used to test the primary 
hypotheses related to PFS and OS comparing the two treatment arms at the levels 
specified below for the Phase II and Phase III components.  A Cox proportional 
hazards (PH) model will be used to estimate the hazard ratios and associated 
confidence intervals.  Analysis of response rates and toxicities will be performed 
using a chi-square or Fisher’s exact test, as appropriate.  The primary analysis of 
IA-PFS for the Phase III component will be done using a PH model score test (or 

 
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in other words, a modified log-rank test at the PFS null hazard ratio of 0.75 [the 
33% improvement in median PFS]).  (14) 
 
Secondary analysis of PFS and OS at the final analysis within each sub-study will 
be a weighted analysis (using Cox regression) standardizing the biomarker 
prevalence among patients with multiple biomarkers to the study population 
prevalence among all patients eligible as defined by the sub-study biomarker 
definition.  The goal of this analysis is to estimate the treatment effects had all 
patients with the sub-study biomarker been assigned to the sub-study (as in a 
stand-alone trial). 
 
Phase II Interim Analyses:  The Phase II analysis is a standard interim analysis (a 
rolling interim analysis) and does not include a temporary halt of accrual for 
evaluation.  This analysis will be performed upon the observation of 55 progression 
events. 
 
Plan A:  For this analysis, the alternative hypothesis of at least a 2-fold increase 
in median IA-PFS with investigational therapy versus SoC will be tested at the 1-
sided 0.10 level, using a PH model score test evaluated at the alternative 
hypothesis of HR = 0.5.  This design has a 90% chance of stopping for futility under 
the null hypothesis.  The approximate threshold for continuation of the study (i.e. 
not rejecting the alternative hypothesis) is the observation of at least a 41% 
improvement in median IA-PFS (HR=0.71), under the design assumptions.  If the 
alternative hypothesis is rejected, then the recommendation to the DSMB will be 
there is not sufficient evidence to continue to the Phase III portion of the study and 
the study should be permanently closed to accrual. 
 
Plan B:  For this analysis, the alternative hypothesis of at least a 2.5-fold increase 
in median IA-PFS with investigational therapy versus SoC will be tested at the 1-
sided 0.05 level (1-Power = β), using a PH model score test evaluated at the 
alternative hypothesis of HR = 0.4.  This design has a 96% chance of stopping for 
futility under the null hypothesis (1-α).  The approximate threshold for continuation 
of the study (i.e. not rejecting the alternative hypothesis) is the observation of at 
least a 63% improvement in median PFS, under the design assumptions.  If the 
alternative hypothesis is rejected, then the recommendation to the DSMB will be 
there is not sufficient evidence to continue to the Phase III portion of the study and 
the study should be permanently closed to accrual. 
 
In addition to evaluating IA-PFS at this analysis (for both Plans A and B), the 
response rate (confirmed and unconfirmed) will be compared between the arms to 
determine if there is evidence to stop the study for early signs of efficacy.  The 
outcome for this analysis will be the best objective response based on RECIST 1.1 
which will be evaluated among patients registered at least 6 weeks before the 
interim analysis or patients with known value for objective response (i.e. 
CR/PR/SD/PD/death). 
 
Response proportions will be compared using a 1-sided Fisher’s exact test at the 
0.001 level.  If the null hypothesis is rejected at the 0.001 level, the 
recommendation will be for the DSMC to evaluate the entirety of the study data to 
determine if the study should be closed early for signs of efficacy.  In other words, 
rejection of the null hypothesis for response is not an automatic stop for efficacy, 
additional efficacy outcomes such as IA-PFS should be supportive of early 
stopping as well. 
 

 
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Should neither the criteria for early stopping based on futility based on IA-PFS or 
early signs of efficacy based on response be met, the recommendation will be that 
study should continue into the Phase III portion of the study. 
 
Phase III Interim Analyses:  If the decision is to continue the study at the Phase II 
analysis, additional formal interim analyses are planned when 50% and 75% of the 
expected deaths have been observed with rules specified on the fixed-sample p-
value scale. 
 
Evidence suggesting early termination of the trial for futility/harm will be if the 
alternative hypothesis of at least 50% improvement in OS or the hypothesis of at 
least a 2-fold improvement in IA-PFS for the investigational therapy arm is rejected 
at the one-sided level 0.0025, using a PH model score test evaluated at the 
alternative hypothesis (e.g. Ha: HR=0.67 for OS and 0.5 for IA-PFS).  (15) 
 
Evidence suggesting early termination of the trial for superiority will be if the 
hypothesis of no difference in OS is rejected at the one-sided 0.0025 level using a 
log-rank test. 
 
The associated approximate thresholds for ratio of medians (as measured by the 
inverse HR or exp (β) from a Cox model) and p-values (against the null) for OS are 
presented in Table 1. 
 
Table 1: Interim Monitoring boundaries associated with monitoring rules 
OS 
events 
Futility Bound 
Efficacy Bound 
HR(SoC/Exp) 
p-value 
HR(SoC/Exp) 
p-value 
50% 
0.95 
0.614 
1.64 
0.0025 
75% 
1.04 
0.391 
1.50 
0.0025 
100% 
1.28 
0.024 
1.28 
0.024 
Against the null hypothesis of HR = 1. 
 
Final Analysis:  If the decision is to continue the study to completion, the final 
analysis of IA-PFS will occur after completion of accrual, when either 290 
progression events have been observed or the final analysis for OS is performed, 
whichever comes first.).  The expected IA-PFS analysis time is between 6 and 12 
months from study closure to accrual.  The final analysis of OS will take place when 
at least 256 events have been observed.  However, should events accumulate 
more slowly than anticipated, the maximum time to final analysis is when 18 
months have passed since the completion of accrual.  The analysis of IA-PFS will 
be a test against the null hypothesis of a 33% improvement in median IA-PFS (HR 
= 0.75) at the 0.014 level (which has 90% power for a 2-fold increase in IA-PFS), 
with an approximate observed threshold of 75% improvement in median IA-PFS 
(HR=0.57) for significance (deemed both significant in statistical and clinical 
terms).  In addition, it is considered that a clinically meaningful difference is the 
observation of at least a 2.25-month difference in median IA-PFS between the two 
arms for sub-studies evaluating single agent investigational therapy versus SoC.  
For sub-studies evaluating investigational therapy combinations, it is considered 
that a clinically meaningful difference is the observation of at least a 2.5-month 
difference in median IA-PFS between the two arms.  This design has less than a 
0.000001 chance of falsely rejecting the null hypothesis of an HR = 1, and therefore 
has a negligible effect on the study-wide false positive rate.  Therefore, in this 
sense, this design has co-primary endpoints IA-PFS and OS.  The final analysis of 
OS will be at level 0.024 to account for the effects of interim monitoring (using a 
modified Haybittle-Peto boundary).  The adjusted level does not account for either 
the IA-PFS assessment for futility or the response assessment for efficacy at the 

 
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Phase II interim analysis as the level of testing response is small (0.001) and the 
decision to stop for efficacy at this time point will also consider other clinical data. 
 
The actual decision to terminate accrual early will be made by the SWOG Data 
and Safety Monitoring Committee (DSMC), and will consider IA-PFS, OS, 
response, and toxicities. 
 
11.2 
Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III) 
 
This design includes two options: an option for evalution of a targeted therapy in a 
biomarker-defined patient population and an evaluation of a non-match therapy in patients 
who have received and progressed on/following therapy with an immunotherapy agent.  
 
a. 
Option for Biomarker-driven Subtudies 
 
1. 
Primary Endpoint 
 
Single Arm Phase II Component:  The primary objective within the Phase 
II component is to evaluate the objective response rate (ORR) (confirmed 
and unconfirmed, complete and partial) in patients treated with 
investigational therapy with advanced stage refractory squamous cell 
carcinoma (SCCA) of the lung.  The investigational therapy arm will be 
judged to have provided sufficient evidence to proceed to the Phase III 
component if the ORR is at least 25% (see Section 11.2c for details). 
 
Phase III Component: The Phase III design has two co-primary objectives: 
an evaluation of IA-PFS and OS. 
 
i. 
The primary PFS objective within the Phase III component is to 
compare investigator-assessed progression-free survival (IA-
PFS) in patients with advanced stage refractory SCCA of the lung 
randomized to receive investigational therapy versus SoC. 
 
ii. 
The primary OS objective within the Phase III component is to 
compare overall survival (OS) in patients with advanced stage 
refractory SCCA of the lung randomized to receive investigational 
therapy versus SoC. 
 
2. 
Secondary Endpoints 
 
Phase II component 
 
i. 
To evaluate PFS and OS with investigational therapy 
 
ii. 
To evaluate the duration of response (DoR) among patients who 
achieve a CR or PR by RECIST 1.1 
 
iii. 
To 
evaluate 
the 
severity 
of 
toxicities 
associated 
with 
investigational therapy versus SoC.  
 
3. 
Phase III Component 
 
i. 
To compare the response rates (confirmed and unconfirmed, 
complete and partial) among patients randomized to receive 
investigational therapy versus SoC.  
 

 
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ii. 
To evaluate the frequency and severity of toxicities associated 
with investigational therapy versus SoC. 
 
4. 
Sample Size with Power Justification 
 
i. 
Phase II Design 
 
A design with 90% power and 1-sided 0.05 level type I error would 
require 40 patients to rule out an ORR of 15% or less if the true 
ORR is 35% or greater.  The observation of at least 10 responses 
of the 40 patients (25%) would be considered evidence to rule out 
an ORR of 15%.   
 
A key secondary objective is an assessment of median IA-PFS 
(mPFS). If the ORR rate is less than 25% but the mPFS is at least 
4.5 months, this may be considered sufficient evidence to 
continue to the follow-on Phase III.  With 40 patients, this design 
has 90% power to rule out a median PFS of 3 months or less, if 
the true mPFS is 6 months, at the 0.05 1-sided level.  The 
observation of an mPFS of at least 4.5 months would be 
considered evidence to rule out a mPFS of 3 months or less.  
 
ii. 
Follow-on Phase III Design (if feasible) 
 
If the conditions for continuation at the phase II are met and it is 
feasible to accrue to a phase III, then a follow-on randomized 
Phase III will be initiated.  Evaluation of the feasibility of a phase 
III will commence around 75% accrual to the phase II. The SoC 
arm of the phase III study will not be defined until this time. The 
follow-on phase III will be submitted as an amendment. 
 
The total sample size for the phase III is determined based on the 
biomarker prevalence, with all other design parameters the same 
across sub-studies using this design.  Patients enrolled during the 
phase II component will not be included in the phase III study 
analyses.  
 
While a co-primary objective is the comparison of IA-PFS between 
the arms, the sample size for Phase III component is based on a 
design that targets a 75% improvement in median OS (HR=0.57) 
with 80% power and a 2.5% 1-sided type I error rate.  This design 
requires 100 deaths.  The median OS and PFS and associated 
sample size assumptions will be updated for each sub-study in the 
planning stage once a control arm has been identified.   
 
iii. 
Phase III Feasibility Considerations 
 
A follow-on randomized Phase III trial will be considered as 
feasible if the expected duration of accrual is approximately 3 
years or less. Upon 75% accrual to the Single Arm component, 
the accrual rate to the sub-study will be assessed and if the 
average monthly accrual rate is at least 2-3 patients per month, 
depending on the designed total study accrual the Phase III will 
be considered feasible.  
 
 

 
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iv. 
Phase II Expansion Considerations 
 
Accrual to a Phase III Trial is Not Feasible 
If the Phase II data meets the definition of a positive Single Arm 
Phase II as defined in Section 11.2c (above) but it is determined 
that a Phase III trial is not feasible, accrual to the Single Arm 
Phase II may be expanded beyond 40 patients.  If the ORR is at 
least 35% (the phase II alternative hypothesis) then the Phase II 
expansion will continue accrual for up to an additional 12 months 
or up to an additional 20 patients (whichever is reached first). 
 
Accrual to a Phase III Trial Is Feasible 
If feasible to accrual to a phase III and the ORR is greater than 
40%, then discussions with between study leadership, the 
pharmaceutical collaborator, NCI, and FDA will commence to 
discuss the potential for FDA approval based on data from a 
Single Arm evaluation of the investigational therapy. In such a 
case, accrual will likely be expanded to a total of up to 100 patients 
treated with the investigational therapy and evaluate the response 
rate, duration of response, median PFS and OS, and toxicity rates 
in this expanded study population. 
 
5. 
Analysis Plan 
 
i. 
Phase II Analysis Plan 
 
An interim analysis will take place when 20 patients are evaluable 
for response, with no halt in accrual.  This interim analysis will only 
evaluate early stopping for futility.  If 2 or fewer responses are 
observed, this will be considered evidence of futility and the 
recommendation will be to close the study for lack of evidence of 
efficacy of the regimen. If the study continues to full accrual, the 
observation of at least 10 responses will be considered evidence 
to rule out the null hypothesis of a 15% response rate.  
 
Response rates and associated confidence intervals will be 
calculated.  Survival IA-PFS, and DoR will be estimated using the 
method of Kaplan-Meier. The Brookmeyer-Crowley method will be 
used to calculate confidence intervals for median OS, IA-PFS, and 
DoR. With 40 patients, ORR and toxicity rates can be estimated 
within 16% with 95% confidence.  Any toxicity with at least 5% 
prevalence has at least an 87%chance of being observed. 
 
ii. 
Phase III Analysis Plan Including Plans for Formal Interim 
Analysis 
 
The Phase III primary analyses will be performed on an intent-to-
treat basis.  Stratified (using randomization stratification factors) 
log-rank test will be used to test the primary hypotheses related to 
PFS and OS comparing the two treatment arms at the levels 
specified.  A Cox proportional hazards (PH) model will be used to 
estimate the hazard ratios and associated confidence intervals.  
Analysis of response rates and toxicities will be performed using 
a chi-square or Fisher’s exact test, as appropriate.   
 

 
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Secondary analysis of PFS and OS at the final analysis within 
each sub-study will be a weighted analysis (using Cox regression) 
standardizing the biomarker prevalence among patients with 
multiple biomarkers to the study population prevalence among all 
patients eligible as defined by the sub-study biomarker definition.  
The goal of this analysis is to estimate the treatment effects had 
all patients with the sub-study biomarker been assigned to the 
sub-study (as in a stand-alone trial). 
 
Phase III Interim Analysis:  If a Phase III trial is initiated, a formal 
interim analysis is planned when 50% of the expected deaths 
have been observed with rules specified on the fixed-sample p-
value scale. 
 
Evidence suggesting early termination of the trial for futility/harm 
will be if the alternative hypothesis of at least 50% improvement 
in OS for the investigational arm is rejected at the one-sided level 
0.0025, using a PH model score test evaluated at the alternative 
hypothesis (Ha: HR=0.67 for OS). (11) Evidence suggesting early 
termination of the trial for superiority will be if the hypothesis of no 
difference in OS is rejected at the one-sided 0.0025 level using a 
log-rank test. 
 
iii. 
Final Analysis 
 
If the decision is to continue the study to completion, the final 
analysis of IA-PFS will occur after completion of accrual, when 
either 100 progression events have been observed or the final 
analysis for OS is performed, whichever comes first. The final 
analysis of OS will take place when at least 100 events have been 
observed.  However, should events accumulate more slowly than 
anticipated, the maximum time to final analysis is when 18 months 
have passed since the completion of accrual. The analysis of IA-
PFS will be a test against the null hypothesis at the 0.0001 level 
(which has 80% power for a 2.5-fold increase in IA-PFS), with an 
approximate observed threshold of 2-fold improvement in median 
IA-PFS (HR=0.5) for significance (deemed both significant in 
statistical and clinical terms). The final analysis of OS will be at 
level 0.024 to account for the effects of interim monitoring (using 
a modified Haybittle-Peto boundary). The adjusted level does not 
account for either the IA-PFS assessment for futility or the 
response assessment for efficacy at the Phase II interim analysis 
as the level of testing response is small (0.0001) and the decision 
to stop for efficacy at this time point will also consider other clinical 
data. 
 
The actual decision to terminate accrual early will be made by the 
SWOG Data and Safety Monitoring Committee (DSMC), and will 
consider IA-PFS, OS, response, and toxicities. 
 
b. 
Option for Non-Match Sub-Studies 
 
This design is specific to non-match therapies in patients who have previously 
received and progressed on/following immunotherapy. Consideration for pursuing 
a Phase III trial, should a Phase II successfully reject the null hypothesis (as 
described below), is not automatic and would follow careful review of the study 

 
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data and discussions with appropriate parties.  The details here are specific to the 
Phase II design. 
 
1. 
Primary Endpoint 
 
The primary objective is to evaluate the objective response rate (ORR) 
(confirmed and unconfirmed, complete and partial) in patients treated with 
investigational non-match therapy with advanced stage refractory 
squamous cell carcinoma (SCCA) of the lung.   
 
2. 
Secondary Endpoints 
 
i. 
To evaluate PFS and OS with investigational therapy 
 
ii. 
To evaluate the duration of response (DoR) among patients who 
achieve a CR or PR by RECIST 1.1 
 
iii. 
To 
evaluate 
the 
severity 
of 
toxicities 
associated 
with 
investigational therapy versus SoC.  
 
3. 
Sample Size with Power Justification 
 
The accrual goal for this design is to accrue up to 60 eligible patients. A 
design with 82% power and 1-sided 0.05 level type I error would require 
60 patients to rule out an ORR of 5% or less if the true ORR is 15% or 
greater.  The observation of at least 6 responses of the 60patients (10%) 
would be considered evidence to rule out an ORR of 5%.  
 
4. 
Analysis Plan 
 
This design includes two interim analyses and a final analysis.  
 
Interim 1: The first interim analysis will take place when 20 patients are 
evaluable for response.  This interim analysis will only evaluate early 
stopping for futility.  If no responses are observed, this will be considered 
evidence of futility and the recommendation will be to close the cohort for 
lack of evidence of efficacy of the regimen.  
 
In addition to evaluating early stopping for futility, this analysis will evaluate 
the safety/tolerability of the regimen.   
 
Interim 2: The second interim analysis will take place when 40 patients are 
evaluable for response.  This interim analysis will also only evaluate early 
stopping for futility.  If 3 or fewer responses are observed, this will be 
considered evidence of futility and the recommendation will be to close the 
cohort for lack of evidence of efficacy of the regimen.  
 
Final Analysis: If a study is not closed to accrual at the first or second 
interim analysis, the study will proceed to full accrual of 60 evaluable 
patients. If the study continues to full accrual, the observation of at least 6 
responses will be considered evidence to rule out the null hypothesis of a 
5% response rate.  
 
 

 
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Summary of analyses: 
Analysis 
Sample Size 
Futility 
Continue/Positive 
1st interim 
20 patients 
No responses 
1+ response (5% RR) 
2nd interim 
40 patients 
≤3 responses 
4+ responses (10% RR) 
Final 
60 patients  
≤5 responses 
6+ responses (10% RR) 
 
Evaluability for response:  Evaluability for response is defined based on 
RECIST 1.1 and accrual to each cohort is to remain open while patients 
are being evaluated for response.  However, if 20 or more eligible patients 
for the first interim analysis or 40 or more eligible patients for the second 
interim analysis, have made it to their second disease assessment and the 
required number of responses to continue past that interim analysis has 
not been observed, then the accrual will be placed in temporary closure 
until the response status for all patients in the interim analysis set is known. 
 
The following table describes the likelihood of stopping at the interim 
analyses under a response rate of 5%, 10%, 15%, and 20% and the 
probability of a rejecting the null.  
 
 
Probability of 
stopping 
Average 
sample 
size 
Expected 
number of 
responses 
 
RR 
Interim 1 
Interim 2 
Probability 
reject null  
5% 
36% 
51% 
36 
2 
5.6% 
10% 
12% 
31% 
49 
5 
46.8% 
15% 
4% 
11% 
56 
8 
82.2% 
20% 
1% 
2% 
59 
12 
96.5% 
 
Response rates and associated confidence intervals will be calculated.  
Survival, IA-PFS, irRC-IA-PFS, and DoR will be estimated using the 
method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to 
calculate confidence intervals for median OS, IA-PFS, and DoR. With 60 
patients, ORR and toxicity rates can be estimated within 13% with 95% 
confidence.  Any toxicity with at least 5% prevalence has at least a 95% 
chance of being observed. 
 
With 60 patients, OS and PFS rates at landmark times can be estimated 
within 13% with 95% confidence. 
 
11.3 
Blinded Independent Centralized Review (BICR) of PFS and/or ORR 
 
BICR is triggered if sub-study data is to be submitted to the FDA to support registration of 
the investigational therapy. If a sub-study is stopped at the Phase II analysis a complete 
case BICR will be performed.  Otherwise, the BICR audit plan will proceed using the 
algorithm detailed in Dodd, et al (2011). PFS by Central Review (PFS-CR) is defined in 
Section 10.8.  For the purposes of a PFS audit, the clinical irrelevance factor (CIF) will be 
the HR threshold of 0.57 (or equivalently an approximate 75% improvement in median 
PFS) as defined above to be a clinically meaningful difference. The initial audit size will be 
33% of the total patients enrolled within a sub-study (approximately 100 patients).  Using 
this initial audit sample, the audit sample size will be calculated based on the formula 
provided in Dodd et al.  If the audit sample size is less than 33%, the audit PFS HR will be 
calculated as defined in Dodd, et. al 2011. (16)  If the audit sample size is >33%, but less 

 
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than 80%, then additional patient scans will be evaluated to increase the audit sample to 
the specified size. If the audit sample size is determined to be > 80% of the total sample 
size, a complete case audit will be performed. To define the equivalence region for the 
local and central review HR estimates an α = 0.05 will be used (see Steps 5, 6, and 7 of 
the algorithm). The specific details of BICR progression assessment are included in the 
Risk Based Monitoring Plan (see Section 18.1d) 
 
11.4 
Accrual Information 
 
There are 55,000 new cases of squamous cell carcinoma (SCCA) of the lung diagnosed 
each year in the United States and approximately 57% of these patients present with 
metastatic disease at diagnosis.  Approximately 70% of early stage patients progress 
following initial therapy and essentially all metastatic patients (95%) progress.  Further we 
assume that 50-60% of these patients will go on to receive 2nd and greater lines of therapy.  
It is therefore anticipated that the approximate available patient pool is 28,800 patients per 
year and of them, 2-3% will participate in this clinical trial. 
 
Accrual projections are based on the following assumptions: 
 
a. 
Pre-screening is allowed after year 1 of study.  Once pre-screening is allowed, 
50% of patients will be pre-screened and 50% of patients will be screened at 
progression. This implies that 50% of patients will be register to their assigned sub-
study as soon as they are notified of their sub-study assignment and 50% of 
patients will need to progress on their current treatment and may even receive 
subsequent lines of treatment prior to registering to a sub-study.  
 
b. 
The median time to enrollment for patients screened at progression is 2 months 
and the distribution of enrollment times is exponential. This assumption accounts 
for the time for sites and patients to work up patients and address any clinical 
issues prior to enrolling onto a sub-study.  
 
c. 
The median time to enrollment for patients screened prior to progression is 9 
months and the distribution of enrollment times is exponential. This assumption 
accounts for the time to progression on current therapy and potentially receipt of 
an additional line of therapy after progressing on therapy during pre-screening and 
prior to sub-study registration.  
 
d. 
The anticipated screen success rate (percentage of patients screened who 
eventually enroll onto a substudy) is 50-60% in the first year of study and 70% 
thereafter, for patients screened at progression and 50% for patients pre-screened 
during prior treatment.  
 
e. 
The rate of patients registering to S1400 to be screened or pre-screened will be 
300-500 patients/year in the first year and a half of study, between 400 and 600 in 
the 2.5-3.5 years after study activation, and between 500 and 800 patients per 
year thereafter. 
 
Under these assumptions, the projected accrual to S1400 and to the sub-studies 
is presented in the following Table 2: 
 
 

 
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Table 2 
Total S1400 
Registrations 
Total Sub-study 
Registrations 
12 months 
270-434 
106-155 
18 months 
469-718 
152-248 
24 months 
699-1035 
224-362 
36 months 
1203-1839 
474-722 
48 months 
1707-2643 
734-1171 
60 months 
2211-3447 
1032-1633 
 
11.5 
Screening Success Rate Evaluation 
 
The screen success rate (SSR) is defined as the ratio of the number of patients that register 
to a sub-study (register to S1400A, S1400B, S1400C, etc.) over the total number of 
patients screened (i.e. that register to S1400).  The SSR will be evaluated on a bi-annual 
basis and reported as part of the SWOG Group Meeting study reports to the SWOG Data 
and Safety Monitoring Committee. The SSR will be evaluated on 1) all S1400 screen 
registrations, 2) among patients who are pre-screened during current treatment, and 3) 
among patients screened at progression. 
 
Formal assessment of screening rates will occur annually and will be reported to the NCI 
and the Thoracic Malignancy Steering committee at the time of the SWOG Spring Group 
meetings.  Consideration for discontinuation of pre-screening patients during current 
therapy will be the observation of less than a 40% screen success rate or if screen success 
rate in the pre-screened group is less than half the rate in the set of patients screened at 
progression.   
 
11.6 
Treatment Arm Randomization Acceptance Rate Evaluation 
 
This evaluation only applies to randomized studies; this does not apply to the single arm 
component of Design #2.  The treatment arm randomization acceptance rate (TARAR) 
within each treatment arm of each randomized sub-study is defined as the ratio of the 
number of patients who receive any protocol treatment over the number that are 
randomized to that sub-study treatment arm.  The TARAR will be evaluated on a bi-annual 
basis and reported as part of the SWOG Group Meeting study reports to the SWOG Data 
and Safety Monitoring Committee.    
 
Formal assessment of the TARAR will occur annually and will be reported to the NCI, and 
the Thoracic Malignancy Steering committee at the time of the SWOG Spring Group 
meetings.    
 
11.7 
Data and Safety Monitoring  
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary.  The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study. 
 
 
 

 
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12.0 
DISCIPLINE REVIEW 
 
This section does not apply to this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
a. 
Patients must register to the S1400 screening step within 5 calendar days prior to 
submitting tissue to Foundation Medicine.  
 
b. 
Patients must plan to begin treatment within 7 calendar days after sub-study 
registration. 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP.  
 
a. 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to register 
and to renew their registration annually.  To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, 
or TRIAD or acting as a primary site contact) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository 
(RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per 
registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 

 
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Documentation Required 
IVR 
NPIVR 
AP 
A 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctepcore.nci.nih.gov/iam/index.jsp For questions, please contact the RCR 
Help Desk by email at  RCRHelpDesk@nih.gov. 
 
b. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
 
1. 
Protocol Specific Tranining (PSR) 
 
A member of each institution (CRA or investigator, etc.) must complete the 
Protocol Specific Requirements (PSR) prior to patient registration.  The 
PSR will need to be renewed prior to patient registration each time a new 
sub-study has been added. The PSR can be satisfied by completing the 
training 
online 
and 
submitting 
the 
verification 
at: 
https://swog.org/members/Training/S1400Training.asp.   
 
To receive credit, institutions are to complete and submit the verification 
form located at the bottom of the webpage.  The SWOG Protocol 
Coordinator and CTSU will be notified of completion.  There is a turn-
around time of three business days for processing this training 
requirement at CTSU after submission of the verification form before the 
first registration may occur.  However, if a registration is pending, please 
notify the CTSU Regulatory staff at CTSURegOffice@ecogchair.org so 
they may be prompted to process the training completion as a priority. 
 
2. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 

 
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approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including 
but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the 
following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 
1572 
• 
An active status on a participating roster at the registering site. 
 
3. 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the S1400 or the specific 
sub-study protocol page located on the CTSU members’ website.  
Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment 
housed in the CTSU RSS. 
• 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the 
protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the SWOG link to expand, then select S1400 or specific 
sub-study.  
• 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided.   
 
4. 
Requirements for Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted) 
• 
Other site registration requirements (i.e., laboratory certifications, 
protocol-specific training (PSR) certifications, or modality 
credentialing) must be submitted to the CTSU Regulatory Office 
or compliance communicated per protocol instructions. 
 
5. 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office via 
the Regulatory Submission Portal, where they will be entered and tracked 
in the CTSU RSS.  

 
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Regulatory Submission Portal: www.ctsu.org (members’ area)  
Regulatory Tab  Regulatory Submission 
 
When applicable original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
6. 
Checking Site’s Registration Status: 
 
Site registration status can be verified on the members’ section of the 
CTSU website.   
 
 Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
 Click on the Regulatory tab at the top of your screen 
 Click on the Site Registration tab 
 Enter your 5-character CTEP Institution Code and click on Go 
 
• 
Note: The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements as outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type.  If a DTL 
is required for the study, the registrar(s) must also be assigned the OPEN Registrar task 
on the DTL.   
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Cooperative Group Credit 
 
f. 
Credit Investigator 
 

 
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g. 
Patient Initials 
 
h. 
Patient’s Date of Birth 
 
i. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
j. 
Country of Residence 
 
k. 
ZIP Code 
 
l. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
m. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
n. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
o. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and initializes the 
patient in the RAVE database. OPEN can be accessed at https://open.ctsu.org or 
from the OPEN tab on the CTSU members’ side of the website at 
https://www.ctsu.org, or from the OPEN Patient Registration link on the SWOG 
CRA Workbench. Patient re-registrating to a sub-study will follow the same the 
same instructions as above.  To assign an IVR or NPIVR as the treating, crediting, 
consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, 
the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used 
on the site’s IRB approval.  If a DTL is required for the study, the IVR or NPIVR 
must also be assigned the appropriate OPEN-related tasks on the DTL. 
 

 
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b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate.  Site staff should 
refer to Section 5.0 to verify eligibility 
 
• 
All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
 
• 
The study site is listed as “approved” in the CTSU RSS.  
 
c. 
Access requirements for OPEN: 
 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ 
side 
of 
the 
CTSU 
website 
at 
https://www.ctsu.org 
or 
at 
https://open.ctsu.org.  For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com.  
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirements for Screening/Pre-Screening Registration 
 
NOTE:  See Section 14.0 for each sub-study data submission requirements. 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible.  
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see below for details. 
 
14.3 
Data Submission Procedures 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical 
data management system.  Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support System 

 
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Version Date 12/18/20 
 
 
 
 
(RSS).  To access Rave via iMedidata, the site user must have an active CTEP-IAM 
account (check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and the appropriate 
Rave role (Rave CRA, Read-Only, Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. To hold the Rave CRA role or CRA Lab Admin role, 
the user must hold a minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can 
hold read-only roles in Rave.  If the study has a DTL, individuals requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL.     
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To 
accept 
the 
invitation, 
site 
users 
must 
log 
into 
the 
Select 
Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page.  Please note, 
site users will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation 
and Study Invitation Acceptance).  Additional information on iMedidata/Rave is available 
on the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ or by 
contacting 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
by 
e-mail 
at 
ctsucontact@westat.com.    
 
a. 
All participating institutions must submit data electronically via the Web using 
Medidata Rave® at the following url: 
 
https://login.imedidata.com/selectlogin 
 
1. 
If prompted, select the ‘CTEP-IAM IdP’ link. 
2. 
Enter your valid and active CTEP-IAM userid and password.  This is the 
same account used for the CTSU members’ web site and OPEN. 
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on Workbenches, 
then CRA Workbench to access the home page for the CRA Workbench and follow 
the link to Rave® provided in the left-hand navigation panel. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page). 
 

 
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For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU) please 
refer to the CTSU Participation Table on Page 5. 
 
14.4 
Data Submission Overview and Timepoints for Screening/Pre-Screening Registration 
 
a. 
WITHIN 7 DAYS OF SCREENING/PRE-SCREENING REGISTRATION, 
SUBMIT: 
 
S1400 Onstudy Form  
 
Pathology report for initial diagnosis documenting histologic confirmation of 
squamous cell lung cancer.* 
 
S1400 Local Pathology Review Form*  
 
* NOTE:  Upload via the Source Documentation:  Baseline form in Rave®. 
 
For patients who consent to the optional S1400GEN Survey Ancillary Study, 
submit the patient and physician contact information page from the patient 
consent form per Section 15.5b.3.   
 
b. 
WITHIN 
5 
CALENDAR 
DAYS 
AFTER 
SCREENING/PRE-SCREENING 
REGISTRATION, SUBMIT TISSUE REQUIRED FOR BROAD PLATFORM CLIA 
BIOMARKER PROFILING: 
 
Submit specimens to Foundation Medicine for biomarker profiling as specified in 
Section 15.0. 
 
c. 
IF PATIENT CONSENTS SUBMIT OPTIONAL SPECIMENS: 
 
Submit optional specimens for translational medicine studies and banking as 
specified in Section 15.0. 
 
d. 
WITHIN 21 DAYS OF RECEIVING SUB-STUDY ASSIGNMENT: 
 
Submit the S1400 Status Update 
 
e. 
EVERY THREE MONTHS FOR THE FIRST YEAR AFTER SCREENING/PRE-
SCREENING REGISTRATION, THEN EVERY SIX MONTHS FOR THE SECOND 
YEAR AND ANNUALLY THEREAFTER UNTIL SUB-STUDY REGISTRATION: 
 
 
Submit the Advanced NSCLC Follow-Up Form. 
 
f. 
PRE-SCREENED PATIENTS ONLY: WITHIN 7 DAYS OF PROGRESSION: 
 
Submit the S1400 Notice of Progression. 
 
 

 
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g. 
AFTER 
RECEIVING 
SUB-STUDY 
ASSIGNMENT 
BUT 
PRIOR 
TO 
REGISTRATION ON ANY SUB-STUDY:  IF PATIENT DOES NOT FULFILL THE 
SUB-STUDY SPECIFIC ELIGIBILITY CRITERIA: 
 
Submit the S1400 Request for Sub-Study Reassignment Form 
 
14.5 
Data Submission FOR PATIENTS WHO WILL NOT BE REGISTERED TO ANY OF THE 
SUB-STUDIES 
 
a. 
WITHIN 7 DAYS OF DECISION NOT TO REGISTER PATIENT: 
 
Submit the S1400 Notice of Intention Not to Register.  
 
All patients will receive a notification email with sub-study assignment along with 
complete gene panel results, provided the submitted tissue is adequate for testing. 
If the S1400 Notice of Intention Not to Register Form is submitted prior to receipt 
of the notification email, it will be sent as usual upon receipt of the biomarker 
analysis from FMI. 
 
b. 
EVERY SIX MONTHS FOR THE FIRST 2 YEARS AFTER SCREENING/PRE-
SCREENING REGISTRATION THEN AT THE END OF YEAR 3 OR DEATH, 
WHICHEVER OCCURS FIRST: 
 
Submit the Advanced NSCLC Follow-Up Form  
 
c. 
WITHIN 28 DAYS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death  
 
14.6 
Data Submission FOR PATIENTS WHO HAVE PROGRESSED ON A SUB-STUDY AND 
WISH TO REGISTER TO A NEW SUB-STUDY  
 
a. 
AFTER PROGRESSION ON A SUB-STUDY: 
 
Submit the S1400 Request for New Sub-Study Assignment 
 
Sites will receive a notification email with a new sub-study assignment, based on 
patient’s biomarker results. 
 
b. 
WITHIN 21 DAYS OF RECEIVING NEW SUB-STUDY ASSIGNMENT: 
 
Submit the S1400 Status Update Form 
 
c. 
AFTER RECEIVING NEW SUB-STUDY ASSIGNMENT BUT PRIOR TO 
REGISTRATION ON NEW SUB-STUDY, IF PATIENT DOES NOT FULFILL THE 
SUB-STUDY SPECIFIC ELIGIBILITY CRITERIA:  
 
Submit the S1400 Request for Sub-Study Reassignment Form 
 
d. 
UNTIL REGISTRATION TO NEW SUB-STUDY: 
 
Continue to follow patient and submit Advanced NSCLC Follow-up Forms per 
Sections 9 and 14.4 of their current sub-study. After registration to the new sub-
study, follow-up is still required on the previous sub-study. 
 

 
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e. 
IF PATIENT WILL NOT BE REGISTERED TO THE NEW SUB-STUDY: 
 
WITHIN 7 DAYS OF DECISION NOT TO REGISTER PATIENT: Submit the S1400 
Notice of Intention Not to Register 
 
Continue to follow patient and submit forms per Sections 9 and 14.4 of the most 
recent sub-study in which patient is enrolled. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using the online 
SWOG Specimen Tracking System (STS). SWOG members may log on to STS via the 
CRA Workbench. To access the CRA Workbench, go to the SWOG Web site 
(http://swog.org) and logon to the Members Area. After you have logged on using your 
SWOG roster ID number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non-SWOG members may access SpecTrack 
using their CTSU UserID and password on the SpecTrack login page located 
at https://spectrack.crab.org (select the option "SWOG - SWOG - CTSU"). SpecTrack start-
up instructions (both written and demo) are available after signing in to SpecTrack. 
 
A copy of the Shipment Packing List produced by the online Specimen Tracking system 
should be printed and placed in the pocket of the specimen bag if it has one, or in a 
separate resealable bag. STS laboratory IDs are used to identify laboratories to which 
specimens are shipped.  
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org. For procedural 
help with logging and shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page  
(https://spectrack.crab.org/Instructions); or contact the Data Operations Center at 206/652-
2267 to be routed to the Data Coordinator for further assistance. 
 
15.2  
Biomarker Profiling (Required) 
 
Note: Previous NGS testing outside this study must be repeated for sub-study assignment. 
 
Tissue for biomarker profiling and c-MET testing must be submitted within 5 calendar days 
of S1400 screening/pre-screening registration. 
 
a. 
The following must be submitted to Foundation Medicine, Lab #211: 
 
1. 
Tissue block (preferred) or at least 12 (4-5 micron) unstained slides (20 
slides are strongly recommended). 
 
2. 
Hematoxilyn-eosin (H&E)-stained slide or Aperio H&E-stained slide. If 
H&E slide is not available, submit an extra unstained slide.  An H&E slide 
is not required with tissue block submission. 
 
3. 
Local pathology report from initial diagnosis 
 

 
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4. 
S1400 Local Pathology Review Form: 
 
Tumor material must be reviewed by a local pathologist to ensure sufficient 
tumor cells are present in the sample. The local pathologist must review 
and sign off on the S1400 Local Pathology Review form prior to enrolling 
patient noting that the tumor volume is at least 0.2 mm3 and the tumor 
tissue contains at least 20% viable tumor cells. This form must be included 
with the tissue submitted to Foundation Medicine. In addition, this form 
must also be uploaded via the Source Documentation:  Baseline form in 
Rave®. 
 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
b. 
When submitting tissue to Foundation Medicine, be prepared to provide answers 
to the following questions in the SWOG specimen Tracking System: 
 
• 
Patient’s date of birth  
• 
Patient’s sex     
• 
Has the patient had any type of transplant? (yes/no) 
• 
Patient’s diagnosis  (NSCLC) 
• 
Site’s local specimen ID number 
 
• 
Tumor histology   (Squamous) 
• 
Primary tumor site   
• 
Specimen tumor site  (Lung, Lymph node, Other) 
• 
Fine needle aspirate (Yes, No) 
• 
Biopsy (Screening biopsy – CT image guided, Screening Biopsy – 
bronchoscopy, Archival Tissue) 
• 
Date unstained slides were cut 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of tumor tissue for SWOG Repository Submission and 
next-generation DNA sequencing testing is identified as follows: 
 
Lab #211:  
Foundation Medicine Inc. 
Attn: Prospective Study Specimen  
 
Contact:  FMI S1400 Distribution List 
Phone: 617/418-2200 
E-mail: S1400@foundationmedicine.com    
 
c. 
Tissue Specifications 
 
Tissue biopsies are requested.  Most optimally, core needle biopsies should be 
obtained.  Cytology smear specimens are not sufficient for the molecular studies 
proposed. However, fine needle aspirates with good cellularity are acceptable as 
long as cell blocks are established. Specimens containing less than 80% nucleated 
cells require greater total volume and may not be suitable to assay. The key 
sample consideration is to submit a total mass of cells that is sufficient to extract 
the amount of DNA necessary for analysis.  Bone biopsies are not allowed. 
 
If patient’s archival tumor material is not adequate for biomarker profiling, tumor 
tissue from a new biopsy must be obtained and submitted as outlined above (see 
S1400 Funding Memorandum for reimbursement details).   
 

 
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If biomarker profiling could not be obtained from the submitted tissue, additional 
tissue will be requested.  
 
d. 
Specimen Use 
 
1. 
Next-generation DNA Sequencing (NGS) 
 
Foundation Medicine will perform next-generation DNA sequencing. The 
molecular panel will require 8-10 sections (4-5 microns, 40 microns total). 
Remaining tissue will be sent to the SWOG Specimen Repository-Solid 
Tissue, Myeloma and Lymphoma Division, Lab #201, for use of the 
Translational Medicine studies within any sub-study the patient is enrolled 
in. SWOG Specimen Repository will prepare and ship the required 
specimens to the appropriate laboratory. The specimen will be kept until 
there are no additional sub-studies for the patient to enroll in or the tissue 
is used up, whichever happens first. With patient’s consent, any leftover 
tissue will remain at the SWOG Repository for future exploratory analysis.  
 
Please see Section 18.1a for more details. 
 
2. 
C-MET Assay 
 
The c-MET IHC assay will be part of S1400 screening, to identify patients 
for registration to S1400K. The assay is currently being employed in 
AbbVie’s Phase 1 study to select c-MET positive patients. The assay 
utilizes the CONFIRM c-MET SP44 rabbit monoclonal Ab from Ventana, 
intended for IVD use (cat #790-4430, Lot G08106). The IHC cutoff for 
positivity in the current Phase 1 study is an H-score of ≥150 membrane 
staining.  In squamous histology NSCLC, about 30% of patients are c-MET 
positive is per the literature (Genentech) with SP44 antibody IHC. 
 
For SP44 assay testing, no on-site processing of specimens will be 
required. The tissue specimens collected for S1400 biomarker profiling will 
be used.  All S1400 tissue specimens are shipped to Foundation Medicine, 
Inc (FMI). For patients with tumor blocks, FMI will prepare two (4-5 micron) 
unstained, charged, and unbaked FFPE slides, per patient.  The slides will 
be shipped to ARUP for staining within 2 calendar days of FMI receiving 
the specimens. 
 
 
 
 
Please see Sub-Study S1400K for more details. 
 
15.3 
Correlative Studies and Banking  (Optional for Patients) 
 
Specimens for correlative studies and banking (submitted to the SWOG Specimen 
Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201) are considered 
optional for the patient: 
 
a. 
With patient's consent, any remaining tumor tissue will be sent from Foundation 
Medicine to the SWOG Specimen Repository - Solid Tissue, Myeloma and 
Lymphoma Division, Lab #201, for future exploratory analysis. 
 
 

 
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b. 
With patient’s consent, Peripheral Blood must be collected and submitted as 
follows: 
 
1. 
Specimen Collection 
 
Specimens must be collected at Screening or Pre-screening within 42 
days prior to registration to a sub-study.  See Section 15.0 of each of the 
sub-studies for additional timepoints. 
 
Approximately 8-10 mL of blood must be collected in EDTA tubes.  Blood 
should be processed within one hour after venipuncture. If immediate 
processing within this time frame is not possible, EDTA tubes that are not 
processed immediately should be refrigerated at 4˚C. The approximate 
time from collection to processing should be recorded as part of the 
patient’s source documentation. EDTA tubes must be centrifuged at 800 
g for 10 minutes at 4˚C for the collection of plasma. Plasma must be 
transferred to one 15 ml centrifuge tube and spun again at 800 g for an 
additional 10 minutes. Plasma must then be pipetted into 1 ml coded 
cryovials at 0.5 ml aliquots. Plasma must be clear before freezing; no cells 
or debris should be present. Each buffy coat layer (the gray-white layer at 
the interface of blood cells and plasma, approximately 1 ml) from the blood 
tube must each be transferred into appropriately labeled 2-ml cryovials.  
Samples must be placed immediately in a -80˚C freezer to ensure long-
term viability.   
 
2. 
Specimen Submission 
 
Samples can be shipped in batches, at least every 3 months if not more 
frequently, to the SWOG Specimen Repository – Solid Tissue, Myeloma 
and Lymphoma Division, Lab #201. 
 
Specimen collection and submission instructions can be accessed on the 
SWOG Specimen Submission webpage  
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp). 
 
3. 
Specimen collection kits are not being provided for this submission; sites 
will use institutional supplies. 
 
15.4 
Radiology Review (Required for all Sub-studies) 
 
CT, PET/CT, and/or MRI images must be locally read and interpreted by the local site 
radiology service.  If patient is registered to an S1400 sub-study, imaging exams must then 
be submitted to the Imaging and Radiation Oncology Core (IROC) at Ohio via TRIAD 
Imaging Submission procedures for central data collection and quality control (QC) check 
as well as retrospective central review. 
 
CT, PET/CT, and/or MRI images must be submitted to IROC Ohio for central review at the 
following timepoints: 
 
a. 
See Section 15 of each of the sub-studies for additional timepoints. 
 
All study participants must have a CT (or MR or PET/CT) exam prior to sub-study 
entry.  Participants must then undergo additional imaging until progression of 
disease, see Section 15 of each of the sub-studies for details.  The same imaging 
modality used for the pre-treatment exam must be used for the post-treatment 

 
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exams (see Section 10.1c). Each exam should be performed per Section 18.1c.  
IROC will perform a QC of the imaging exams.   
 
Clinical management and treatment decisions will be made by the treating 
physician based on local site assessments and other clinical appropriate 
considerations. 
Central review of scans will not be triggered if the study will not be submitted to the 
FDA for FDA approval of the investigational therapy.  Central review of scans will 
be triggered only if deemed necessary for FDA evaluation. A detailed description 
of the central radiology PFS review, including image acquisition parameters and 
image submission instructions, can be found in Section 18.1c. 
 
b. 
TRIAD Digital Image Submission  
 
TRIAD is the American College of Radiology’s (ACR) image exchange application.  
TRIAD provides sites participating in clinical trials a secure method to transmit 
DICOM RT and other objects. TRIAD anonymizes and validates the images as 
they are transferred. 
 
1. 
TRIAD Access Requirements: 
 
TRIAD will be the sole means of image transfer to the IROC Ohio. TRIAD 
should be installed prior to study participant enrollment to ensure prompt 
secure, electronic submission of imaging. 
 
• 
Site staff who submit images through TRIAD will need to be registered 
with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP-IAM account (see Section 13.2). 
 
• 
To submit images, the site user must be on the site’s affiliate rosters 
and be assigned the 'TRIAD site user' role on the CTSU roster.  Users 
should contact the site’s CTSU Administrator or Data Administrator to 
request assignment of the TRIAD site user role.   
 
2. 
TRIAD Installations: 
 
After a user receives a CTEP-IAM account with the proper user role, 
he/she will need to have the TRIAD application installed on his/her 
workstation to be able to submit images. TRIAD installation documentation 
can be found by following this link https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
15.5 
S1400GEN Survey Ancillary Study (Optional for Patient) 
 
Ancillary Study to Evaluate Patient and Physician Knowledge, Attitudes, and Preferences 
Related to Return of Genomic Results in S1400.  
 
a. 
Institutions must seek consent for the Optional Research Survey Study 
(S1400GEN) with in the screening consent forms to submit information for the 
following ancillary study: 

 
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“S1400GEN Ancillary Study to Evaluate Patient and Physician Knowledge, 
Attitudes, and Preferences Related to Return of Genomic Results in S1400.” 
 
b. 
Directions: 
 
1. 
Site staff should download a copy of the Lung-MAP (S1400GEN) 
Appendix 1a Patient Survey and the S1400GEN Patient Survey Cover 
Letter from the protocol abstract page on the SWOG website 
(www.swog.org) and via the CTSU website and provide a copy of each to 
study physicians as they prepare to recruit patients to S1400. NOTE: The 
survey and cover sheet is provided to the patient to track the questions 
that will be asked during the phone interview. The patient may not 
complete the form other than via the phone interview (unless the study 
team decides, at a later date, to provide an online Patient Survey option.  
If the study team does provide an online Patient Survey option, sites will 
be notified and the online version of the patient survey will be found on the 
SWOG website mentioned above and be labeled Appendix 1b Patient 
Survey). 
 
2. 
Study physicians will provide S1400GEN patient participants with a hard 
copy of the Lung-MAP (S1400GEN) Patient Survey and the S1400GEN 
Patient Survey Cover Letter at the time of informed consent.  Patient 
participation is optional and their care or involvement in the parent trial, 
S1400, will not be affected if they choose not to participate in the 
S1400GEN ancillary study.  
 
3. 
After patient registration to S1400GEN, site staff will submit the patient’s 
contact information found on the last page of the “Optional Research 
Survey Study (S1400GEN)” consent form to the S1400GEN study center 
at the Fred Hutchinson Cancer Research Center (Fred Hutch). Site staff 
must complete the “For Site Use Only” section prior to submission of the 
page (documenting the patient’s SWOG ID number, initials, the name and 
contact for the site staff submitting the form and the name and contact 
information for the physician who enrolled the patient in S1400.  The site 
staff must fax the information to <TBD fax number> within 7 calendar days 
after registration. 
 
4. 
Fred Hutchinson Cancer Research Center (Fred Hutch) staff will contact 
the ancillary study patient participants (within 30 days after screening/pre-
screening registration) to conduct the 30-minute telephone-based survey 
(or send them an email link to the survey if it is decided to offer that option). 
The hard copy of the Lung-Map (S1400GEN) Patient Survey, provided at 
time of consent, will help to improve patient tracking and comprehension 
during the telephone interview.  
 
5. 
The 15-minute Lung-MAP (S1400GEN) Physician Survey will be 
administered online. A copy of it will be made available on the SWOG and 
CTSU webpages. 
 
6. 
Study staff at Fred Hutch will be responsible for approaching, consenting, 
and sending a link to the Physician Surveys within 30 days of physicians 
registering a patient to the patient survey component of this ancillary study.  
 
 

 
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7. 
S1400GEN study participants (patients and physicians) will be mailed a 
$20 Amazon gift card to thank them for their time within 30 days of 
completing the surveys. Study staff at Fred Hutch will be responsible for 
distributing all survey compensation payments. 
 
Questions regarding ancillary study should be directed to the Study Co-Chair, Dr. 
Josh Roth at 206-667-7867 or jroth@fredhutch.org. 
 
c. 
For additional information see Section 18.1f of S1400. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46.  
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312 and the CTEP Investigator’s Handbook. 
 
Publication and Industry Contact 
 
The agents supplied by CTEP, DCTD, NCI used in this protocol are provided to the NCI under 
Collaborative Agreements (CRADA, CTA, CSA) between the Pharmaceutical Companies 
(hereinafter referred to as "Collaborators") and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines  in addition to the provisions in the 
"Intellectual Property Option to Collaborator"  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award  apply to the use of the Agents in this study: 
 
1. 
Agents may not be used for any purpose outside the scope of this protocol, nor can Agents 
be transferred or licensed to any party not participating in the clinical study.  Collaborators 
data for Agents are confidential and proprietary to Collaborators and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of 
the NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 

 
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2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative Agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data"): 
 
a. 
NCI will provide all Collaborators with written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations which would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborators, the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborators for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborators for advisory review and 
comment prior to submission for publication.  Collaborators will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator's confidential and 
proprietary data, in addition to the Collaborator’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborators for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but 
in any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/media presentation should be sent 
to: 
 
E-mail:  ncicteppubbs@mail.nih.gov  
 

 
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The Regulatory Affairs Branch will then distribute them to the Collaborators.  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
Trial Master File 
  
This study has the potential for FDA registration; therefore, all participating sites should be FDA 
"inspection ready". This entails maintaining a Trial Master File that includes essential documents 
that may be subject to FDA oversight. A list of essential documents is available on the SWOG 
website under QA/Audits, https://swog.org/Visitors/QA/Index.asp. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
See Section 16.0 in each of the sub-study appendices (Section 18.2) for sub-study specific 
adverse event reporting requirements. 
 
 

 
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17.0 
BIBLIOGRAPHY
 
1  
Gandara DR, Li Tianhong, Lara PN Jr., Mack PC, Kelly K, Miyamoto S, et al. Algorithm for 
codevelopment of new drug-predictive biomarker combinations: accounting for inter-and 
intrapatient tumor heterogeneity. Clin Lung Cancer. 2012 Jun 5. [Epub ahead of print], 2012. 
 
2  
Barker AD, Sigman CC, Kelloff GJ, Hylton NM, et al. I-SPY 2: an adaptive breast cancer trial design 
in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 86(1):97-100, 2009. Epub 
2009/05/15. doi: 10.1038/clpt.2009.68. PubMed PMID: 19440188. 
 
3  
Kim ES, Herbst RS, Wistuba, II, Lee JJ, Blumenschein GR, Jr., Tsao A, et al. The BATTLE trial: 
personalizing therapy for lung cancer. Cancer discovery 1(1):44-53, 2011. Epub 2012/05/16. doi: 
10.1158/2159-8274.CD-10-0010. PubMed PMID: 22586319. 
 
4  
ACS. Cancer Facts and Figures 2013. Available from:  
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acsp
c-036845.pdf. 
 
5  
Hammerman PS, Lawrence MS, Voet D, Jing R, Cibulskis et al. Comprehensive genomic 
characterization of squamous cell lung cancers. Nature. 2012. Epub 2012/09/11. doi: 
10.1038/nature11404. PubMed PMID: 22960745. 
 
6  
Heger M. TCGA Lung Cancer Study IDs Potential Drug Targets in Majority of Cases. GenomeWeb 
[Internet]. Available from: http://www.genomeweb.com/sequencing/tcga-lung-cancer-study-ids-
potential-drug-targets-majority-cases, 2012. 
 
7  
Li t, Kung HJ, Mack PC, Gandara DR. Genotyping and genomic profiling of non-small cell lung 
cancer:  implications for current and future therapies. 10:31(8):1039-49, JCO, 2013. 
 
8  
Brahmer J, Reckamp KL, Baas P, et al. N Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non-Small-Cell Lung Cancer. N Engl J Med. PMID [PMID: 26028407], 2015. 
 
9  
Frampton GM, Fichtenholtz A, Otto GA, et al.  Development and validation of a clinical cancer 
genomic profiling test based on massively parallel DNA sequencing. Nature Biotechnology. 
Advance online publication. doi: 10.1038/NBT.2696, 2013. 
 
10  
Edelman M Spigel D, O'Byrne K, Mok T, Mocci S, Yu W, Paton V, Paz-Ares L. The prevalence of 
MET expression by immunohistochemistry (IHC) in the MetLung (OAM4971g) trial: a randomized, 
placebo-controlled, phase III study with erlotinib + onartuzumab (MetMab) vs erlotinib + placebo in 
patients with previously treated non-small cell lung cancer Journal of Thoracic Oncology 8:S2-
S1348, [Abstract MO12.07], 2013. 
 
11  
Watermann I, Schmitt B, Stellmacher F, et al: Improved diagnostics targeting c-MET in non-small 
cell lung cancer: expression, amplification and activation? Diagn Pathol 10:130, 2015. 
 
12  
Frampton GM, Fichtenholtz A, Otto GA, et al.  Development and validation of a clinical cancer 
genomic profiling test based on massively parallel DNA sequencing. Nature Biotechnology. 
Advance online publication.  doi: 10.1038/NBT.2696, 2013. 
 
13  
Redman MW, Goldman BH, LeBlanc M, Schott A, Baker L. Modeling the relationship between 
progression-free survival and overall survival: the phase II/III trial. Clin Cancer Res. (in press), 2013 
 
 

 
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14  
Harrington D, Fleming T, Green S. In Crowley J and Johnson RA Eds. Survival Analysis. Hayward, 
CA: IMS Lecture Notes Monograph Series, 2:269-286, 1982. 
 
15  
Redman MW, Goldman BH, LeBlanc M, Schott A, Baker L. Modeling the relationship between 
progression-free survival and overall survival: the phase II/III trial. Clin Cancer Res 2013;19:xx-xx 
(in press) 
 
16  
Dodd LE, Korn EL, Freidlin B, Gray R, Bhattacharya S. An audit strategy for progression-free 
survival. Biometrics. ;67(3):1092-9. doi: 10.1111/j.1541-0420.2010.01539.x. Epub 2011 Jan 6. 
PMID:  21210772, 2011. 
 

 
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18.0 
APPENDIX 
 
18.1 
S1400 Appendices 
 
a. 
Biomarker-Testing Algorithm and Clinical Assays 
 
b. 
New York Heart Association Classification 
 
c. 
Risk- Based Monitoring Plan 
 
d. 
Dose and Administration Schedules Overview   
 
e. 
Specimen Flow Diagram 
 
f. 
S1400GEN Ancillary Study 
 
18.2 
List of Sub-Study Attachments 
 
 
 

 
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18.1a 
Biomarker-Testing Algorithm and Clinical Assays 
 
Biomarker Reporting  
 
Biomarker Screening and Reporting to SWOG 
All patients will be screened with the NGS-based assay. Specimens will be sent from the 
site to Foundation Medicine, Inc. (FMI) using the SWOG Specimen Tracking System. FMI 
will perform the NGS-based assay. FMI will upload sub-study biomarker eligibility status 
report and a report containing the complete gene panel results for each patient to a Secure 
File Transport Protocol (sFTP) site within 16 days after submission of the specimen. An 
automated process will upload the data into the SWOG database.  
 
Sites will be notified of patient tissue that fails the biomarker screening along with the failure 
reason by the SWOG Statistical Center within 16 days after submission of the specimen.   
 
Sub-study assignment and Biomarker Reporting for patients screened at progression 
Sites will receive the patient’s sub-study assignment via email from the SWOG Statistical 
Center within 1 day from receipt of the biomarker analysis from FMI for patients 
successfully screened at the time of progression. In addition to containing the sub-study 
assignment, this email will include the report containing the complete gene panel results 
and educational material on the interpretation or lack thereof of the biomarker report. The 
treating physician is responsible for providing this information to the patients. 
 
If at any time it is determined that the patient will not register to a sub-study (either before 
or after sub-study assignment), the S1400 Notice of Intention Not to Register form must be 
submitted.  Sites will receive the email containing the sub-study assignment along with the 
complete gene panel results, as described above, upon receipt of the biomarker analysis 
from FMI. The treating physician is responsible for providing this information to the patients.  
Should the decision to not register a patient to their assigned sub-study be reversed, sub-
study registration is allowed despite submission of the S1400 Notice of Intention not to 
Register form. 
 
Sub-study assignment and Biomarker Reporting for patients pre-screened during current 
treatment 
Sites will receive the patient’s sub-study assignment via email from the SWOG Statistical 
Center within 1 day from receipt of the S1400 Notice of Progression (provided at least 16 
days have passed since the screening registration). The email will include the report 
containing the complete gene panel results and educational material on the interpretation 
or lack thereof of the biomarker report. The treating physician is responsible for providing 
this information to the patients. 
 
If at any time it is determined that the patient will not register to a sub-study (prior to 
progression or after sub-study assignment), the S1400 Notice of Intention Not to Register 
form must be submitted.  Sites will receive an email containing the complete gene panel 
results and educational material, upon receipt of the S1400 Notice of Intention Not to 
Register Form. If the S1400 Notice of Intention Not to Register form is submitted prior to 
receipt of the complete gene panel results, these results will be provided within 1 day from 
receipt at the SWOG statistical center.  The treating physician is responsible for providing 
this information to the patients. Should the decision to not register a patient to their 
assigned sub-study be reversed, sub-study registration is allowed despite submission of 
the Notice of Intention not to Register form. If the S1400 Notice of Intention Not to Register 
Form was submitted prior to progression, submission of the S1400 Notice of Progression 
is required to receive the patient’s sub-study assignment. 
 
 

 
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NGS-Based Cancer Gene Test 
 
Assay Description 
The next-generation DNA sequencing (NGS) (or massively parallel) assay based on 
Foundation Medicine’s FoundationOne™ assay for cancer gene profiling is a Clinical Trial 
Assay for this study. It is used to identify genomic alterations in squamous NSCLC on which 
assignment of patients into a sub-study with the appropriate matched treatment is based. 
Subjects without specific genomic alterations are eligible for the non-match arm. 
 
The laboratory process described below for the assay is a robust, multi-step protocol to 
generate targeted deep sequence data from adaptor-ligated sequencing libraries of DNA 
extracted from FFPE tissue. The workflow is executed in a Clinical Laboratory 
Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP) 
accredited laboratory and begins with sample receipt and accessioning into a laboratory 
information management system (LIMS), incorporates the generation of targeted 
sequencing data on an NGS platform, and culminates with a customized analysis pipeline 
capable of detecting genomic alterations with high accuracy. Multiple steps of the process 
are run on automated liquid handlers to ensure consistency/efficiency. The assay includes 
process-matched controls in each run, and defined quality control (QC) metrics are used 
throughout the process to monitor sample and assay performance.  
 
DNA Extraction and Library Construction 
A 4 µm section of a hematoxylin and eosin-stained slide is pathology reviewed to 
ensure a sample volume of ≥ 0.2 mm3, nucleated cellularity ≥ 80% or ≥ 30,000 cells 
and that ≥ 20% of the nuclei in the sample are derived from the tumor. A macro-
dissection to enrich specimens between 10% < and ≤ 20% tumor content is 
performed when warranted. DNA is extracted from 40 µm of unstained FFPE 
sections, typically 4 x 10 µm sections, by overnight digestion in a proteinase K buffer 
for 8-18 hours followed by purification with the KingFisher Flex with customized 
extraction kits. Double-stranded DNA (dsDNA) is quantified by a PicoGreen 
fluorescence assay using the provided lambda DNA standards (Invitrogen).  50-1000 
ng of dsDNA in 55 uL water in microTUBEs is fragmented to ~200 bp by sonication 
(175 sec, 30 % duty, 450 Peak Incident Power, 200 cycles/burst; Covaris LE2200) 
before purification using a 90 uL volume of AMPure® XP Beads (Agencourt®).  Solid-
phase reversible immobilization (SPRI) purification containing mixes for end repair, 
dA addition and ligation, are performed in 96-well plates (Eppendorf) on a Bravo 
Benchbot (Agilent) using the “with-bead” protocol 1to maximize reproducibility and 
library yield. (1) Indexed (8 bp barcodes) sequencing libraries are PCR amplified with 
HiFi™ Hotstart (Kapa) for 10 cycles, 90 uL SPRI purified and quantified Oligreen 
fluorescence assay (Invitrogen) and sized on a LabChip® GX (Caliper); size selection 
is not performed. Samples yielding less than 22 ng of extracted DNA or 500 ng of 
DNA library or less than 140 ng of sequencing library are failed. 
 
Hybrid Selection & Sequencing 
Solution hybridization is performed using a > 50-fold molar excess of a pool of 
individually synthesized 5’-biotinylated DNA 120 bp oligonucleotides (Integrated 
DNA Technology). The baits target ~1.5 Mb of the human genome including all 
coding exons of 287 cancer-related genes, 47 introns of 19 genes frequently re-
arranged in cancer, plus > 3,500 polymorphisms located throughout the genome. 
Baits were designed by taking overlapping 120 bp DNA sequence intervals covering 
target exons (60 bp overlap) and introns (20 bp overlap), with a minimum of three 
baits per target; SNP targets were allocated 1 bait each. Intronic baits were filtered 
for repetitive elements as defined by the UCSC Genome RepeatMasker track. (2) 
Hybrid selection of targets demonstrating reproducibly low coverage was boosted 

 
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by increasing the number of baits for these targets. As described previously, 500-
2000 ng of sequencing library is lyophilized in a 96-well plate and suspended in 
water, heat denatured at 95°C for 5 minutes and then incubated at 68°C for 5 minutes 
before addition of the baitset reagent in hybridization buffer. (3) After a 24 hour 
incubation, the library-bait duplexes are captured on paramagnetic MyOne™ 
streptavidin beads (Invitrogen) and off-target library is removed by washing one time 
with 1X SSC at 25°C and four times with 0.25 X SSC at 55°C.  The PCR master mix is 
added to directly amplify (12 cycles) the captured library from the washed beads. (4) 
After amplification, the samples are 90 uL SPRI purified, quantified by PicoGreen 
fluorescence assay (Invitrogen) and sized on a LabChip® GX (Caliper).  Libraries are 
normalized to 1.75 nM and pooled, prior to 49 x 49 paired end sequencing using 
manufacturer’s protocols on the Illumina HiSeq 4,000 system targeting at least 250 
x median unique sequence coverage. Any protocol updates will be validated by 
demonstrating equivalent or superior performance on key metrics, including 
coverage. 
 
Sequence data processing 
Sequence data is mapped to the human genome (hg19) using BWA aligner v0.5.8c. PCR 
duplicate read removal and sequence metric collection is performed using Picard 1.47 
(http://picard.sourceforge.net) and Samtools 0.1.16. (5, 6) Local alignment optimization is 
performed using Genome Analysis Toolkit (GATK) 1.0.4705. (7) Variant calling is 
performed only in genomic regions targeted by the test. 
 
Base substitution detection 
Base substitution detection is performed using a Bayesian methodology, which allows 
detection of novel somatic mutations at low mutant allele frequency (MAF) and increased 
sensitivity for mutations at hotspot sites through the incorporation of tissue-specific prior 
expectations. (8) Reads with mapping quality < 25 are discarded, as are base calls with 
quality ≤ 2. The equations governing this evaluation are: 
 
 
 
 
 
 
 
 
 
 
 
is evaluated with a multinomial distribution of the observed allele counts at each candidate 
mutation site, using empirically observed error rates. Call candidates are issued if 
. Final calls are made at MAF ≥ 5% (MAF ≥1% at hotspots) after filtering 

 
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for strand bias (Fisher’s test, p<1e-6), read location bias (KS test, p <1e-6), and presence 
in 2 or more normal controls.  
 
Indel detection 
To detect indels, de novo local assembly in each targeted exon is performed using the de-
Bruijn approach.  (9) Key steps are: 
 
• 
Collecting all read-pairs for which at least one read maps to the target region. 
• 
Decomposing each read into constituent k-mers and constructing an enumerable 
graph representation (de-Bruijn) of all candidate non-reference haplotypes present. 
• 
Evaluating the support of each alternate haplotype with respect to the raw read data 
to generate mutational candidates. All reads are compared to each of the candidate 
haplotypes via ungapped alignment, and a read ‘vote’ for each read is assigned to the 
candidate with best match. Ties between candidates are resolved by splitting the read 
vote, weighted by the number of reads already supporting each haplotype. This 
process is iterated until a ‘winning’ haplotype is selected.   
• 
Aligning candidates against the reference genome to report mutation calls. Indel 
candidates arising from direct read alignment are also considered. 
 
Filtering of indel candidates is carried out as described for base substitutions above (strand 
bias p<1e-10, MAF ≥ 3% at hotspots), with an empirically increased MAF thresh-hold at 
repeats and adjacent sequence quality metrics as implemented in GATK: % of neighboring 
base mismatches < 25%, average neighboring base quality > 25, average number of 
supporting read mismatches ≤ 2.  
 
Copy number alteration detection 
Copy number alterations (CNAs) are detected using a comparative genomic hybridization 
(CGH)-like method. First, we obtain a log-ratio profile of the sample by normalizing the 
sequence coverage obtained at all exons and ~3,500 genome-wide SNPs against a 
process-matched normal control. This profile is segmented and interpreted using allele 
frequencies of sequenced SNPs to estimate tumor purity and copy number at each 
segment. Briefly, if 
 is a genomic segment at constant copy number in the tumor, let  be 
the length of 
, 
 be the coverage measurement of exon j within 
, and 
 be the minor 
allele frequency of SNP k within 
. We seek to estimate , tumor purity, and 
, the copy 
numbers 
of 
. 
We 
jointly 
model 
 
and 
, 
given 
 
and  
: 
) and 
), where 
 is the 
copy number of minor alleles at 
, distributed as integer 
. 
 and 
 reflect 
noise observed in the CGH and SNP data, respectively. Fitting is performed using Gibbs 
sampling, assigning absolute copy number to all segments. Model quality is reviewed and 
alternative explanations considered9, and amplifications are called at segments with ≥6 
copies (or ≥ 7 for triploid/≥ 8 for tetraploid tumors) and homozygous deletions at 0 copies, 
in samples with purity ≥ 20%. (10) 
 
Gene fusions.  
Genomic rearrangements are identified by analyzing chimeric read pairs (read pairs for 
which reads map to separate chromosomes, or at a distance of over 10 Mbp). Pairs are 
clustered by genomic coordinate of the pairs, and clusters containing at least five chimeric 
pairs (3 known fusions) are identified as rearrangement candidates. Filtering of candidates 
is performed by mapping quality (MQ>30) and distribution of alignment positions (standard 
deviation > 10). Rearrangements are annotated for predicted function (e.g., creation of 
fusion gene). 
 
 

 
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Laboratory 
Clinical sample testing is done centrally at Foundation Medicine (FMI)'s CAP-
accredited/CLIA-certified diagnostic laboratory (Cambridge, MA).  
 
Tumor Scoring 
Positivity for each mutation for sub-study eligibility will be defined as presence of an 
alteration call by the methods above, with the list of eligible alterations specified in Section 
5.0 of each sub-study. The estimated mutant allele frequency, read depth, or copy level 
are recorded for each alteration, as appropriate. The definition of eligible alterations 
remains fixed for the duration of each sub-study. Any analysis software updates are subject 
to a Good Clinical Practice (GCP)-compliant change control process (available upon 
request), which must demonstrate equivalent or superior accuracy of alteration calls. (11) 
 
Validation 
The assay platform is commercially available. Validation studies were conducted on 
previously characterized cancer cell lines known to contain defined sets of genomic 
alterations in line with guidelines established by the Next Generation Sequencing: 
Standardization of Clinical Testing work group. (12) The NGS assay was found to be highly 
accurate in identifying genomic alternations, with sensitivity >99% for detection of base 
substitutions in samples in which as few as 5% of the nuclei were derived from cancer cells 
containing the alterations, 98% for detection of insertions and deletions in samples in which 
as few as 10% were derived from cancer cells containing the alterations, and > 95% for 
detection of copy number alterations in which as few as 30% of the nuclei were derived 
from cancers cells containing the alterations. In aggregate, the positive predictive value 
was 99% in the validation study. The validation procedure is discussed in detail in the 
attached publication with supplementary information. (13) 
 
REFERENCES 
 
 
1  
Fisher S, et al. A scalable, fully automated process for construction of sequence-ready human 
exome targeted capture libraries. Genome Biol 12, R1, 2011. 
 
2. 
Karolchik D, et al. The UCSC Table Browser data retrieval tool. Nucleic Acids Res 32, D493-496, 
2004. 
 
3. 
Gnirke A, et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel 
targeted sequencing. Nat Biotechnol 27, 182-189, 2009. 
 
4  
Van Loo P, et al. Allele-specific copy number analysis of tumors. Proc Natl Acad Sci U S A 107, 
16910-16915, 2010. 
 
5. 
Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. 
Bioinformatics 26, 589-595, 2010. 
 
6. 
Li H, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078-2079, 
2009. 
 
7. 
DePristo MA, et al. A framework for variation discovery and genotyping using next-generation 
DNA sequencing data. Nat Genet 43, 491-498, 2011. 
 
 

 
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8. 
Forbes SA, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic 
Mutations in Cancer. Nucleic Acids Res 39, D945-950, 2011. 
 
9  
Compeau PE, Pevzner PA, Tesler G. How to apply de Bruijn graphs to genome assembly. Nat 
Biotechnol 29, 987-991, 2011. 
 
10  
Gargis AS, Kalman L, Berry MW, Bick DP, et al. Assuring the quality of next-generation sequencing 
in clinical laboratory practice. Nat Biotechnol 30:1033-1036, 2012. Pubmed PMID:  23138292 
 
 
11  
Gargis AS, Kalman L, Berry MW, Bick DP, et al. Assuring the quality of next-generation 
sequencing in clinical laboratory practice. Nat Biotechnol 30:1033-1036, 2012. Pubmed PMID:  
23138292. 
 
12  
Gargis AS, Kalman L, Berry MW, Bick DP, et al. Assuring the quality of next-generation sequencing 
in clinical laboratory practice. Nat Biotechnol 30:1033-1036, 2012. Pubmed PMID:  23138292. 
 
13  
Frampton GM, et al. Development and validation of a clinical cancer genomic profiling test based 
on massively parallel DNA sequencing. Nat Biotechnol 31, 1023-1031, 2013. 
 
 
 

 
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18.1b 
New York Heart Association Classification 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by 
the physician. 
** 
At accustomed occupation or usual tasks. 
 
 

 
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18.1c 
Risk Based Monitoring Plan 
 
On Site Auditing 
 
NCI guidelines for Auditing Clinical Trials for the National Clinical Trials Network (NCTN) 
Program, Community Clinical Oncology Program (CCOP)/NCI Community Oncology 
Research Program (NCORP) and Research Bases: 
http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ctmbauditguidelines.pdf. 
 
The Quality Assurance Program of the Groups participating in the NCTN was developed 
to enhance the reliability and validity of clinical trials data through the use of routine 
monitoring procedures which includes auditing as one component.  The purpose of an audit 
is to document the accuracy of data submitted to the Data Operations Center and to verify 
compliance with protocol and regulatory requirements.  The program also surveys data 
management practices at each institution in order to provide educational support to the 
sites regarding issues related to data quality, data management, and other aspects of 
quality assurance. 
 
Each institution is audited at least once every three years, but remains at annual risk of an 
audit.  Routine monitoring of Institutional Performance Review reports and timeliness of 
reporting of Serious Adverse Events is conducted to identify institutions that may require 
more frequent audits. 
 
The audit team consists of qualified individuals capable of providing a medical assessment 
of the patient cases (Quality Assurance representative from the research base, physician, 
nurse or experienced clinical research associate [CRA]).  A number of patients equal to 
10% of the accrual since the last audit with a minimum of three are randomly selected for 
review at each institution.  In addition, a limited review of eligibility and consent only is 
conducted for at least one unannounced case at each on site audit. 
 
The major objective of the audit process is to verify study data that could affect the 
interpretation of primary study endpoints.  This is done through independent verification of 
study data against the source documents.  Primary source documentation reviewed during 
an audit includes the following: research records, hospital charts, clinic charts, lab reports, 
x-rays, scans, radiotherapy reports, operative reports, pathology reports and other special 
studies required by protocol. 
 
By comparing the data collection forms submitted to each Groups’ Data Operations Center 
with the primary records and referring to the protocol, the audit team reviews the records 
to determine compliance with protocol requirements for eligibility, treatment administration, 
response assessment, toxicity reporting and general data quality.  NCTN investigators and 
institutions are expected to follow the protocol and lead Group policy in treating patients 
registered on Group protocols.  Among other requirements, investigators/institutions must 
follow Group's dosing principles requirements for reporting Serious Adverse Events, and 
follow-up of all patients. 
 
The audit team verifies that the protocol and its amendments received initial and continuing 
IRB review and approval and that safety reports and serious adverse events were 
submitted to the IRB.  Investigational drug accountability record forms (DARFs) are 
reviewed and random patients are cross referenced against the medical record.  A tour of 
the pharmacy is conducted to verify security and storage conditions as well as the physical 
inventory.  Auditors also verify that the current IRB-approved version of the consent form 
was signed prior to registration and that subjects were informed of new findings that could 
affect their willingness to participate in the study.    
 

 
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The audit report is comprised of three components: 1) conformance to IRB and informed 
consent requirements, 2) the pharmacy and use of NCI DARFs, and 3) patient case review.  
An acceptable rating requires no deficiencies, few lesser deficiencies, or major deficiencies 
that were addressed prior to the audit.  Institutions found to be "unacceptable" or 
"acceptable, but requires “follow-up” on any component are required to submit a written 
response and/or corrective and preventative (CAPA) action plan.  Failure to submit a 
written response including a corrective and preventative action plan within the required 
timeframe will result in suspension of registration privileges.  A re-audit of any component 
rated as unacceptable will be conducted within one year after the unacceptable audit.  An 
unacceptable rating for the same audit component on two consecutive audits will result in 
probation.  Accrual will be suspended pending submission of a site improvement plan that 
addresses key infrastructural issues contributing to poor performance.  An unacceptable 
rating at the second re-audit may result in termination from the group.  If systematic 
misrepresentation of data is identified, an immediate repeat audit is scheduled by the 
representatives from the Group with the NCI and/or the FDA present. 
 
In some cases, non-compliance for issues such as timeliness of data submission, SAE 
reporting and submission of specimens is monitored off site rather than scheduling a re-
audit.  Failure to show improvement may result in scheduling of a re-audit or other 
disciplinary action. 
 
Results of all Quality Assurance Audits are reported to the NCI, the Principal Investigator 
of the institution that was audited, and representative of the Group.  Protocol specific audit 
results are also sent to the Lead Group to inform the statisticians, data chairs and study 
chairs of all discrepancies involving eligibility, treatment, toxicity or response assessment. 
 
The Quality Assurance Program performs their educational role through several 
mechanisms including presentations during the Group Meetings online Clinical Trials 
Training Courses, collaboration with others such as Pharmacy Committees and Statistical 
Centers to develop training tools, and memos and newsletter articles that are distributed 
to all Group institutions to educate research staff about changes in regulatory and quality 
assurance issues and audit procedures. 
On Site Monitoring 
In addition to the standard auditing process outlined above, the following additional 
requirements will be implemented for this study: 
• 
First on-site monitoring visit at each institution within 3 months of first patient 
registration to a sub-study. 
• 
On site monitoring for all sites with patients registered to a sub-study twice per 
year.  Additional monitoring visits to a site will be scheduled in response to several 
factors - rate of accrual, previous monitoring visit results, centralized electronic 
monitoring outcome, change in staff, etc.   
• 
An exception to the onsite monitoring requirement will be allowed in the following 
circumstances: 
-  
Sites that use a centralized pharmacy and data management team may be 
monitored at this central location.   
-    Sites that had an acceptable pharmacy audit in the last year may be audited off 
site at a central location.    
-     Sites that had an acceptable patient case review outcome at their last audit 
and have not enrolled patients to any new sub-studies may be put on an 
annual schedule.   
 
 

 
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Two full time monitors with 100% effort to S1400 are in charge of conducting monitoring 
visits.  Additional monitoring responsibilities are shared by the SWOG audit team members 
at the Operations Office and Statistical Center.  Additional monitoring visits may be sub-
contracted with other Network Groups, if necessary. 
 
Centralized Data Coordinator Monitoring at the SWOG Statistics and Data Management 
Center 
 
The SWOG Statistics and Data Management Center (SDMC) will support the risk based 
monitoring approach for this trial with the following actions: 
 
• 
Monitor data quality through routine review of submitted data such as on-study, 
baseline and follow up tumor assessment, lab, treatment, off treatment, and follow 
up case report forms to identify and follow-up on missing data, inconsistent data, 
data outliers, and potential protocol deviations that may be indicative of systemic 
or significant errors in data collection and reporting at a site. 
 
• 
Analyze site characteristics, performance metrics and clinical data to identify trial 
sites with characteristics correlated with poor performance or noncompliance 
through the SWOG Institutional Performance Reporting mechanism and other 
available reports. 
 
• 
Verify critical source data remotely via the collection and review of pathology, 
radiology and applicable lab reports.  This includes the review and confirmation of 
appropriate disease classification as determined by the pathology report, and 
assessment of response to treatment utilizing RECIST 1.1 based on scan reports 
uploaded to the Electronic Data Capture (EDC) system and submitted follow-up 
tumor assessment forms. 
 
• 
To assure data are as consistent, complete and accurate as possible, all subject 
data must undergo careful review by Data Coordinators (DCs).  After verifying that 
all data forms required to determine eligibility have been received or at a time point 
designated when all the required forms should have been received, the DC reviews 
the data and completes an initial evaluation. 
 
The initial review includes the following: 
 
• 
Determine that all required data fields on each form were completed and are 
consistent with other data. 
• 
Determine if all prestudy tests and exams were performed within protocol specified 
time limits. 
• 
Determine if each eligibility criterion was met and properly documented. 
• 
Review and confirm pathology based on the pathology report uploaded to the EDC 
system. 
• 
Verify that stratification and/or descriptive factors (if applicable) were correctly 
identified at registration. 
• 
Verify that the subject received the assigned study treatment and correct dose(s). 
• 
Verify that the treatment was started within the time limit indicated in the protocol 
(if applicable). 
• 
Determine if adverse events reported are consistent with other data and entered 
as required by study specifications. 

 
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• 
Post internal notes to add additional information which may be useful to the study 
sponsor, monitors, or statisticians, but which do not require action by site 
personnel. 
• 
Use the query tool to request additional data classifications and corrections of the 
CRA. 
 
The DC will perform subsequent review of data when new data become available or 
queries are answered.  Regular review will also occur while patients are still on-study, at 
the time of progression, once they are removed from study and at the time of death. 
 
Subsequent reviews include the following: 
 
• 
Determine if all required data fields on each newly submitted form were completed 
and consistent with other data. 
• 
Evaluate all new treatment documentation for correct treatment and dose. 
• 
Conduct assessment of response to treatment utilizing RECIST 1.1 based on scan 
reports uploaded to the EDC and submitted follow-up tumor assessment forms. 
• 
Review and code any new concomitant medications as required by study 
specifications. 
• 
Evaluate if the subject is or should be off protocol treatment per protocol criteria. 
• 
Review and evaluate death if death of subject is reported. 
• 
Use the query tool to request additional data classifications and corrections. 
• 
Post internal query notes to add additional information that may be useful to the 
study sponsor, monitor, or statisticians but which do not require action by site 
personnel. 
• 
Review site responses to the queries and the corrected or amended eCRF pages.  
When corrections and responses are considered satisfactory, queries are closed 
by the data coordinators.  Unsatisfactory responses are re-queried and tracked. 
• 
Perform re-evaluations promptly after responses to queries are received. 
 
Centralized Monitoring Review by the SDMC Monitors (Implemented as of Revision # 9) 
 
Off-site monitoring includes auditable elements for the Screening/Pre-Screening 
Registration for the first two patients registered to S1400 at each new study site or sites 
where an on-site S1400 audit has not occurred.  
 
Within one month after the S1400 Registration, a SDMC monitor will email the head CRA 
at the study site with the instructions for uploading auditable elements for the remote 
review.  Site staff are to upload source documents to support the Eligibility Criteria (Section 
5.0) and applicable forms submitted in Rave® for the Screening/Pre-Screening 
Registration.  The review will also consist of timeliness of data submission, specimen 
collection and specimen submission. 
 
Required Documents for Uploading to Rave®: 
Screening/Pre-Screening Informed Consent Form Pages: 
• 
Title Page 
• 
Response to Future Contact question 
• 
Responses to Samples for Future Research Studies questions 
• 
Signature Page 
Eligibility: 
• 
S1400 Registration Worksheet (signed and dated by the Registering Investigator) 
• 
Source Documents to Support Section 5.0 Eligibility Criteria  
• 
Source Documents to Support the S1400 Onstudy Form 

 
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• 
Source Documents to Support Other Forms if applicable (Examples: Notice of 
Progression, Status Update, Notice of Death, etc.) 
 
Safety Specific Centralized Monitoring 
 
Each Serious Adverse Event (SAE) report submitted (via National Cancer Institute systems 
CTEP-AERS) will be reviewed by the SWOG SAE Coordinator.  For each report supporting 
documentation will be requested and compiled with the report and sent to the Physician 
Reviewer.  As mentioned below all sites will undergo mandatory training and this will 
include training regarding SAE reporting.  SWOG regularly monitors timeliness of SAE 
reporting and addresses any issues of poor performance with individual sites. 
 
The study will be monitored for under reporting/missed Serious Adverse Events:  The 
SWOG SAE Coordinator receives a weekly report from the data base that includes all 
adverse events that are submitted through routine submission that potentially also meet 
expedited reporting criteria but for which no CTEP-AERS report is found.  The Coordinator 
is responsible for following up with the responsible site to ensure that SAEs are not 
missed/under-reported. 
 
The study will be monitored for trends in Serious Adverse Events:  A “new SAE on study” 
report is generated each time a new Serious Adverse Event is entered into the SWOG data 
base.  It is a cumulative report that lists all SAEs reported for the protocol.  This allows 
those who review the report to identify concerning trends in reported events; events that 
may be occurring at greater intensity (higher toxicity grade) or frequency than expected.  
The SAE Coordinator and Physician Reviewer are responsible for regularly monitoring this 
report as well as the Study Chair, and assigned Statisticians. 
Additional Approaches to be Used 
 
• 
Mandatory training of key site personnel prior to first patient registration. 
• 
Timely review of all monitoring reports to identify sites that require additional 
training, monitoring, disciplinary action, etc. 
• 
Routine monthly communication between monitor and site staff to assess potential 
problem areas, provide feedback, identify staff turnover, etc. 
• 
Additional mandatory centralized training to be provided to all sites if major 
changes to the protocol occur or common problem areas are identified. 
Blinded Independent Central Review of Response and Progression-Free Survival Endpoint 
 
All participants will undergo serial CT or MRI imaging: baseline/pre-treatment and every 6 
weeks until progression of disease (as determined by local site assessment). 
 
Collection and storage of all images as well as management of the independent review 
process will be the responsibility of the National Cancer Institute’s (NCTN) Imaging and RT 
Quality Assurance Service Core (IROC). 
 
The same imaging modality MUST be used for an individual patient throughout the 
course of the trial, with the exception of a PET/Spiral CT is used at baseline where 
the CT is of diagnostic quality, follow-up scans can be done by a spiral CT or if a 
PET/conventional CT is used at baseline where the CT is of diagnostic quality, 
follow-up scans can be done by conventional CT.  No other methods of assessments 
are interchangeable.  The pre- and post-treatment CT or MRI images must be 
submitted to IROC for all study participants.  CT is the preferred imaging modality 
unless there is a medical contraindication. 
 

 
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Clinical management and treatment decisions will be made by the treating physician based 
on local site assessments and other clinically appropriate considerations.   The study will 
collect and archive 100% of scans for randomized patients through the time of confirmed 
progression.  These will be ready for independent review should a sub-study terminate 
early for a large effect on PFS or ORR. 
 
At the time that central review is indicated, SWOG will provide IROC with the registration 
date and patient number, along with a blinded code indicating which reviewer will be 
assigned to each case.  This ensures that each reader reviews a balanced number of cases 
from each study arm.  An experienced team of radiologists will be identified by IROC.  A 
designated radiologist will review each image for assessment of progression of disease 
per RECIST 1.1 criteria.  The same reviewer will read all study images of an individual 
study participant.  Data from local reviews will not be provided to the central reviewers in 
order to keep the central reviewers blinded to the results of the local investigator-assessed 
PFS. 
 
The actual progression will be determined at the SWOG Statistical Center, using a 
composite of the IROC assessment, in conjunction with possible data on progression or 
symptomatic deterioration (see Section 10.7).  Results of the central review will NOT be 
communicated to the local site.  Decisions regarding clinical management of the patient 
will be made by the treating physician based on local site assessments/reviews and other 
clinical considerations. 
 
The BICR audit analysis will proceed following the algorithm specified in Dodd et.al 2011. 
(1)  Specific details for the inputs of this algorithm are described in Section 11.5. 
 
Review of pre-treatment CT/MRI exam will be performed as follows:  The reader will 
review all anatomic areas (chest, abdomen) imaged and available.  The target lesions to 
be evaluated will be defined/determined by the review of the pre-treatment exam.  A 
maximum of 5 target lesions will be defined with a maximum of 2 in a single organ.  The 5 
target lesions will be chosen with representation from all organs involved with the tumor.  
Additional significant non-target lesions and areas of non-measurable disease will be 
noted.  A screen capture of each target lesion, annotated with a pointer and a lesion 
reference number assigned to the target lesion, will be generated and archived.  This will 
be used on subsequent reads to ensure concordance of lesions on follow-up/post-
treatment exams.  Measurements will be made from the axial scan (generally the post 
contrast scan) that best demonstrates the lesion as distinct from background.  All 
measurements will be made by electronic calipers.  A screen capture of the actual 
measurement axis with calipers will be saved and archived with the exam permanently at 
IROC. 
 
Review of post-treatment image exam(s) will be performed as follows:  The pre-
treatment annotated exam and CRF will be reviewed to ensure lesion concordance.  
Readers will review all images for the current time point prior to making measurements.  
All measurements will be made by electronic calipers.  A screen capture of the actual 
measurement axis with calipers will be saved and archived with the exam permanently at 
IROC. 
 
1. 
Communication of Monitoring Results 
 
The monitoring team will meet monthly to share all aspects of monitoring (on sites, 
centralized, safety, alternative).  When needed, the SWOG Executive Officer for 
Quality Assurance will be consulted. 
 

 
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Routine site audits will be reported according to NCI Clinical Trials Monitoring 
Branch requirements.  Additional monitoring visits (those performed at greater 
frequency than required by the Clinical Trials Monitoring Branch) will be maintained 
in the CTMB-AIS data base and regularly reviewed by SWOG monitoring staff. 
 
Summarized results of all monitoring visits will be provided annually to the study’s 
Data and Safety Monitoring Committee, the SWOG Board of Governors, the study 
team and the FDA. 
 
2. 
Management of Noncompliance 
 
Issues of particular concern related to patient safety and questions of site fraud will 
be managed according to SWOG standard policies and the policies of the NCI 
Clinical Trials and Monitoring Branch for auditing of clinical trials under the NCI 
National Clinical Trials Network (NCTN) Program. 
 
Where important deviations are discovered, additional site training components 
will be developed and implemented. 
 
As with standard NCTN procedures, sites will be required to develop and 
implement corrective action plans in response to any deficiencies identified at a 
monitoring visit. 
 
3. 
Ensuring Quality Monitoring 
 
All staff involved in monitoring are required to undergo training in the principles of 
clinical investigations and human subject’s protection.  They are also required to 
complete the same protocol specific training required of the site staff. 
 
All monitoring and auditing process for the study will be reviewed by study 
leadership twice per year to ensure conformance to the monitoring plan. 
 
4. 
Monitoring Plan Amendments 
 
At each formal review of the monitoring plan and conformance to it, the study 
leadership will make a recommendation regarding the need for amendments to the 
monitoring plan.  These amendments will be reviewed and approved by NCI and 
provided in this protocol section and will be submitted to the FDA. 
 
REFERENCES 
 
 
 
1  
Harrington D, Fleming T, Green S. In Crowley J and Johnson RA Eds. Survival 
Analysis. Hayward, CA: IMS Lecture Notes Monograph Series, 2:269-286, 1982. 

 
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18.1d 
Dose and Administration Schedules Overview 
 
1.0 
List of Sub-studies 
Table 1.1 Sub-studies Open to Accrual 
None 
 
Table 1.2 Sub-studies Closed to Accrual 
 
Sub-
study 
Investigational 
Agent(s) 
Target 
Manufactur
er 
Structural 
Class 
Dose 
Route 
Day 
Cycle 
Control 
Closure 
Date 
S1400A 
MEDI4736 
PD-L1 
inhibitor (non-
match arm) 
MedImmun
e, Inc. 
Monoclonal 
antibody 
(IgG1ĸ) 
10 mg/kg 
IV (over 60 
minutes) 
1 
14 days 
N/A a 
12/18/15 
S1400B 
GBC-0032 
PI3K inhibitor 
Genentech 
Small 
molecule 
4 mg QD 
PO 
1-21 
21 days 
N/A a 
12/12/16 
S1400C 
Palbociclib 
CDK4/6 
inhibitor 
Pfizer, Inc. 
Small 
molecule 
125 mg 
QD 
PO 
1-21, 
followed 
by 7 
days off 
28 days 
N/A a 
09/01/16 
S1400D 
AZD4547 
FGFR1/2/3 
inhibitor 
Astra 
Zeneca 
Small 
molecule 
80 mg BID 
PO 
1-21 
21 days 
N/Aa 
10/31/16 
S1400E 
Rilotumumab + 
Erlotinib 
HGF/c-MET 
inhibitor 
Amgen 
Monoclonal 
antibody 
(IgG2) 
15 mg/kg 
IV 
1 
21 days 
Erlotinib 
11/25/14 
S1400I 
Nivolumab + 
Ipilimumab 
Anti-PD-
Linhibitor, 
CTLA-4 
inhibitor (non-
match arm) 
Bristol-
Myers 
Squibb 
Monoclonal 
antibody 
(CD279) 
3 mg/kg 
1 mg/kg 
IV (Over 
30/60 
minutes) 
1 
14 days/42 
days (q 3 
cycles) 
Nivoluma
b 
4/23/18 
S1400G 
Talazoparib 
PARP 
inhibitor 
Medivation 
Small 
molecule 
1000 mcg 
PO 
1-21 
21 days 
N/A 
7/23/18 
S1400F 
MEDI4736 + 
Tremelimumab 
Anti-PD-
1/PD-L1 
Inhibitor 
Resistant 
Astra 
Zeneca 
monoclonal 
antibody 
(1gG1, 1gG2) 
1500 mg 
75 mg 
IV (Over 
60 
minutes) 
1 
28 days 
(Treme – 
Cycle 1-4 
only) 
N/A 
3/24/20 
S1400K 
ABBV-399 
c-MET 
inhibitor 
AbbVie 
Monoclonal 
antibody 
(IgG1) 
2.7 mg/kg 
IV (over 30 
min) 
1 
21 days 
N\A 
12/21/18 
a Arm 2 – The control arm Docetaxel has been closed to accrual with Revision #3 

 
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2.0  
Protocol Instructions for Addition and Release of Investigational Agents 
 
The protocol is structured to enable seamless addition and release of investigational agents over the course 
of the trial.  
 
When an investigational agent is added or released from use in this trial, the following will require updating 
or addition: 
 
o 
SCHEMA  
o 
Section 18.1d: Overview of all investigational agents/sub-studies. Each investigational agent 
falls into one of two categories: 1) Activated Sub-studies, and 2) Inactivated Sub-studies. 
o 
Section 18.2: List of individual sub-study protocols. As investigational agents/sub-studies are 
added to the trial, they will be listed in alphabetical order. Sub-study-specific Model Treatment 
Consent 
 
Adding a Sub-study to the Trial 
The procedure for adding a new sub-study depends on its readiness. If all requirements have been met for 
activation (drug supply, contracts, etc.), a one-step process is followed. If activation is pending fulfillment 
of one or more requirements for activation, a two-step process is followed. For example, agent supply may 
not yet be available for distribution, although all other requirements have been addressed.  
 
If activation of a new sub-study is pending, the protocol is amended to include: 1) the new sub-study section 
2) a separate, sub-study-specific treatment consent, and 3) an updated Section 18.1d showing the new 
agent in Table 1.1 (Activated Sub-studies). The protocol amendment will be considered a major modification 
to the protocol, requiring CTEP amendment review, full IRB committee review; however, assignment to the 
already active sub-studies is not affected. Assignment to the new sub-study at an individual site may begin 
after IRB approval has been obtained. 
 
If all requirements for activation of a new sub-study have already been met, the protocol is amended to 
include: 1) the new sub-study section, 2) a separate sub-study treatment consent, 3) an updated Section 
18.1d showing the new agent in Table 1.1 (Activated Sub-studies) 4) and the new sub-study in the 
SCHEMA. The protocol amendment will be considered a major modification to the protocol and will require 
CTEP amendment review and full IRB committee review. Assignment to the sub-study at an individual site 
can begin after IRB approval has been obtained. 
 
Releasing a Sub-study from the Trial 
When an investigational agent/sub-study is closed to accrual, a protocol administrative change will be 
generated that includes: 1) an updated Section 18.1d showing the sub-study moved from Table 1.1 (Sub-
studies Open to Accrual) to Table 1.2 (Sub-studies Closed to Accrual), 2) a watermark ("Closed Effective 
XX/XX/XXXX ") on the sub-study section, which will remain in the protocol, 3) a watermark ("Closed 
Effective XX/XX/XXXX") on the separate, sub-study-specific treatment consent, and 4) removal of the sub-
study from SCHEMA in S1400. Assignment to the active sub-studies is not affected. 
 
 

 
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18.1e 
Specimen Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site 
Lab #211: Foundation 
Medicine, Inc. (FMI) 
 
Test: Biomarker Profiling 
(Required) 
 
See S1400 Section 15.2 
For approved 
translational medicine 
studies,  
SWOG Specimen 
Repository will forward 
the required specimens  
to the corresponding 
testing lab. 
 
See Sub-Study Section 
15.0. 
Lab #201: SWOG Specimen 
Repository – Solid Tissue 
 
Banking 
(Optional c) 
 
See Sub-Study Section 15.0. 
Screening/Pre-Screening 
Tumor Tissue 
(Required) 
 
See S1400 Section 5.1 
Peripheral Blood  
(Optional a) 
 
See S1400 Section 15.3 and 
Sub-Study Section 15.0. 
Re-biopsy Tumor Tissue at 
Progression (Optional a,b) 
 
See Sub-StudySection 15.0. 
a 
With patient's consent. 
 
b 
Among patients who initially responded to protocol treatment. 
 
c 
Remaining tissue will be sent to the SWOG Specimen Repository-Solid Tissue, Myeloma and 
Lymphoma Division, Lab #201, for use of the Translational Medicine studies within any sub-study the 
patient is enrolled in. SWOG Specimen Repository will prepare and ship the required specimens to 
the appropriate laboratory. The specimen will be kept until there are no additional sub-studies for the 
patient to enroll in or the tissue is used up, whichever happens first. With patient’s consent, any 
leftover tissue will remain at the SWOG Repository for future exploratory analysis. 

 
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18.1f 
S1400GEN 
 
Ancillary Study to Evaluate Patient and Physician Knowledge, 
Attitudes, and Preferences Related to Return of Genomic Results in S1400 
 
STUDY CHAIRS: 
 
Scott Ramsey MD, PhD 
Joshua A. Roth, PhD, MHA 
Hutchinson Institute for Cancer Outcomes Research 
1100 Fairview Avenue North 
Seattle, WA 98109 
Phone: 206-667-7846 
FAX: 206-667-5977 
E-mail:  sramsey@fredhutch.org 
 
jroth@fredhutch.org 
 
 
Dawn L. Hershman, MD, MS 
Katherine Crew, MD, MS 
Herbert Irving Comprehensive Cancer Center 
Columbia University 
161 Fort Washington, 1068 
New York, NY 10032 
Phone: 212 305-1945 
FAX: 212 305-0178 
E-mail:dlh23@cumc.columbia.edu 
 kd59@cumc.columbia.edu 
 
The purpose of this exploratory pilot study is to evaluate patient and physician knowledge, attitudes, 
and preferences about genomic profiling findings in the SWOG 1400 (S1400) study. This data will 
be gathered using a one-time only survey. The survey questions are principally focused on 
evaluating patient attitudes and preferences about return of incidental somatic mutation findings 
suggestive of a germline mutation in the context of a biomarker-driven clinical trial. Additionally, the 
study evaluates patient and physician knowledge of the differences between germline and somatic 
mutations, and physician attitudes and preferences about return of incidental genomic findings. 
The results of this study will be used to generate hypotheses for future research regarding return 
of genomic results in biomarker-driven clinical trial settings.   
 
 
 
 

 
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SCHEMA 
 
 
1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To evaluate patient attitudes and preferences about return of somatic 
mutation findings suggestive of a germline mutation in the S1400 master 
protocol trial. 
 
1.2 
Secondary Objective(s) 
 
a. 
To evaluate S1400 study physician attitudes and preferences 
about return of somatic mutation findings suggestive of a germline 
mutation in the S1400 master protocol trial.  
 
b. 
To evaluate S1400 patients’ and study physicians’ knowledge of 
cancer genomics. 
 

 
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c. 
To evaluate S1400 patients’ and study physicians’ knowledge of 
the design of the S1400 master protocol trial. 
 
d. 
To explore whether physician and patient knowledge of cancer 
genomics and attitudes and preferences about return of genomic 
profiling findings are correlated.  
 
2.0 
BACKGROUND 
 
Rationale 
‘Master protocol’ or ‘biomarker-driven’ trials (hereafter referred to as ‘biomarker-
driven’) that are guided by genomic profiling results are rapidly increasing in 
number, and may represent the beginning of a new paradigm in clinical trial 
research in oncology.  (1,2) Because these types of trials involve many 
independently conducted sub-studies that may involve different eligibility criteria 
and treatments, they are particularly complex to design and communicate. (3,4) 
As such, there is a threat that patients and study physicians participating in the 
initial genomic screening portion of biomarker-driven trials may not be fully 
informed about the many nuances of the return of genomic results, relationships 
between genomic results and eligibility for participation in sub-studies, or 
alternative treatment options (or lack thereof) within sub-studies. Furthermore, 
patient knowledge and attitudes about the return of genomic profiling results 
remains poorly studied outside the scope of a given clinical trial (hereafter referred 
to as “incidental findings”), and protocols for return of incidental findings in clinical 
trial settings are not established as they are in clinical practice. (5) Several studies 
have evaluated patient knowledge, attitudes, and preferences about genomic 
profiling in clinical care, but no studies have investigated these issues in the 
context of a biomarker-driven clinical trial. (6,7,8,9,10) As a result, there is urgent 
need to develop understanding of patient and study physician perspectives on 
genomic testing in clinical trials to: 1) evaluate if they have sufficient understanding 
of genomic principles to discuss the implications of participation in such trials, 2) 
improve return of genomic result processes in ongoing trials, and 3) inform the 
design of future biomarker-driven trials.  
 
SWOG 1400 (hereafter referred to as ‘S1400’) is an example of an ongoing 
biomarker-driven clinical trial where the issues outlined above are particularly 
pertinent. S1400 is a phase II/III screening/clinical registration protocol that 
involves genomic profiling of patients with advanced stage squamous cell lung 
cancer to direct patients to sub-studies investigating targeted (or ‘matched’) and 
‘non-matched’ therapies (11,12) These study characteristics create an ideal 
setting to study patient and physician knowledge, attitudes, and preferences about 
genomic findings because: 1) patients and study physician knowledge of the 
genomic testing procedures and return of results can be evaluated in a natural 
setting; 2) the Foundation Medicine next-generation sequencing platform used in 
the study has the ability to detect incidental genomic findings (i.e. genetic 
alterations not directly related to decisions in the S1400 trial), such as the 56 
recommended by the American College of Medical Genetics3--making study 
participants uniquely able to provide insights about attitudes and preferences 
related to incidental findings based on their own experience and feelings; and 3) 
study patients have poor survival prognosis, so they are in a natural position to 
reflect on the important issue of preferences for return of genomic testing results 
to family members in the event that they die prior to receiving the results 
themselves. (13,14) Furthermore, many organizations and individual researchers 

 
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have noted the need for studies evaluating these issues both in cancer patients in 
general, and in cancer patients in clinical trial settings. (15,16,17) 
 
We propose to conduct an ancillary survey study focused on patient and physician 
knowledge, attitudes, and preferences about somatic mutation findings suggestive 
of a germline mutation alongside S1400 to leverage the opportunities outlined 
above. Specifically, we will administer a one-time survey to a sample of S1400 
patients (n=200) at the master protocol screening step, as well as S1400 study 
physicians (n=30) providing care to those patients enrolled in this ancillary study. 
The ancillary study sample will be enriched for patients from geographically diverse 
National Cancer Institute Community Oncology Research Program (NCORP) 
Minority/Underserved (M/U) sites to enhance statistical power to evaluate 
differences in knowledge, attitudes, and preferences by education level, 
race/ethnicity, urban/rural status, social support level, and other factors. This 
exploratory study can provide an initial view of the landscape of knowledge, 
attitudes, and preferences about genomic profiling in biomarker-driven trials; allow 
evaluation of heterogeneity in these factors by matched/non-matched status, 
race/ethnicity, and socioeconomic status; and can be used to generate hypotheses 
to be evaluated in future biomarker-driven trials. 
 
This ancillary study is important because it will provide timely insight into patient 
and study physician knowledge, attitudes, and preferences about return of 
genomic profiling findings in an innovatively designed National Cancer Institute 
biomarker-driven trial. The results from this ancillary study can inform efforts to 
improve patient and physician understanding of genomic information in the context 
of clinical trials, including incidental genomic findings. Additionally, the study’s 
findings can be used to design patient- and physician-centered processes for 
return of genomic findings in clinical trial settings, and to generate hypotheses 
about issues related to return of genomic findings in future biomarker-driven 
clinical trials. 
 
Study Data 
The attached preliminary patient and physician surveys (Appendix 1 & 2) include 
questions that were developed with the input of behavioral science and genomics 
ethical, legal, and social implications (ELSI) experts to evaluate issues unique to 
return of genomic results in the context of the S1400 study. The survey questions 
were both adapted from prior studies of patient and physician knowledge, attitudes, 
and preferences about genomic testing in clinical cancer care, and created 
specifically for the purposes of this study. (18,19,20,21,22) 
 
The survey questions evaluate the domains outlined below in bold text. 
 
Knowledge of cancer genomics and return of results in the S1400 trial 
• 
Patient and physician knowledge of the distinctions between somatic and 
germline mutation testing  
• 
Patient and physician knowledge of the types of genomic results that are 
returned in the S1400 trial 
• 
Patient and physician knowledge of the likely outcomes of ‘matched’ and 
‘non-matched’ treatments  
 
Attitudes about return of genomic results in the S1400 trial 
• 
Patient attitudes about the genomic testing information presented in the 

 
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S1400 trial  
• 
A limited number of open-ended questions provide deeper insights into 
patient attitudes (motivations and concerns) about participating in the 
S1400 trial 
• 
Physician attitudes about return of different types of genomic findings in 
the S1400 trial  
 
Preferences for return of genomic results in the S1400 trial 
• 
Patient and physician preferences for return of different types of genomic 
findings in the S1400 trial Patient and physician preferences for return of 
results to family members in the event of germline mutation findings or 
somatic mutation findings suggestive of germline mutation 
• 
Patient preferences for return of genomic findings to family members in 
the event of their death prior to receiving results themselves  
 
The patient survey (Appendix 1) will be reduced and simplified with the input of 
patients. The physician survey (Appendix 2) will be reduced and simplified with the 
input of oncology physicians.  The survey development process is described 
below. 
 
First, we will conduct cognitive debriefing interviews, using preliminary drafts of the 
patient and physician surveys, with local convenience samples of advanced cancer 
patients, one lung cancer patient advocate (n=5) and oncologists (n=3 physicians).  
The purpose of this survey cognitive debriefing phase is to test understanding of 
the survey questions, impacts of alternative phrasing and formatting approaches, 
and redundancies in question domains. We will aim to recruit a minimum of 4 
patients who are not Caucasian/white and/or have a lower educational status (e.g. 
less than college education) to ensure that we receive early feedback from patients 
representing these important sub-groups. We will recruit the patient participants 
for the cognitive debriefing interviews from the Columbia University MU-NCORP 
site. Study staff at Fred Hutchinson Cancer Research Center will recruit, consent, 
and conduct the physician cognitive debriefing using oncologists who are members 
of the Fred Hutch/UW Cancer Consortium.  The physicians will complete an online 
survey and a study team member will conduct an interview with them afterwards 
to gather their feedback.   The Patient and Physician surveys will then be modified 
according to the feedback received. 
 
Second, we will conduct a quality control check of the modified surveys with 10 
S1400 patients and 3 S1400 study physicians to evaluate participant ability to 
complete the surveys and to detect potential issues prior to fielding the final survey. 
The quality control checks will use methods similar to the actual surveys with 
patients completing the survey by telephone and physicians completing the survey 
online. 
 
After completing the cognitive debriefing and quality control check, the investigator 
team will reevaluate the survey questions, simplify problematic phrasing and/or 
structure, and reduce the number of survey questions so that it can be completed 
within targeted periods of time (25-30 minutes for the telephone-based patient 
survey and 10-15 minutes for the web-based physician survey). We will re-engage 
our lung cancer patient advocate to assist in this process as needed. There may 
be a future option for participants to complete the survey online if participants 
strongly prefer and request that option. 
 

 
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3.0 
ELIGIBLITY 
All U.S. English language speaking patients registered to the S1400 master 
protocol study will be eligible for participation in this ancillary study.  
All S1400 study physicians that have patients who enroll in this ancillary study will 
be eligible for participation in this ancillary study. 
 
4.0 
STRATIFICATION FACTORS 
 
This study will use a stratified recruitment approach to accrue a total sample of 
200 patients enriched for representation of patients from NCORP minority-
underserved (M/U) sites. The proposed sampling approach will result in the 
following sub-groups: 1) patients from NCORP non-M/U sites (N=150) and 2) 
patients from NCORP M/U sites (N=50). This stratified recruitment approach is 
expected to provide a diverse sample in terms of educational level, race/ethnicity, 
rural/urban residence, socioeconomic status, social support level, and study site—
providing enhanced statistical power to conduct exploratory evaluation of 
differences in genomic testing knowledge, attitudes, and preferences between 
sub-groups.  
 
Potential patient participants (i.e. those enrolled in S1400 master protocol) will 
provide consent for participation in this ancillary study in an appendix to the S1400 
master protocol screening and pre-screening consent forms. S1400 site study staff 
will download the Lung-MAP (S1400GEN) Patient Survey and S1400GEN Patient 
Survey Cover Letter from the S1400 Protocol page on the SWOG website. Study 
physicians will provide patient participants with a hard copy of the survey (at the 
time of informed consent) to improve tracking and comprehension during the 
telephone interview. The surveys will be conducted over the phone. The option to 
complete the surveys online may be added at a later date if requested by a large 
number of S1400GEN participants. Following informed consent, a trained 
researcher from Fred Hutchinson Cancer Research Center (Fred Hutch) will 
contact ancillary study participants (within 30 days of screening/prescreening 
registration) to conduct the telephone-based survey. The patient survey is targeted 
to take 25-30 minutes or less to complete. Participants will be mailed a $20 gift 
card to compensate them for their time within 30 days of completing the telephone 
interview.  Staff at Fred Hutch will be responsible for distributing the survey 
compensation payments. 
 
Additionally, we will recruit and survey 30 study physicians that are providing care 
to patients enrolled in the S1400 ancillary study over an 18-month period beginning 
with ancillary study activation. This physician-patient matched design will allow us 
to evaluate associations between physician and patient genomic profiling 
knowledge, attitudes, and preferences. Fred Hutch staff will email a letter of 
introduction asking for physician participation, provide a Physician informed 
consent form, and a link to the online physician survey within 30 days of physicians 
registering a patient to the patient survey component of this ancillary study. The 
physician survey is targeted to take 15-20 minutes or less to complete. Physician 
participants will be sent a $20 gift card in compensation for their time within 30 
days of completing the online survey by study staff at Fred Hutch if they provide 
their contact information at the end of the survey. 
 
 

 
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5.0 
STATISTICAL CONSIDERATIONS 
 
Sample Size 
 
Target accrual has been set by budget to a sample size of 200 patient participants 
and 30 physician participants. We do not present formal power calculations given 
that this is an exploratory pilot study intended to generate hypotheses for 
evaluation in future studies. 
 
Analysis 
 
The primary objective of this pilot study is to conduct an exploratory evaluation of 
patient attitudes and preferences about return of somatic mutation findings 
suggestive of a germline mutation in the S1400 study. Since this study is 
hypothesis generating, and will include a sample diverse in educational level, 
race/ethnicity, socio-economic status, urban/rural setting, and social support level 
we will compare responses between sub-groups defined by these factors and 
promising items will be examined in a future study. Patient questionnaire 
responses will be profiled and descriptive statistics will be provided. Additionally, 
we will conduct unadjusted and multivariate logistic regression analyses to 
evaluate the association between patient characteristics (e.g. educational level, 
race/ethnicity, socio-economic status, education, urban/rural setting, and social 
support level) and attitudes and preferences related to return of genomic findings.  
Multivariate analyses will adjust for demographic, socioeconomic, and cancer-
specific clinical factors, and we will conduct formal tests of multiplicative interaction 
as appropriate. Similar exploratory analyses will be conducted to evaluate the 
secondary objectives of patient knowledge about cancer genomics and the design 
of the S1400 master protocol trial.   
 
Given the small number of study physicians who will be enrolled (n=30), power to 
compare responses between groups and to explore associations with patient 
questionnaire responses will be limited. Physician questionnaire responses about 
knowledge, attitudes, and preferences about return of genomic findings in S1400 
will be profiled and descriptive statistics provided. Correlation between patient and 
study physician responses will be evaluated using the chi squared statistic. 
 
No formal interim analyses will be conducted in support of this exploratory survey 
study.  
 
Though the surveys (Appendix 1 and 2) ask only hypothetical questions about 
incidental genomic findings (i.e. patients are not asked about their specific results), 
it is possible that some patients may experience stress or concern as a result of 
participating in the survey. To assess and address this issue, we conclude the 
patient surveys with a question asking if the questions caused substantial stress 
or worry, and will advise patients to speak with a member of their healthcare team 
about any issues of concern.  
 
6.0 
ENDPOINTS 
 
6.1 
Primary Endpoint 
Patient attitudes and preferences about return of somatic mutation findings 
suggestive of a germline mutation 
 

 
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6.2 
Secondary Endpoint 
a. 
Patient knowledge of cancer genomics 
 
b. 
Physician attitudes and preferences about return of genomic 
profiling results 
 
c. 
Physician knowledge of cancer genomics 
 
 
7.0 
BIBLIOGRAPH
 
1  
Redman MW, Allegra CJ. The Master Protocol Concept. Seminars in oncology. 
42(5):724-730, 2015. 
 
2  
Herbst RS, Gandara DR, Hirsch FR, et al. Lung Master Protocol (Lung-MAP)-A 
Biomarker-Driven Protocol for Accelerating Development of Therapies for 
Squamous Cell Lung Cancer: SWOG S1400. Clinical cancer research: an official 
journal of the American Association for Cancer Research. 21(7):1514-1524, 2015/ 
 
3  
Redman MW, Allegra CJ. The Master Protocol Concept. Seminars in oncology. 
42(5):724-730, 2015;. 
 
4   
Herbst RS, Gandara DR, Hirsch FR, et al. Lung Master Protocol (Lung-MAP)-A 
Biomarker-Driven Protocol for Accelerating Development of Therapies for 
Squamous Cell Lung Cancer: SWOG S1400. Clinical cancer research: an official 
journal of the American Association for Cancer Research. 2015;21(7):1514-1524. 
5  
Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of 
incidental findings in clinical exome and genome sequencing. Genetics in 
medicine: official journal of the American College of Medical Genetics. 15(7):565-
574. 2013. 
 
6  
Gray SW, Hicks-Courant K, Lathan CS, Garraway L, Park ER, Weeks JC. Attitudes 
of patients with cancer about personalized medicine and somatic genetic testing. 
Journal of oncology practice / American Society of Clinical Oncology. 8(6):329-
335, 322 p following 335, 2012. 
 
7  
Gray SW, Hicks-Courant K, Cronin A, Rollins BJ, Weeks JC. Physicians' attitudes 
about multiplex tumor genomic testing. Journal of clinical oncology: official journal 
of the American Society of Clinical Oncology. 32(13):1317-1323, 2014. 
 
8  
Miller FA, Hayeems RZ, Bytautas JP, et al. Testing personalized medicine: patient 
and physician expectations of next-generation genomic sequencing in late-stage 
cancer care. European journal of human genetics: EJHG. 22(3):391-395, 2014. 
 
9  
Blanchette PS, Spreafico A, Miller FA, et al. Genomic testing in cancer: patient 
knowledge, attitudes, and expectations. Cancer. 120(19):3066-3073, 2014. 
 
10  
Middleton A, Morley KI, Bragin E, et al. Attitudes of nearly 7000 health 
professionals, genomic researchers and publics toward the return of incidental 
results from sequencing research. European journal of human genetics: EJHG. 
2015. 
 
 

 
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11  
Herbst RS, Gandara DR, Hirsch FR, et al. Lung Master Protocol (Lung-MAP)-A 
Biomarker-Driven Protocol for Accelerating Development of Therapies for 
Squamous Cell Lung Cancer: SWOG S1400. Clinical cancer research: an official 
journal of the American Association for Cancer Research. 21(7):1514-1524, 2015. 
 
12  
Steuer CE, Papadimitrakopoulou V, Herbst RS, et al. Innovative Clinical Trials: 
The LUNG-MAP Study. Clinical pharmacology and therapeutics. 97(5):488-491, 
2015. 
 
13  
Breitkopf CR, Petersen GM, Wolf SM, et al. Preferences Regarding Return of 
Genomic Results to Relatives of Research Participants, Including after Participant 
Death: Empirical Results from a Cancer Biobank. The Journal of law, medicine & 
ethics: a journal of the American Society of Law, Medicine & Ethics. 43(3):464-
475, 2015. 
 
14  
Wolf SM, Branum R, Koenig BA, et al. Returning a Research Participant's Genomic 
Results to Relatives: Analysis and Recommendations. The Journal of law, 
medicine & ethics: a journal of the American Society of Law, Medicine & Ethics. 
43(3):440-463, 2015;. 
 
15  
Parsons DW, Roy A, Plon SE, Roychowdhury S, Chinnaiyan AM. Clinical tumor 
sequencing: an incidental casualty of the American College of Medical Genetics 
and Genomics recommendations for reporting of incidental findings. Journal of 
clinical oncology: official journal of the American Society of Clinical Oncology. 
32(21):2203-2205, 2014;. 
 
16  
Raymond VM, Gray SW, Roychowdhury S, et al. Germline Findings in Tumor-Only 
Sequencing: Points to Consider for Clinicians and Laboratories. Journal of the 
National Cancer Institute. 108(4), 2016;. 
 
17  
Bombard Y, Robson M, Offit K. Revealing the incidentalome when targeting the 
tumor genome. Jama. 310(8):795-796, 2013. 
 
18  
Gray SW, Hicks-Courant K, Lathan CS, Garraway L, Park ER, Weeks JC. Attitudes 
of patients with cancer about personalized medicine and somatic genetic testing. 
Journal of oncology practice / American Society of Clinical Oncology. 8(6):329-
335, 322 p following 335, 2012. 
 
19  
Gray SW, Hicks-Courant K, Cronin A, Rollins BJ, Weeks JC. Physicians' attitudes 
about multiplex tumor genomic testing. Journal of clinical oncology: official journal 
of the American Society of Clinical Oncology. 32(13):1317-1323, 2014. 
 
20  
Miller FA, Hayeems RZ, Bytautas JP, et al. Testing personalized medicine: patient 
and physician expectations of next-generation genomic sequencing in late-stage 
cancer care. European journal of human genetics: EJHG. 22(3):391-395, 2014. 
 
21  
Blanchette PS, Spreafico A, Miller FA, et al. Genomic testing in cancer: patient 
knowledge, attitudes, and expectations. Cancer. 120(19):3066-3073, 2014. 
 
22  
Middleton A, Morley KI, Bragin E, et al. Attitudes of nearly 7000 health 
professionals, genomic researchers and publics toward the return of incidental 
results from sequencing research. European journal of human genetics: EJHG. 
2015. 
 
 

 
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18.2 
List of Sub-study Attachments 
 
S1400A: (Non-Match sub-study):  Anti-PD-L1 – MEDI4736  
 
S1400B: PI3K - GBC-0032 
 
S1400C: CDK4/6 – Palbociclib 
 
S1400D: FGFR – AZD4547 
 
S1400E: HGF – Rilotumumab + Erlotinib versus Erlotinib 
 
 
S1400F: (Non-Match sub-study): Anti-PD-1/PD-L1 Inhibitor Resistant Durvalumab 
(MEDI4736) plus Tremelumumab 
 
S1400G: HRRD-Talazoparib (BMN 673)  
 
S1400I: (Non-Match sub-study): Nivolumab + Ipilimumab versus Nivolumab 
 
S1400K: C-MET – ABBV-399 (Process II)