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on site auditing

NCI guidelines for Auditing Clinical Trials for the National Clinical Trials Network (NCTN)
Program, Community Clinical Oncology Program (CCOP)/NCI Community Oncology Research Program (NCORP) and Research Bases:
http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ctmbauditguidelines.pdf.  
The Quality Assurance Program of the Groups participating in the NCTN was developed to enhance the reliability and validity of clinical trials data through the use of routine monitoring procedures which includes auditing as one component. The purpose of an audit is to document the accuracy of data submitted to the Data Operations Center and to verify compliance with protocol and regulatory requirements. The program also surveys data management practices at each institution in order to provide educational support to the sites regarding issues related to data quality, data management, and other aspects of quality assurance.  
Each institution is audited at least once every three years, but remains at annual risk of an audit. Routine monitoring of Institutional Performance Review reports and timeliness of reporting of Serious Adverse Events is conducted to identify institutions that may require more frequent audits.  
The audit team consists of qualified individuals capable of providing a medical assessment of the patient cases (Quality Assurance representative from the research base, physician, nurse or experienced clinical research associate [CRA]). A number of patients equal to 10% of the accrual since the last audit with a minimum of three are randomly selected for review at each institution. In addition, a limited review of eligibility and consent only is conducted for at least one unannounced case at each on site audit.  
The major objective of the audit process is to verify study data that could affect the interpretation of primary study endpoints. This is done through independent verification of study data against the source documents. Primary source documentation reviewed during an audit includes the following: research records, hospital charts, clinic charts, lab reports, x-rays, scans, radiotherapy reports, operative reports, pathology reports and other special studies required by protocol.  
By comparing the data collection forms submitted to each Groups' Data Operations Center with the primary records and referring to the protocol, the audit team reviews the records to determine compliance with protocol requirements for eligibility, treatment administration, response assessment, toxicity reporting and general data quality. NCTN investigators and institutions are expected to follow the protocol and lead Group policy in treating patients registered on Group protocols. Among other requirements, investigators/institutions must follow Group's dosing principles requirements for reporting Serious Adverse Events, and follow-up of all patients. The audit team verifies that the protocol and its amendments received initial and continuing  
 IRB review and approval and that safety reports and serious adverse events were submitted to the IRB. Investigational drug accountability record forms (DARFs) are reviewed and random patients are cross referenced against the medical record. A tour of the pharmacy is conducted to verify security and storage conditions as well as the physical inventory. Auditors also verify that the current IRB-approved version of the consent form was signed prior to registration and that subjects were informed of new findings that could affect their willingness to participate in the study.  
The audit report is comprised of three components: 1) conformance to IRB and informed consent requirements, 2) the pharmacy and use of NCI DARFs, and 3) patient case review.  
An acceptable rating requires no deficiencies, few lesser deficiencies, or major deficiencies that were addressed prior to the audit. Institutions found to be "unacceptable" or
"acceptable, but requires "follow-up" on any component are required to submit a written response and/or corrective and preventative (CAPA) action plan. Failure to submit a written response including a corrective and preventative action plan within the required timeframe will result in suspension of registration privileges. A re-audit of any component rated as unacceptable will be conducted within one year after the unacceptable audit. An unacceptable rating for the same audit component on two consecutive audits will result in probation. Accrual will be suspended pending submission of a site improvement plan that addresses key infrastructural issues contributing to poor performance. An unacceptable rating at the second re-audit may result in termination from the group. If systematic misrepresentation of data is identified, an immediate repeat audit is scheduled by the representatives from the Group with the NCI and/or the FDA present.  
In some cases, non-compliance for issues such as timeliness of data submission, SAE
reporting and submission of specimens is monitored off site rather than scheduling a reaudit. Failure to show improvement may result in scheduling of a re-audit or other disciplinary action.  
Results of all Quality Assurance Audits are reported to the NCI, the Principal Investigator of the institution that was audited, and representative of the Group. Protocol specific audit results are also sent to the Lead Group to inform the statisticians, data chairs and study chairs of all discrepancies involving eligibility, treatment, toxicity or response assessment.  
The Quality Assurance Program performs their educational role through several mechanisms including presentations during the Group Meetings online Clinical Trials Training Courses, collaboration with others such as Pharmacy Committees and Statistical Centers to develop training tools, and memos and newsletter articles that are distributed to all Group institutions to educate research staff about changes in regulatory and quality assurance issues and audit procedures.
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on site monitoring

In addition to the standard auditing process outlined above, the following additional requirements will be implemented for this study:
- First on-site monitoring visit at each institution within 3 months of first patient registration to a sub-study.  
- On site monitoring for all sites with patients registered to a sub-study twice per year. Additional monitoring visits to a site will be scheduled in response to several factors - rate of accrual, previous monitoring visit results, centralized electronic monitoring outcome, change in staff, etc.  
- An exception to the onsite monitoring requirement will be allowed in the following circumstances: - Sites that use a centralized pharmacy and data management team may be monitored at this central location.  
- Sites that had an acceptable pharmacy audit in the last year may be audited off site at a central location.  
- Sites that had an acceptable patient case review outcome at their last audit and have not enrolled patients to any new sub-studies may be put on an annual schedule.  
Two full time monitors with 100% effort to **S1400** are in charge of conducting monitoring visits. Additional monitoring responsibilities are shared by the SWOG audit team members at the Operations Office and Statistical Center. Additional monitoring visits may be subcontracted with other Network Groups, if necessary.
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centralized data coordinator monitoring at

The SWOG Statistics and Data Management Center (SDMC) will support the risk based monitoring approach for this trial with the following actions:  
- Monitor data quality through routine review of submitted data such as on-study, baseline and follow up tumor assessment, lab, treatment, off treatment, and follow up case report forms to identify and follow-up on missing data, inconsistent data, data outliers, and potential protocol deviations that may be indicative of systemic or significant errors in data collection and reporting at a site.
- Analyze site characteristics, performance metrics and clinical data to identify trial sites with characteristics correlated with poor performance or noncompliance through the SWOG Institutional Performance Reporting mechanism and other available reports.  
- Verify critical source data remotely via the collection and review of pathology, radiology and applicable lab reports. This includes the review and confirmation of appropriate disease classification as determined by the pathology report, and assessment of response to treatment utilizing RECIST 1.1 based on scan reports uploaded to the Electronic Data Capture (EDC) system and submitted follow-up tumor assessment forms.
- To assure data are as consistent, complete and accurate as possible, all subject data must undergo careful review by Data Coordinators (DCs). After verifying that all data forms required to determine eligibility have been received or at a time point designated when all the required forms should have been received, the DC reviews the data and completes an initial evaluation.  
The initial review includes the following:
- Determine that all required data fields on each form were completed and are  
  
consistent with other data.  
- Determine if all prestudy tests and exams were performed within protocol specified time limits.  
- Determine if each eligibility criterion was met and properly documented. - Review and confirm pathology based on the pathology report uploaded to the EDC
system.  
- Verify that stratification and/or descriptive factors (if applicable) were correctly identified at registration.  
- Verify that the subject received the assigned study treatment and correct dose(s).  
- Verify that the treatment was started within the time limit indicated in the protocol
(if applicable).  
- Determine if adverse events reported are consistent with other data and entered as required by study specifications.  
- Post internal notes to add additional information which may be useful to the study sponsor, monitors, or statisticians, but which do not require action by site personnel.  
- Use the query tool to request additional data classifications and corrections of the CRA.
The DC will perform subsequent review of data when new data become available or queries are answered. Regular review will also occur while patients are still on-study, at the time of progression, once they are removed from study and at the time of death.  
Subsequent reviews include the following:
- Determine if all required data fields on each newly submitted form were completed and consistent with other data.  
- Evaluate all new treatment documentation for correct treatment and dose.  
- Conduct assessment of response to treatment utilizing RECIST 1.1 based on scan reports uploaded to the EDC and submitted follow-up tumor assessment forms.  
- Review and code any new concomitant medications as required by study specifications.  
- Evaluate if the subject is or should be off protocol treatment per protocol criteria.  
- Review and evaluate death if death of subject is reported.  
- Use the query tool to request additional data classifications and corrections.  
- Post internal query notes to add additional information that may be useful to the study sponsor, monitor, or statisticians but which do not require action by site personnel.  
- Review site responses to the queries and the corrected or amended eCRF pages.  
When corrections and responses are considered satisfactory, queries are closed by the data coordinators. Unsatisfactory responses are re-queried and tracked.  
- Perform re-evaluations promptly after responses to queries are received.  
Centralized Monitoring Review by the SDMC Monitors (Implemented as of Revision \# 9)
Off-site monitoring includes auditable elements for the Screening/Pre-Screening Registration for the first two patients registered to **S1400** at each new study site or sites where an on-site **S1400** audit has not occurred.  
Within one month after the **S1400** Registration, a SDMC monitor will email the head CRA
at the study site with the instructions for uploading auditable elements for the remote review. Site staff are to upload source documents to support the Eligibility Criteria (Section 5.0) and applicable forms submitted in Rave® for the Screening/Pre-Screening Registration. The review will also consist of timeliness of data submission, specimen collection and specimen submission.  
Required Documents for Uploading to Rave®:  
  
Screening/Pre-Screening Informed Consent Form Pages:
- Title Page
- Response to Future Contact question - Responses to Samples for Future Research Studies questions - Signature Page Eligibility:
- **S1400** Registration Worksheet (signed and dated by the Registering Investigator)
- Source Documents to Support Section 5.0 Eligibility Criteria
- Source Documents to Support the **S1400** Onstudy Form
- Source Documents to Support Other Forms if applicable (Examples: Notice of Progression, Status Update, Notice of Death, etc.)
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safety specific centralized monitoring

Each Serious Adverse Event (SAE) report submitted (via National Cancer Institute systems CTEP-AERS) will be reviewed by the SWOG SAE Coordinator. For each report supporting documentation will be requested and compiled with the report and sent to the Physician Reviewer. As mentioned below all sites will undergo mandatory training and this will include training regarding SAE reporting. SWOG regularly monitors timeliness of SAE
reporting and addresses any issues of poor performance with individual sites.  
The study will be monitored for under reporting/missed Serious Adverse Events: The SWOG SAE Coordinator receives a weekly report from the data base that includes all adverse events that are submitted through routine submission that potentially also meet expedited reporting criteria but for which no CTEP-AERS report is found. The Coordinator is responsible for following up with the responsible site to ensure that SAEs are not missed/under-reported.  
The study will be monitored for trends in Serious Adverse Events: A "new SAE on study" report is generated each time a new Serious Adverse Event is entered into the SWOG data base. It is a cumulative report that lists all SAEs reported for the protocol. This allows those who review the report to identify concerning trends in reported events; events that may be occurring at greater intensity (higher toxicity grade) or frequency than expected.  
The SAE Coordinator and Physician Reviewer are responsible for regularly monitoring this report as well as the Study Chair, and assigned Statisticians. Additional Approaches to be Used
- Mandatory training of key site personnel prior to first patient registration. - Timely review of all monitoring reports to identify sites that require additional training, monitoring, disciplinary action, etc.  
- Routine monthly communication between monitor and site staff to assess potential problem areas, provide feedback, identify staff turnover, etc.  
- Additional mandatory centralized training to be provided to all sites if major changes to the protocol occur or common problem areas are identified.  
Blinded Independent Central Review of Response and Progression-Free Survival Endpoint All participants will undergo serial CT or MRI imaging: baseline/pre-treatment and every 6 weeks until progression of disease (as determined by local site assessment). Collection and storage of all images as well as management of the independent review process will be the responsibility of the National Cancer Institute's (NCTN) Imaging and RT Quality Assurance Service Core (IROC).  
The same imaging modality MUST be used for an individual patient throughout the  
  
course of the trial, with the exception of a PET/Spiral CT is used at baseline where the CT is of diagnostic quality, follow-up scans can be done by a spiral CT or if a PET/conventional CT is used at baseline where the CT is of diagnostic quality, follow-up scans can be done by conventional CT. No other methods of assessments are interchangeable. The pre- and post-treatment CT or MRI images must be submitted to IROC for all study participants. CT is the preferred imaging modality unless there is a medical contraindication.  
Clinical management and treatment decisions will be made by the treating physician based on local site assessments and other clinically appropriate considerations. The study will collect and archive 100% of scans for randomized patients through the time of confirmed progression. These will be ready for independent review should a sub-study terminate early for a large effect on PFS or ORR.  
At the time that central review is indicated, SWOG will provide IROC with the registration date and patient number, along with a blinded code indicating which reviewer will be assigned to each case. This ensures that each reader reviews a balanced number of cases from each study arm. An experienced team of radiologists will be identified by IROC. A designated radiologist will review each image for assessment of progression of disease per RECIST 1.1 criteria. The same reviewer will read all study images of an individual study participant. Data from local reviews will not be provided to the central reviewers in order to keep the central reviewers blinded to the results of the local investigator-assessed PFS.  
The actual progression will be determined at the SWOG Statistical Center, using a composite of the IROC assessment, in conjunction with possible data on progression or symptomatic deterioration (see Section 10.7). Results of the central review will NOT be communicated to the local site. Decisions regarding clinical management of the patient will be made by the treating physician based on local site assessments/reviews and other clinical considerations.  
The BICR audit analysis will proceed following the algorithm specified in Dodd et.al 2011.  
(1) Specific details for the inputs of this algorithm are described in Section 11.5.  
Review of pre-treatment CT/MRI exam will be performed as follows: The reader will review all anatomic areas (chest, abdomen) imaged and available. The target lesions to be evaluated will be defined/determined by the review of the pre-treatment exam. A maximum of 5 target lesions will be defined with a maximum of 2 in a single organ. The 5 target lesions will be chosen with representation from all organs involved with the tumor. Additional significant non-target lesions and areas of non-measurable disease will be noted. A screen capture of each target lesion, annotated with a pointer and a lesion reference number assigned to the target lesion, will be generated and archived. This will be used on subsequent reads to ensure concordance of lesions on follow-up/posttreatment exams. Measurements will be made from the axial scan (generally the post contrast scan) that best demonstrates the lesion as distinct from background. All measurements will be made by electronic calipers. A screen capture of the actual measurement axis with calipers will be saved and archived with the exam permanently at IROC.  
Review of post-treatment image exam(s) will be performed as follows: The pretreatment annotated exam and CRF will be reviewed to ensure lesion concordance.  
Readers will review all images for the current time point prior to making measurements.  
All measurements will be made by electronic calipers. A screen capture of the actual measurement axis with calipers will be saved and archived with the exam permanently at IROC.  
1. Communication of Monitoring Results The monitoring team will meet monthly to share all aspects of monitoring (on sites,  
 centralized, safety, alternative). When needed, the SWOG Executive Officer for Quality Assurance will be consulted. Routine site audits will be reported according to NCI Clinical Trials Monitoring Branch requirements. Additional monitoring visits (those performed at greater frequency than required by the Clinical Trials Monitoring Branch) will be maintained in the CTMB-AIS data base and regularly reviewed by SWOG monitoring staff.  
Summarized results of all monitoring visits will be provided annually to the study's Data and Safety Monitoring Committee, the SWOG Board of Governors, the study team and the FDA.
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2. management of noncompliance

Issues of particular concern related to patient safety and questions of site fraud will be managed according to SWOG standard policies and the policies of the NCI
Clinical Trials and Monitoring Branch for auditing of clinical trials under the NCI National Clinical Trials Network (NCTN) Program.  
Where important deviations are discovered, additional site training components will be developed and implemented.  
As with standard NCTN procedures, sites will be required to develop and implement corrective action plans in response to any deficiencies identified at a monitoring visit.
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3. ensuring quality monitoring

All staff involved in monitoring are required to undergo training in the principles of clinical investigations and human subject's protection. They are also required to complete the same protocol specific training required of the site staff.  
All monitoring and auditing process for the study will be reviewed by study leadership twice per year to ensure conformance to the monitoring plan.  
4. Monitoring Plan Amendments
At each formal review of the monitoring plan and conformance to it, the study leadership will make a recommendation regarding the need for amendments to the monitoring plan. These amendments will be reviewed and approved by NCI and provided in this protocol section and will be submitted to the FDA.
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references

1 Harrington D, Fleming T, Green S. In Crowley J and Johnson RA Eds. Survival  
  
Analysis. Hayward, CA: IMS Lecture Notes Monograph Series, 2:269-286, 1982.  
  
Version Date 12/18/20
18.1d Dose and Administration Schedules Overview  
| Substudy                                                                                 | Investigational  Agent(s)          | Target               | Manufactur                    | Structural  Class   | Dose       | Route       | Day       | Cycle    | Control   | Closure   |
|---------------------------------------------------------------------------------|------------------------------------|----------------------|-------------------------------|---------------------|------------|-------------|-----------|----------|-----------|-----------|
| er                                                                              | Date                               |                      |                               |                     |            |             |           |          |           |           |
| PD-L1                                                                           | MedImmun                           |                      |                               |                     |            |             |           |          |           |           |
| S1400A                                                                          | MEDI4736                           | inhibitor (nonmatch arm)                      | e, Inc.                       | Monoclonal          | 10 mg/kg   | IV (over 60 |           |          |           |           |
| antibody                                                                        | minutes)                           | 1                    | 14 days                       | N/A a               | 12/18/15   |             |           |          |           |           |
| (IgG1ĸ)                                                                         |                                    |                      |                               |                     |            |             |           |          |           |           |
| S1400B                                                                          | GBC-0032                           | PI3K inhibitor       | Genentech                     | Small  molecule     | 4 mg QD    | PO          | 1-21      | 21 days  | N/A a     | 12/12/16  |
| 1-21,  followed  by 7  days off                                                 |                                    |                      |                               |                     |            |             |           |          |           |           |
| S1400C                                                                          | Palbociclib                        | CDK4/6  inhibitor    | Pfizer, Inc.                  | Small               | 125 mg  QD | PO          |           |          |           |           |
| molecule                                                                        | 28 days                            | N/A a                | 09/01/16                      |                     |            |             |           |          |           |           |
| S1400D                                                                          | AZD4547                            | FGFR1/2/3            | Astra                         | Small  molecule     | 80 mg BID  | PO          | 1-21      | 21 days  | N/Aa      | 10/31/16  |
| inhibitor                                                                       | Zeneca                             | Monoclonal  antibody | 15 mg/kg                      | IV                  | 1          | 21 days     | Erlotinib | 11/25/14 |           |           |
| (IgG2)                                                                          |                                    |                      |                               |                     |            |             |           |          |           |           |
| S1400E                                                                          | Rilotumumab +                      | HGF/c-MET  inhibitor | Amgen                         |                     |            |             |           |          |           |           |
| Erlotinib                                                                       | Anti-PDLinhibitor,  CTLA-4  inhibitor (nonmatch arm)                                    | BristolMyers  Squibb                      | Monoclonal  antibody  (CD279) | IV (Over            | 14 days/42 |             |           |          |           |           |
| 30/60                                                                           | 1                                  | days (q 3            |                               |                     |            |             |           |          |           |           |
| minutes)                                                                        | cycles)                            |                      |                               |                     |            |             |           |          |           |           |
| S1400I                                                                          | Nivolumab +  Ipilimumab            | 3 mg/kg 1 mg/kg      | Nivoluma b                    | 4/23/18             |            |             |           |          |           |           |
| S1400G                                                                          | Talazoparib                        | PARP  inhibitor      | Medivation                    | Small  molecule     | 1000 mcg   | PO          | 1-21      | 21 days  | N/A       | 7/23/18   |
| Anti-PD1/PD-L1  Inhibitor  Resistant                                                                                 | 28 days  (Treme - Cycle 1-4  only) |                      |                               |                     |            |             |           |          |           |           |
| monoclonal  antibody  (1gG1, 1gG2)                                              | IV (Over  60                       | 1                    |                               |                     |            |             |           |          |           |           |
| minutes)                                                                        |                                    |                      |                               |                     |            |             |           |          |           |           |
| S1400F                                                                          | MEDI4736 +  Tremelimumab           | Astra  Zeneca        | 1500 mg 75 mg                 | N/A                 | 3/24/20    |             |           |          |           |           |
| Monoclonal                                                                      | 2.7 mg/kg                          | IV (over 30          |                               |                     |            |             |           |          |           |           |
| antibody                                                                        | min)                               | 1                    | 21 days                       | N\A                 | 12/21/18   |             |           |          |           |           |
| (IgG1)                                                                          |                                    |                      |                               |                     |            |             |           |          |           |           |
| S1400K                                                                          | ABBV-399                           | c-MET  inhibitor     | AbbVie                        |                     |            |             |           |          |           |           |
| a Arm 2 - The control arm Docetaxel has been closed to accrual with Revision #3 |                                    |                      |                               |                     |            |             |           |          |           |           |
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2.0 protocol instructions for addition

The protocol is structured to enable seamless addition and release of investigational agents over the course of the trial.  
When an investigational agent is added or released from use in this trial, the following will require updating or addition:
o SCHEMA
o Section 18.1d: Overview of all investigational agents/sub-studies. Each investigational agent falls into one of two categories: 1) Activated Sub-studies, and 2) Inactivated Sub-studies.  
o Section 18.2: List of individual sub-study protocols. As investigational agents/sub-studies are added to the trial, they will be listed in alphabetical order. Sub-study-specific Model Treatment Consent
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adding a sub-study to the

The procedure for adding a new sub-study depends on its readiness. If all requirements have been met for activation (drug supply, contracts, etc.), a one-step process is followed. If activation is pending fulfillment of one or more requirements for activation, a two-step process is followed. For example, agent supply may not yet be available for distribution, although all other requirements have been addressed. If activation of a new sub-study is pending, the protocol is amended to include: 1) the new sub-study section 2) a separate, sub-study-specific treatment consent, and 3) an updated Section 18.1d showing the new agent in Table 1.1 (Activated Sub-studies). The protocol amendment will be considered a major modification to the protocol, requiring CTEP amendment review, full IRB committee review; however, assignment to the already active sub-studies is not affected. Assignment to the new sub-study at an individual site may begin after IRB approval has been obtained.  
If all requirements for activation of a new sub-study have already been met, the protocol is amended to include: 1) the new sub-study section, 2) a separate sub-study treatment consent, 3) an updated Section 18.1d showing the new agent in Table 1.1 (Activated Sub-studies) 4) and the new sub-study in the SCHEMA. The protocol amendment will be considered a major modification to the protocol and will require CTEP amendment review and full IRB committee review. Assignment to the sub-study at an individual site can begin after IRB approval has been obtained.
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releasing a sub-study from the

When an investigational agent/sub-study is closed to accrual, a protocol administrative change will be generated that includes: 1) an updated Section 18.1d showing the sub-study moved from Table 1.1 (Substudies Open to Accrual) to Table 1.2 (Sub-studies Closed to Accrual), 2) a watermark ("**Closed Effective**
XX/XX/XXXX ") on the sub-study section, which will remain in the protocol, 3) a watermark ("**Closed**
Effective XX/XX/XXXX") on the separate, sub-study-specific treatment consent, and 4) removal of the substudy from SCHEMA in **S1400**. Assignment to the active sub-studies is not affected.  
18.1e Specimen Flow Diagram  
  
  
  
  
a With patient's consent.  
b Among patients who initially responded to protocol treatment.  
c Remaining tissue will be sent to the SWOG Specimen Repository-Solid Tissue, Myeloma and Lymphoma Division, Lab \#201, for use of the Translational Medicine studies within any sub-study the patient is enrolled in. SWOG Specimen Repository will prepare and ship the required specimens to the appropriate laboratory. The specimen will be kept until there are no additional sub-studies for the patient to enroll in or the tissue is used up, whichever happens first. With patient's consent, any leftover tissue will remain at the SWOG Repository for future exploratory analysis.
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18.1f s1400gen

Ancillary Study to Evaluate Patient and Physician Knowledge, Attitudes, and Preferences Related to Return of Genomic Results in S1400
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study chairs

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

1.1 Primary Objective To evaluate patient attitudes and preferences about return of somatic mutation findings suggestive of a germline mutation in the **S1400** master protocol trial.  
1.2 Secondary Objective(s)
a. To evaluate **S1400** study physician attitudes and preferences about return of somatic mutation findings suggestive of a germline mutation in the **S1400** master protocol trial.  
b. To evaluate **S1400** patients' and study physicians' knowledge of  
  
cancer genomics.  
c. To evaluate **S1400** patients' and study physicians' knowledge of the design of the **S1400** master protocol trial.
d. To explore whether physician and patient knowledge of cancer genomics and attitudes and preferences about return of genomic profiling findings are correlated.
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2.0 background

Rationale
'Master protocol' or 'biomarker-driven' trials (hereafter referred to as 'biomarkerdriven') that are guided by genomic profiling results are rapidly increasing in number, and may represent the beginning of a new paradigm in clinical trial research in oncology. *(1,2)* Because these types of trials involve many independently conducted sub-studies that may involve different eligibility criteria and treatments, they are particularly complex to design and communicate. *(3,4*)
As such, there is a threat that patients and study physicians participating in the initial genomic screening portion of biomarker-driven trials may not be fully informed about the many nuances of the return of genomic results, relationships between genomic results and eligibility for participation in sub-studies, or alternative treatment options (or lack thereof) within sub-studies. Furthermore, patient knowledge and attitudes about the return of genomic profiling results remains poorly studied outside the scope of a given clinical trial (hereafter referred to as "incidental findings"), and protocols for return of incidental findings in clinical trial settings are not established as they are in clinical practice. (5) Several studies have evaluated patient knowledge, attitudes, and preferences about genomic profiling in clinical care, but no studies have investigated these issues in the context of a biomarker-driven clinical trial. *(6,7,8,9,10)* As a result, there is urgent need to develop understanding of patient and study physician perspectives on genomic testing in clinical trials to: 1) evaluate if they have sufficient understanding of genomic principles to discuss the implications of participation in such trials, 2)
improve return of genomic result processes in ongoing trials, and 3) inform the design of future biomarker-driven trials.  
SWOG **1400** (hereafter referred to as '**S1400'**) is an example of an ongoing  
  
biomarker-driven clinical trial where the issues outlined above are particularly pertinent. **S1400** is a phase II/III screening/clinical registration protocol that involves genomic profiling of patients with advanced stage squamous cell lung cancer to direct patients to sub-studies investigating targeted (or 'matched') and
'non-matched' therapies *(11,12)* These study characteristics create an ideal setting to study patient and physician knowledge, attitudes, and preferences about genomic findings because: 1) patients and study physician knowledge of the genomic testing procedures and return of results can be evaluated in a natural setting; 2) the Foundation Medicine next-generation sequencing platform used in the study has the ability to detect incidental genomic findings (i.e. genetic alterations not directly related to decisions in the **S1400** trial), such as the 56 recommended by the American College of Medical Genetics3--making study participants uniquely able to provide insights about attitudes and preferences related to incidental findings based on their own experience and feelings; and 3) study patients have poor survival prognosis, so they are in a natural position to reflect on the important issue of preferences for return of genomic testing results to family members in the event that they die prior to receiving the results themselves. *(13,14)* Furthermore, many organizations and individual researchers have noted the need for studies evaluating these issues both in cancer patients in general, and in cancer patients in clinical trial settings. *(15,16,17)*
We propose to conduct an ancillary survey study focused on patient and physician knowledge, attitudes, and preferences about somatic mutation findings suggestive of a germline mutation alongside **S1400** to leverage the opportunities outlined above. Specifically, we will administer a one-time survey to a sample of **S1400**
patients (n=200) at the master protocol screening step, as well as **S1400** study physicians (n=30) providing care to those patients enrolled in this ancillary study.  
The ancillary study sample will be enriched for patients from geographically diverse National Cancer Institute Community Oncology Research Program (NCORP) Minority/Underserved (M/U) sites to enhance statistical power to evaluate differences in knowledge, attitudes, and preferences by education level, race/ethnicity, urban/rural status, social support level, and other factors. This exploratory study can provide an initial view of the landscape of knowledge, attitudes, and preferences about genomic profiling in biomarker-driven trials; allow evaluation of heterogeneity in these factors by matched/non-matched status, race/ethnicity, and socioeconomic status; and can be used to generate hypotheses to be evaluated in future biomarker-driven trials. This ancillary study is important because it will provide timely insight into patient and study physician knowledge, attitudes, and preferences about return of genomic profiling findings in an innovatively designed National Cancer Institute biomarker-driven trial. The results from this ancillary study can inform efforts to improve patient and physician understanding of genomic information in the context of clinical trials, including incidental genomic findings. Additionally, the study's findings can be used to design patient- and physician-centered processes for return of genomic findings in clinical trial settings, and to generate hypotheses about issues related to return of genomic findings in future biomarker-driven clinical trials.
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study data

The attached preliminary patient and physician surveys (Appendix 1 & 2) include questions that were developed with the input of behavioral science and genomics ethical, legal, and social implications (ELSI) experts to evaluate issues unique to return of genomic results in the context of the **S1400** study. The survey questions were both adapted from prior studies of patient and physician knowledge, attitudes, and preferences about genomic testing in clinical cancer care, and created specifically for the purposes of this study. *(18,19,20,21,22)*
The survey questions evaluate the domains outlined below in bold text.  
Knowledge of cancer genomics and return of results in the S1400 **trial**
- Patient and physician knowledge of the distinctions between somatic and germline mutation testing
- Patient and physician knowledge of the types of genomic results that are returned in the **S1400** trial
- Patient and physician knowledge of the likely outcomes of 'matched' and
'non-matched' treatments Attitudes about return of genomic results in the S1400 **trial**  
  
- Patient attitudes about the genomic testing information presented in the S1400 trial
- A limited number of open-ended questions provide deeper insights into patient attitudes (motivations and concerns) about participating in the S1400 trial
- Physician attitudes about return of different types of genomic findings in the **S1400** trial
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preferences for return of genomic

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

All U.S. English language speaking patients registered to the **S1400** master protocol study will be eligible for participation in this ancillary study.  
All **S1400** study physicians that have patients who enroll in this ancillary study will be eligible for participation in this ancillary study.
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4.0 stratification factors

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

Target accrual has been set by budget to a sample size of 200 patient participants and 30 physician participants. We do not present formal power calculations given that this is an exploratory pilot study intended to generate hypotheses for evaluation in future studies.
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analysis

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

6.1 Primary Endpoint Patient attitudes and preferences about return of somatic mutation findings  
 suggestive of a germline mutation 6.2 Secondary Endpoint  
a. Patient knowledge of cancer genomics b. Physician attitudes and preferences about return of genomic profiling results c. Physician knowledge of cancer genomics
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7.0 bibliograph

1 Redman MW, Allegra CJ. The Master Protocol Concept. Seminars in oncology.  
42(5):724-730, 2015.  
2 Herbst RS, Gandara DR, Hirsch FR, et al. Lung Master Protocol (Lung-MAP)-A
Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400. Clinical cancer research: an official journal of the American Association for Cancer Research. 21(7):1514-1524, 2015/  
3 Redman MW, Allegra CJ. The Master Protocol Concept. Seminars in oncology.  
42(5):724-730, 2015;.
4 Herbst RS, Gandara DR, Hirsch FR, et al. Lung Master Protocol (Lung-MAP)-A
Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400. Clinical cancer research: an official journal of the American Association for Cancer Research. 2015;21(7):1514-1524.  
5 Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine: official journal of the American College of Medical Genetics. 15(7):565574. 2013.  
6 Gray SW, Hicks-Courant K, Lathan CS, Garraway L, Park ER, Weeks JC. Attitudes of patients with cancer about personalized medicine and somatic genetic testing. Journal of oncology practice / American Society of Clinical Oncology. 8(6):329335, 322 p following 335, 2012.  
7 Gray SW, Hicks-Courant K, Cronin A, Rollins BJ, Weeks JC. Physicians' attitudes about multiplex tumor genomic testing. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 32(13):1317-1323, 2014.  
8 Miller FA, Hayeems RZ, Bytautas JP, et al. Testing personalized medicine: patient and physician expectations of next-generation genomic sequencing in late-stage cancer care. European journal of human genetics: EJHG. 22(3):391-395, 2014.
9 Blanchette PS, Spreafico A, Miller FA, et al. Genomic testing in cancer: patient knowledge, attitudes, and expectations. Cancer. 120(19):3066-3073, 2014.  
10 Middleton A, Morley KI, Bragin E, et al. Attitudes of nearly 7000 health  
  
professionals, genomic researchers and publics toward the return of incidental results from sequencing research. European journal of human genetics: EJHG. 2015.
11 Herbst RS, Gandara DR, Hirsch FR, et al. Lung Master Protocol (Lung-MAP)-A
Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400. Clinical cancer research: an official journal of the American Association for Cancer Research. 21(7):1514-1524, 2015.  
12 Steuer CE, Papadimitrakopoulou V, Herbst RS, et al. Innovative Clinical Trials:
The LUNG-MAP Study. Clinical pharmacology and therapeutics. 97(5):488-491, 2015.
13 Breitkopf CR, Petersen GM, Wolf SM, et al. Preferences Regarding Return of Genomic Results to Relatives of Research Participants, Including after Participant Death: Empirical Results from a Cancer Biobank. The Journal of law, medicine &
ethics: a journal of the American Society of Law, Medicine & Ethics. 43(3):464475, 2015.  
14 Wolf SM, Branum R, Koenig BA, et al. Returning a Research Participant's Genomic Results to Relatives: Analysis and Recommendations. The Journal of law, medicine & ethics: a journal of the American Society of Law, Medicine & Ethics.  
43(3):440-463, 2015;.
15 Parsons DW, Roy A, Plon SE, Roychowdhury S, Chinnaiyan AM. Clinical tumor sequencing: an incidental casualty of the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings. Journal of clinical oncology: official journal of the American Society of Clinical Oncology.  
32(21):2203-2205, 2014;.  
16 Raymond VM, Gray SW, Roychowdhury S, et al. Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. Journal of the National Cancer Institute. 108(4), 2016;.  
17 Bombard Y, Robson M, Offit K. Revealing the incidentalome when targeting the tumor genome. Jama. 310(8):795-796, 2013.  
18 Gray SW, Hicks-Courant K, Lathan CS, Garraway L, Park ER, Weeks JC. Attitudes of patients with cancer about personalized medicine and somatic genetic testing. Journal of oncology practice / American Society of Clinical Oncology. 8(6):329335, 322 p following 335, 2012.  
19 Gray SW, Hicks-Courant K, Cronin A, Rollins BJ, Weeks JC. Physicians' attitudes about multiplex tumor genomic testing. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 32(13):1317-1323, 2014.  
20 Miller FA, Hayeems RZ, Bytautas JP, et al. Testing personalized medicine: patient and physician expectations of next-generation genomic sequencing in late-stage cancer care. European journal of human genetics: EJHG. 22(3):391-395, 2014.  
21 Blanchette PS, Spreafico A, Miller FA, et al. Genomic testing in cancer: patient knowledge, attitudes, and expectations. Cancer. 120(19):3066-3073, 2014.  
22 Middleton A, Morley KI, Bragin E, et al. Attitudes of nearly 7000 health  
  
professionals, genomic researchers and publics toward the return of incidental results from sequencing research. European journal of human genetics: EJHG. 2015.  
18.2 List of Sub-study Attachments S1400A: (Non-Match sub-study): Anti-PD-L1 - MEDI4736 S1400B: PI3K - GBC-0032 S1400C: CDK4/6 - Palbociclib S1400D: FGFR - AZD4547 S1400E: HGF - Rilotumumab + Erlotinib versus Erlotinib S1400F: (Non-Match sub-study): Anti-PD-1/PD-L1 Inhibitor Resistant Durvalumab
(MEDI4736) plus Tremelumumab S1400G: HRRD-Talazoparib (BMN 673) S1400I: (Non-Match sub-study): Nivolumab + Ipilimumab versus Nivolumab S1400K: C-MET - ABBV-399 (Process II)