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PRIVILEGED COMMUNICATION Distribution IRB Review Only 5/28/14 FOR INVESTIGATIONAL USE ONLY Activated June 16, 2014
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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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cctg study chair

Natasha Leighl, BSc, MMSc, M.D. Univ. Health Network-Princess Margaret Hospital E-mail: Natasha.leighl@uhn.ca
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participants

| ECOG-ACRIN/ECOG-ACRIN Cancer Research Group CCTG/Canada CancerTrials Group NRG/NRG Oncology SWOG/SWOG   |
|---------------------------------------------------------------------------------------------------------|
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participants

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| PARTICIPANTS                                                      |                                                                                                                                                                 |
| TABLE OF CONTENTS                                                 |                                                                                                                                                                 |
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION |                                                                                                                                                                 |
| SCHEMA                                                            |                                                                                                                                                                 |
| 1.0                                                               | OBJECTIVES .                                                                                                                                                    |
| 1.1                                                               | Primary Objective of the Master Protocol (S1400) .                                                                                                              |
| 1.2                                                               | Design #1: Phase II/III Design .                                                                                                                                |
| 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                                                                                                                   |
| 2.0                                                               | B BACKGROUND                                                                                                                                                    |
| 2.1                                                               | General Background .                                                                                                                                            |
| 2.2                                                               | Choice of Disease Setting                                                                                                                                       |
| 2.3                                                               | STING IN THE STATE                                                                                                                                              |
| 2.4                                                               | SP44 anti-C-MET Immunohistochemistry (IHC) Assay .                                                                                                              |
| 2.5                                                               | Inclusion of Women and Minorities                                                                                                                               |
| 3.0                                                               | DRUG INFORMATION .                                                                                                                                              |
| STAGING CRITERIA                                                  |                                                                                                                                                                 |
| 4.0                                                               |                                                                                                                                                                 |
| 5.0                                                               | ELIGIBILITY CRITERIA .                                                                                                                                          |
| 5.1                                                               | Screening/Pre-Screening Registration                                                                                                                            |
| 5.2                                                               | SURE                                                                                                                                                            |
| 6.0                                                               | STRATIFICATION FACTORS                                                                                                                                          |
| 7.0                                                               | TREATMENT PLAN .                                                                                                                                                |
| 7.1                                                               | T Treatment                                                                                                                                                     |
| 7.2                                                               | Radiology Review .                                                                                                                                              |
| 7.3                                                               | D Discontinuation of Treatment .                                                                                                                                |
| 7.4                                                               | Follow Up Period                                                                                                                                                |
| 8.0                                                               |                                                                                                                                                                 |
| 9.0                                                               | STUDY CALENDAR                                                                                                                                                  |
| CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS                     |                                                                                                                                                                 |
| 10.0                                                              |                                                                                                                                                                 |
| 10.1                                                              | Measurability of Lesions                                                                                                                                        |
| 10.2                                                              | Objective Status at Each Disease Evaluation                                                                                                                     |
| 10.3                                                              | Best Response                                                                                                                                                   |
| 10.4                                                              | Performance Status .                                                                                                                                            |
| 10.5                                                              | Time to Death                                                                                                                                                   |
| 10.6                                                              | Investigator-Assessed Progression-Free Survival                                                                                                                 |
| 10.7                                                              | Progression-Free Survival by Central Review                                                                                                                     |
| 10.8                                                              | Duration of Response (DoR)                                                                                                                                      |
| 1.0                                                               | STATISTICAL CONSIDERATIONS .                                                                                                                                    |
| 1.1                                                               | Design #1: Phase II/III Design .                                                                                                                                |
| 11.2                                                              | Design #2: Phase II followed by Phase III (Sequential Phase II to Phase III) .....................................31                                            |
| 1.3                                                               | Blinded Independent Centralized Review (BICR) of PFS and/or ORR ...............................................36                                               |
| Accrual Information                                               |                                                                                                                                                                 |
| 1.4                                                               |                                                                                                                                                                 |
| 1.5                                                               | Screening Success Rate Evaluation                                                                                                                               |
| 1.6                                                               | Treatment Arm Randomization Acceptance Rate Evaluation                                                                                                          |
| 1.7                                                               | D DATA AND SAFETY MONITORING .                                                                                                                                  |
| 12.0                                                              | DISCIPLINE REVIEW                                                                                                                                               |
| REGISTRATION GUIDELINES                                           |                                                                                                                                                                 |
| 13.0                                                              |                                                                                                                                                                 |
| 13.1                                                              | Registration Timing                                                                                                                                             |
| 13.2                                                              | Investigator/Site Registration .                                                                                                                                |
| 13.3                                                              | OEN Registration Reguirements ...............................................................................................................................42 |
| 13.4                                                              | Registration Procedures                                                                                                                                         |  
  
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Version Date 12/18/20  
| Version Date 12/18/20   |                                                                                                             |
|-------------------------|-------------------------------------------------------------------------------------------------------------|
| 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 SUBSTUDIES 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                                                                            |  
  
| CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                     |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| To submit site registration                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | For patient                                                                                                                                                                                                                                                                                     | Submit study data directly to the Lead                                                                                                                              |
| documents:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | enrollments:                                                                                                                                                                                                                                                                                    | Cooperative Group unless otherwise specified in the protocol:                                                                                                       |
| Regulatory documentation must  be submitted to the CTSU via the  Regulatory Submission Portal:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 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.                                                              | Data collection for this study will be done  exclusively through Medidata  Rave. Please see the data submission  section of the protocol for further  instructions. |
| Regulatory Submission Portal  (Sign in at www.ctsu.org, and  select the Regulatory  Submission sub-tab under the  Regulatory tab.)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | 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. |                                                                                                                                                                     |
| 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 Help  Desk with any OPENrelated questions at  ctsucontact@westat.com.                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                     |
| Contact the CTSU Regulatory  Help Desk at 1-866-651-2878 for  regulatory assistance. 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 |                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                     |  
  
  
SCHEMA
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

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 biomarkerdrug 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.
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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 substudy by comparing investigator-assessed progression-free survival (IAPFS) between investigational therapy versus standard therapy (SoC) in patients with advanced stage refractory squamous cell carcinoma (SCCA)
of the lung.
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2. phase iii component

The co-primary objectives of the Phase III component are:
i. To determine if there is both a statistically and clinicallymeaningful 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.
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  
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 clinicallymeaningful 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.
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.
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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.
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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 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 T**herapeutic 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.
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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.  
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)
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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 formalinfixed 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.  
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.
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2.4 sp44 anti-c-met immunohistochemistry (ihc)

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. ABBV399 (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.
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2.5 inclusion of women and

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.  
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     |
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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.
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regional lymph nodes (n)

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 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)
** 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.
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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.
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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/IASLCclassification 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 platinumbased chemotherapy regimen and disease progression on the platinumbased 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 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
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progress and the s1400 notice

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 nextgeneration 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 will provide participants with a hard copy of the survey (at the time of informed consent) to improve tracking and comprehension during the interview.
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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 substudy, 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   |
|-----------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|-------------------------|
| L858R, T790M, A289V, G719A, S768I,  G719C, R108K, G598V, R222C, L62R, |                                                                                                           |                         |
| Substitution                                                          | L861Q, P596L, V774M non-frame shifting insertions or deletions  between amino acids 740 and 780, in exons |                         |
| Indel                                                                 | 19 and 20, transcript NM_005228                                                                           |                         |
| EGFR                                                                  | Fusion                                                                                                    | None                    |
| Amplification                                                         | None                                                                                                      |                         |
| Substitution                                                          | None                                                                                                      |                         |
| Indel                                                                 | None EML4-ALK, CLIP4-ALK, CLTC-ALK, KIF5BALK, NPM1-ALK, RANB2-ALK, STRN-ALK,                                                                                                           |                         |
| Fusion                                                                | TFG-ALK                                                                                                   |                         |
| ALK                                                                   | Amplification                                                                                             | None                    |  
  
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 substudy 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 nonmeasurable 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.  
† 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 substudy 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.  
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.
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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 substudy specific stratification factors.
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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.
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8.0 toxicities to be monitored

See Section 18.2 for sub-study specific toxicities to be monitored and dose modifications.
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10.0 criteria for evaluation and

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 nonmeasurable 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.
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note regarding diagnostic quality ct

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.
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pet/ct - positron emission tomography

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.
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.  
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.  
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.
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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.
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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.
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10.7 progression-free survival by central

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.
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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.
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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 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 substudy 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.
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11.1 design #1 phase ii/iii

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 substudy 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 substudy is to compare overall survival (OS) in patients with advanced stage refractory SCCA of the lung randomized to receive investigational therapy versus SoC.
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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.
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c. sample size with power

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 substudy is included in the Statistical Considerations in the sub-study protocol for each sub-study. (13)
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. Substudies 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 IAPFS 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.
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d. analysis plan including plans

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 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 1sided 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 1sided 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.  
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 pvalue 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  Futility Bound Efficacy Bound events 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 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
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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 (IAPFS) 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.  
ii. To evaluate the frequency and severity of toxicities associated with investigational therapy versus SoC.
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4. sample size with power

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.
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ii. follow-on phase iii design

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.
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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.  
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.
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5. analysis plan i. phase

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-totreat 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.  
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 pvalue 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.
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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 IAPFS 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.
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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 data and discussions with appropriate parties. The details here are specific to the Phase II design.
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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.
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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.
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3. sample size with power

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%.
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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.  
| 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.  
| Expected  number of  responses   | Probability          |           |             |    |       |
|----------------------------------|----------------------|-----------|-------------|----|-------|
| RR                               | Interim 1            | Interim 2 | 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% |
| Probability of  stopping         | Average  sample size |           |             |    |       |  
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.
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11.3 blinded independent centralized review

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 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)
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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 substudy 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:  
| Table 2       | Total S1400   | Total Sub-study   |
|---------------|---------------|-------------------|
| Registrations | 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         |
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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.
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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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13.0 registration guidelines 13.1 registration

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.
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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.
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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                                                             |      |        |     |     |  
  
| 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).
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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 turnaround 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.
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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 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.
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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.
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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.
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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.  
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
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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  
  
g. Patient Initials h. Patient's Date of Birth 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
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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.  
i. Patient SSN (SSN is desired, but optional. Do not enter invalid numbers.)
j. Country of Residence k. ZIP Code 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.
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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.
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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
(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).  
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.
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b. within 5 calendar days

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
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14.5 data submission for patients

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.
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c. within 28 days of

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
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a. after progression on a

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
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d. until registration to new

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 substudy, follow-up is still required on the previous sub-study.  
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.
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15.0 special instructions 15.1 swog

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 startup 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 206/6522267 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

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
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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).  
If biomarker profiling could not be obtained from the submitted tissue, additional tissue will be requested.
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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.
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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.  
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 longterm viability.
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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 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.
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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.
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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.
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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:
"**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/prescreening 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.  
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**.
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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:
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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.
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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.
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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.
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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.  
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 MultiParty 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 nonCooperative 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  
  
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.
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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.
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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.
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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-idspotential-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 SquamousCell 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  
  
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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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, substudy 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.  
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 macrodissection 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®). Solidphase 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 rearranged 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 by increasing the number of baits for these targets. As described previously, 5002000 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.  
_Frequency of mutation ${}^{2}F>0|R\rangle=1-P(F=0|R)$_
$\frac{24}{5}$ 3.
$\square$
$\begin{array}{c}\mbox{P}(F=0|R)=\frac{\mbox{P}(R|F=0)\mbox{P}(F=0)}{\mbox{P}(F=0)}\\ \mbox{P}(F=0|R)=\frac{\mbox{P}(R|F=0)\mbox{P}(F=0)}{\mbox{P}(F=0)}\end{array}$  
$$*{\mathcal{V}}{\mathcal{F}}^{\pi}$$  
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:  
$$\operatorname{LU}\,$$
$$P\left(R\left|F={\frac{i}{\pi}}\right)\right)$$
$$\mathbf{F}=0)=$$
* [16] A. A. K.  
  
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 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.
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indel detection

To detect indels, *de novo* local assembly in each targeted exon is performed using the deBruijn 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.
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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).  
Laboratory Clinical sample testing is done centrally at Foundation Medicine (FMI)'s CAPaccredited/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)*
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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.  
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.  
  
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.                                                                |             |                     |                   |