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8.3 analyses plans

8.3.1 Analysis Population All patients who receive a dose of osimertinib will be analyzed for safety and efficacy. Participants who discontinue from study participation prior to surgical resection may be replaced after discussion with the Study PI. Demographic and baseline characteristics will be summarized. In general, frequency distribution and percentage will be used to summarize categorical measurements, while mean with standard deviation and median with interquartile range will be used to describe symmetric and skewed continuous measurements, respectively. Univariate analysis among variables will be assessed using the two-sample t-test, Wilcoxon-rank-sum test, or Chi-square test, as appropriate.  
8.3.2 Primary Analysis (or Analysis of Primary Endpoints)
MPR rate (primary endpoint) will be determined in patients who receive at least one dose of study drug. Patients who receive one dose of study drug and become ineligible for surgery either because of disease progression or adverse event will be deemed not to have achieved MPR. In patients who undergo surgical resection or their lung tumor resection specimens will be processed at the local institution following CAP and CLIA guidelines. Immediate sampling of the tumor and overnight fixation in 10% buffered formalin for paraffin embedding, usually within 2024 hours after fixation. For histopathological evaluation, at least one sample per every 1-cm of diameter will be submitted for FFPE processing and pathology analysis. The local institutional study pathologist will assess each case for MPR, using percentage of viable tumor cells (cutoff as + MPR is ≤ 10% of viable tumor cells) as has been reported [24]. The pathological response should be reported as average percentage of viable tumor cells by slide examined. Pathology slides (H&E and IHC and special stains) will be forwarded to the designated central pathologists for the study and MPR will be determined as described above. In order to more fully evaluate the specimens associated with this trial, the central review pathologists will score the material using criteria as follows: Pathological CR: Residual viable tumor: 0% MPR: Residual viable tumor: ≤ 10% Pathological response (not meeting major response criteria) 11-49% residual viable tumor. No pathological response: 50% or greater residual viable tumor. Predominant reaction type: Necrosis, Fibrosis Tumors that exhibit ≤ 10% **viable tumor will meet the criteria for an MPR as has been** previously described [24]. The MPR rate will be reported with 95% confidence intervals. As needed, a sub-set of tissues will be independently evaluated by both pathologists for assessment of inter-pathologist reproducibility for this scoring. Whenever possible, the following will be included:  
Concurrent submission of pre-treatment biopsy or FNA sample. This can help inform pathologic evaluation in that pre-treatment necrosis can be assessed, within the context of potential sampling bias.  
Whenever feasible, all post-treatment surgical tumor samples will be submitted for pathologic examination (full lesion block-in), after tissue procurements have been completed.  
Samples will be identified, accrued and sent for central review in groups of no less than 10 cases to minimize criteria drift. If fewer than 10 cases are sent in any individual batch, the cases will be held until a minimum of 10 cases are available for review.
8.3.3 Secondary Analysis (or Analysis of Secondary Endpoints)
5-Year DFS: DFS will be calculated as 1+ the number of days from date of surgical resection to documented radiographic relapse/progression or death due to any cause over a period of 60 months. The Kaplan-Meier analysis will be used to calculate the median DFS with 95% confidence interval. 5-year DFS rate will be calculated as the percentage of patients who are disease free at 5 years. This will be calculated using the Kaplan-Meier method. Assuming alpha of 0.05 and a set sample size of 27, as well as a null hypothesis of 50% 5-year DFS [53], we will have a power of 80% to detect a 25% increase in 5-year DFS. Objective Response Rate: The objective response rate is defined as the best overall response recorded from the start of the treatment until time of surgery. The frequency and percentages of patients with a best ORR of CR, PR, SD, or PD will be determined. The objective response rate will be reported with 95% confidence intervals. Pathologic Complete Response Rate (pCR): The pCR is defined as absence of (0%) viable tumor present histologically in the resected tumor specimen. Scoring for pathologic response is described above. 5-Year Overall survival (OS) rate: 5-year OS rate will be calculated using the Kaplan-Meier method . OS will be defined as the 1+ the number of days from surgical resection to death due to any cause over a period of 60 months. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval. Depth of Response (DpR): DpR will be defined as the percentage change in tumor burden by RECIST criteria at best response versus baseline imaging. DpR will be summarized using descriptive statistics and correlated with patient outcomes using hazard ratios via the Cox proportional hazards model. Safety and Tolerability: AE terms recorded on the CRFs will be mapped to preferred terms using the MedDRA. Seriousness, severity grade and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the NCI CTCAE v4.03. Listings of AEs will be provided. Rate of conversion from operable to non-operative will be recorded as rate of patients initially assessed as surgically resectable, who are subsequently unable to undergo surgical resection due to either treatment-related AEs or PD. Rate of surgical complications occurring prior to the end of treatment visit will be recorded.
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8.3.4 other analyses/assessments

Exploratory Analysis:
We will record rates of adverse pathologic features including rates of positive margins, LVI, and pathologic upstaging (e.g., by T or N status) as compared to clinical staging based on pre-operative scans, for comparison to historical controls.
We will perform RNA sequencing and whole exome sequencing analysis on isolated cancer cell populations from pre-treatment tumor biopsy specimens, as well as tumor tissue acquired at the time of surgical resection (post-osimertinib). Gene Set Enrichment Analysis will be performed to identify osimertinib-induced changes in common cancer related pathways, including: RAS-RAF-MAPK, PI3K-AKT, WNT- β catenin, JAK-STAT, HGF-MET, and IGF-1R, as well as emerging pathways of resistance (i.e. NF-kB and Hippo-YAP) [1, 46, 47]. We will determine whether there is a statistically significant increase in oncogenic/survival pathway related gene expression signatures in the postosimertinib compared to the pre-treatment sample using established methods [48]. We will compare MPR rates in tumors that exhibit specific oncogenic/survival pathway activation post-osimertinib treatment compared to tumors that do not. IHC analysis will be performed on pre-treatment and post-surgical specimens to confirm pathway activation identified by transcriptional analysis (i.e. phosphorylated-ERK (indicative of MAPK signaling), phosphorylated-AKT (indicative of PI3K signaling) or nuclear NF-kB (RELA), or - β -catenin expression). Samples will be scored in a continuous manner and difference among time points will be determined by a two-tailed T-test.  
We will assess for shifts in the cellular make-up of the tumor microenvironment induced by osimertinib treatment by performing single cell dissociation and fluorescence associated cell sorting (FACS) on fresh pre-treatment tumor biopsies and postosimertinib tumor resection specimens. Using FACS gating strategies established and validated by the Krummel lab at UCSF [49], we will isolate CD45+ immune cells and determine how osimertinib treatment alters the proportions of cells that make up the lymphoid (CD4+ and CD8+ T cells, Tregs, NK cells, B cells) and myeloid (macrophages, neutrophils, mast cells, dendritic cells) compartments. We will then use RNA-Seq to assess the transcriptional profiles of populations of TAMs, CD4+ and CD8+ T Cells **(Fig.** 5). We hypothesize that osimertinib treatment will induce a pro-tumor immune microenvironment that allows for tumor cell persistence. Specifically, we will assess the polarization of TAMs by assessing the mRNA expression profiles of genes classically associated with TH1-skewed (i.e. TNF-α, IL-6, IL-12p40, and IL-1β, *and Nos2*) and TH2skewed polarization (i.e. ARG1, *TGFB, CD163, CD206*), many of which are targets of NF-kB transcriptional activation[50]. We will also investigate whether osimertinib affects T-cell phenotypes. CD4+ T cells will be assessed for the expression of genes indicative of TREG, TH1, TH2, or TH17 activity (i.e. GATA3, T-bet, FOXP3, IFNγ, *IL-4, IL-13, IL10*, and *IL-17a*)[50], and CD8+ T cells will be assessed for expression of cytotoxic effector molecules (IFN, *GRZA, GRZB, and PRF1)[50]*. Finally, tumor cells and infiltrating immune cells will be assessed for shifts in PD-1 and PD-L1 expression (by RNA-Seq and IHC), a phenomenon that has been linked to NF-kB activity[41], and which may indicate changes in anti-tumor immunity induced by osimertinib. Comparisons will be made to PBMCs when possible. Assessment of TIL and TAM infiltration into the tumor microenvironment, and of TAM polarization will be confirmed by IHC analysis for relevant macrophage attributes including CD68, CD163, CD206, iNOS, HLA-DR, as well as for CD4, CD8, and PD-L1, as well as for cancer-associated fibroblasts. Comparisons will be made to PBMCs when possible. Samples will be scored in a continuous manner and difference among time points will be determined by a two-tailed T-test.  
We will assess peripheral blood samples for ctDNA analysis. Descriptive statistics and graphical methods will be used to analyze the data.
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8.4 evaluation of safety

Analyses will be performed for all patients having received at least one dose of study drug. The study will use the NCI CTCAE v4.03.
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9 study management 9.1 pre-study

This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable regulatory requirements. Before initiating this trial, the Investigator will have written and dated approval from the IRB for the protocol, written informed consent form, participant recruitment materials, and any other written information to be provided to participants before any protocol related procedures are performed on any participants. The clinical investigation will not begin until either FDA has determined that the study under the IND Application is allowed to proceed or the Investigator has received a letter from FDA stating that the study is exempt from IND requirements. The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR §50, §54, and §312), GCP- International Conference on Harmonization (ICH) guidelines, and all applicable regulatory requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.
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9.2 irb approval

The protocol, the proposed informed consent form, and all forms of participant information related to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the UCSF IRB. Prior to obtaining IRB approval, the protocol must be approved by the HDFCCC Site Committee and by the PRC. The initial protocol and all protocol amendments must be approved by the IRB prior to implementation.
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9.3 informed consent

All participants must be provided a consent form describing the study with sufficient information for each participant to make an informed decision regarding their participation. Participants must sign the IRB-approved informed consent form prior to participation in any study specific procedure. The participant must receive a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file.
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9.4 changes in the protocol

Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be documented in the form of an amendment. The amendment must be signed by the Investigator and approved by PRC and the IRB prior to implementation. If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an amendment may be implemented prior to IRB approval. In this circumstance, however, the Investigator must then notify the IRB in writing within five (5) working days after implementation. The Study Chair and the UCSF study team will be responsible for updating any participating sites.
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9.5 handling and documentation of

The UCSF PI and each participating site will maintain complete records showing the receipt, dispensation, return, or other disposition of all investigational drugs. The date, quantity and batch or code number of the drug, and the identification of patients to whom study drug has been dispensed by patient number and initials will be included. The sponsor- investigator will maintain written records of any disposition of the study drug. The PI shall not make the investigational drug available to any individuals other than to qualified study patients. Furthermore, the PI will not allow the investigational drug to be used in any manner other than that specified in this protocol.
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9.6 case report forms

The PI and/or his/her designee will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study specific CRFs will document safety and treatment outcomes for safety monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion of the study visit; the Investigator will review and approve the completed CRFs. The information collected on CRFs shall be identical to that appearing in original source documents. Source documents will be found in the patient's medical records maintained by UCSF personnel. All source documentation should be kept in separate research folders for each patient. In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all completed CRFs to attest that the information contained on the CRFs is true and accurate. All source documentation and CTMS data will be available for review/monitoring by the UCSF DSMC and regulatory agencies. The PI will be responsible for ensuring the accurate capture of study data. At study completion, when the CRFs have been declared to be complete and accurate, the database will be locked. Any changes to the data entered into the CRFs after that time can only be made by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project Manager. Each participating site will complete study specific CRFs for safety monitoring and data analysis. Each site will enter the study data into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The participating site's CRC will complete the CRFs; the Investigator will review and approve the completed CRFs - this process must be completed within 3 business days of the visit. Study data from the participating site will be reported and reviewed in aggregate with data from patients enrolled at the coordinating center, UCSF. All source documentation and CTMS data will be available for review/monitoring as needed.
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9.7 oversight and monitoring plan

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for all HDFCCC institutional clinical trials. A summary of DSMC activities for this trial includes:  
Semiannual auditing (depending on trial accrual) Review of serious adverse events Minimum of biennial regulatory auditing
For more information regarding the Data Safety and Monitoring Plan, see Appendix 3.
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9.8 multicenter communication

The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate monthly conference calls with the participating sites. The following issues will be discussed as appropriate:  
Enrollment information.  
Adverse events (i.e., new adverse events and updates on unresolved adverse events and new safety information).  
Protocol Violations.  
Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The data (i.e., copies of source documents) from the participating sites will be downloaded into the PC console of OnCore prior to the remote monitoring visits in order for the DSMC to monitor the participating site's compliance with the protocol and applicable FDA regulations.
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9.9 record keeping and record

The PI is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by participants, as well as written records of the disposition of the drug when the study ends. The PI is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the CRFs and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. Study documentation includes all CRFs, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study.  
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed, or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
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9.10 coordinating center documentation of

It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of study documents as well as their receipt (when possible). The HDFCCC recommends that the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.). Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover letters, amendment outlines (summary of changes), etc., along with distribution documentation and (when available) documentation of receipt. Correspondence log: should be a brief list of all documents distributed including the date sent, recipient(s), and (if available) a tracking number and date received. At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its updates and safety information are distributed.
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9.11 regulatory documentation

Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA authorization and any other information pertaining to participants must be approved by the UCSF IRB. Prior to implementing this protocol at the participating sites, approval for the UCSF IRB approved protocol must be obtained from the participating site's IRB. The following documents must be provided to UCSF HDFCCC before the participating site can be initiated and begin enrolling participants:  
Participating Site IRB approval(s) for the protocol, appendices, informed consent form, and HIPAA authorization Participating Site IRB approved consent form Participating Site IRB membership list Participating Site IRB's Federal Wide Assurance number and OHRP Registration number Curriculum vitae and medical license for each investigator and consenting professional Documentation of Human Subject Research Certification training for investigators and key staff members at the Participating Site Participating site laboratory certifications and normals.
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant permission to proceed with enrollment. For more information on participating site required documents, see Appendix 5.
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10 protection of human subjects

Each clinical site is responsible for protecting all participants involved in human experimentation. This is accomplished through the IRB mechanism and the process of informed consent. The IRB reviews all proposed studies involving human experimentation and ensures that the participant's rights and welfare are protected and that the potential benefits and/or the importance of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed consent document associated with each study in order to ensure that the consent document accurately and clearly communicates the nature of the research to be done and its associated risks and benefits.
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10.2 protection of privacy

Patients will be informed of the extent to which their confidential health information generated from this study may be used for research purposes. Following this discussion, they will be asked to sign the HIPAA form and informed consent documents. The original signed document will become part of the patient's medical records, and each patient will receive a copy of the signed document. The use and disclosure of protected health information will be limited to the individuals described in the informed consent document.
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44. Ou, S.H., N. Agarwal, and S.M. Ali, High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer, 2016. 98: p. 59-61.  
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51. Osimertinib Investigator's Brochure. October 2016. Edition 7. 52. D'Cunha, J., et al., Poor correspondence between clinical and pathologic staging in stage 1 non-small cell lung cancer: results from CALGB 9761, a prospective trial. Lung Cancer, 2005. 48(2): p. 241-6.  
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appendix 1 schedule of study

| D15 Postop  Lab Draw                                                      |                                   |          |          |                 |        |           |     |    |             |                        |
|------------------------------------------------------|-----------------------------------|----------|----------|-----------------|--------|-----------|-----|----|-------------|------------------------|
| Period/Procedure                                     | Pre                                   |          |          |                 |        |           |     |    |             |                        |
| screening1                                           | Screening                         | Cycle 1  | Cycle 24 | Day of  Surgery | End of | Long Term |     |    |             |                        |
| Treatment                                            | Follow Up Every 3/6  mo after EOT |          |          |                 |        |           |     |    |             |                        |
| Informed consent                                     | X                                 |          |          |                 |        |           |     |    |             |                        |
| EGFR mutation testing  (if status unknown)           | X                                 | X5       |          |                 |        |           |     |    |             |                        |
| Baseline conditions 2                                | X                                 |          |          |                 |        |           |     |    |             |                        |
| Contraceptive counseling                             | X                                 |          |          |                 |        |           |     |    |             |                        |
| AE assessment                                        | X                                 | X        | X        | X               | X      | X         | X12 |    |             |                        |
| Concomitant medications                              | X                                 | X        | X        | X               | X      | X         | X   | X  |             |                        |
| Tumor tissue for correlative  studies5               | X                                 | X13      | X13      | X               |        |           |     |    |             |                        |
| Survival status and other  therapies                 | X17                               |          |          |                 |        |           |     |    |             |                        |
| Treatment/Drug Administration Osimertinib Dispensing | X                                 | X14      | X        | X               |        |           |     |    |             |                        |
| Clinical procedures Physical exam                    | X                                 | X        | X        | X               | X      | X         | X   | X  |             |                        |
| Vital signs                                          | X                                 | X        | X        | X               | X      | X         | X   | X  |             |                        |
| Medical history                                      | X                                 | X        | X        | X               | X      | X         | X   | X  |             |                        |
| Disease assessment                                   | X                                 | X        | X        | X               |        |           |     |    |             |                        |
| Performance status                                   | X                                 | X        | X        | X               | X      | X         | X   | X  |             |                        |
| Biopsy or archived tissue  procurement               | X5                                | X13      | X13      |                 |        |           |     |    |             |                        |
| Laboratory procedures CBC w/ Diff6                   | X                                 | X        | X        | X               | X      | X         | X   | X  | X           |                        |
| Blood Chemistry7                                     | X                                 | X        | X        | X               | X      | X         | X   | X  | X           |                        |
| Coagulation8                                         | X                                 | X        | X        | X               | X      | X         | X   | X  | X           |                        |
| Urinalysis                                           | X                                 | X        | X19      | X               | X      |           |     |    |             |                        |
| Pregnancy test (HCG)9                                | X                                 | X        | X19      | X               | X      |           |     |    |             |                        |
| Blood for ctDNA and PBMCs                            | X                                 | X        | X        | X               | X      | X         | X   | X  | X           |                        |
| Imaging procedures Imaging (CT) C/A/P                | X10                               | X        | X        | X               | X18    |           |     |    |             |                        |
| Study Day/Visit Day1                                 | Within 60  days of D1             | -30 to 0 | 1        | 15              | 283    | 1         | 15  | 28 | 15D post-op | 30D after  D15 post-op |
| Phase II - Osimertinib                               | Page 70 of 85                     |          |          |                 |        |           |     |    |             |                        |  
| D15 Postop  Lab Draw                                                                                                                                                                                |                                   |                        |          |                 |        |           |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|------------------------|----------|-----------------|--------|-----------|----|
| Period/Procedure                                                                                                                                                               | Pre                                   |                        |          |                 |        |           |    |
| screening1                                                                                                                                                                     | Screening                         | Cycle 1                | Cycle 24 | Day of  Surgery | End of | Long Term |    |
| Treatment                                                                                                                                                                      | Follow Up Every 3/6  mo after EOT |                        |          |                 |        |           |    |
| PET-CT                                                                                                                                                                         | X16                               |                        |          |                 |        |           |    |
| MRI Brain                                                                                                                                                                      | X16                               |                        |          |                 |        |           |    |
| ECG/EKG                                                                                                                                                                        | X                                 | X                      | X        | X               | X      | X         | X  |
| MUGA or TTE                                                                                                                                                                    | X                                 | X15                    | X15      | X               |        |           |    |
| 1  Window for each study visit is +/- 3 days. Screening procedures allowed within 30 days prior to day 1. Study Day/Visit Day1 Within 60  days of D1 -30 to 0 1 15 283 1 15 28 | 15D post-op                       | 30D after  D15 post-op |          |                 |        |           |    |  
Every 3/6 mo after EOT
PET-CT X16 MRI Brain X16 ECG/EKG X X X X X X X
MUGA or TTE X X15 X15 X
1 Window for each study visit is +/- 3 days. Screening procedures allowed within 30 days prior to day 1.  
2 Baseline conditions assessment per DSMC policy (Baseline Conditions VI Form)
3 C1D28 visit only for patients not receiving second cycle of osimertinib 4 Optional second cycle as per investigator discretion. Those receiving second cycle osimertinib do not attend the C1D28 visit 5 Screening biopsy within 30 days prior to C1D1. Tissue from screening biopsy and surgical resection will be used for correlative studies (see Section 1.4). If there is not enough tissue for pre-screening EGFR mutation testing, tissue from this biopsy will also be collected for EGFR mutation testing. This biopsy can be deferred if the procedure is deemed to represent an unacceptable safety risk to the patient by the principal investigator.  
6 Including CBC with differential and platelet count 7 Including ALP, ALT/AST total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting or non-fasting glucose, potassium, sodium, chloride, bicarbonate. Magnesium required at screening only.  
8 Including PT/PTT/INR
9 In women of child-bearing potential. At screening to be done within 3 days of C1D1.  
10 Imaging within 28 days prior to C1D1. If CT contraindicated, MRI acceptable 11 If not be receiving second cycle of osimertinib 12 Including documentation of AEs leading to inability to proceed with surgical resection and of surgical complications 13Optional research biopsy for patients who will be unable to undergo surgical resection, within 30 days of C1D28 or C2D28 14Dispensing of up to 14 days' supply osimertinib for treatment until pre-surgical washout period if will be proceeding to resection after first cycle of osimertinib.  
15 TTE is only required if the patient is proceeding to surgical resection following first cycle of osimertinib therapy. For patients receiving the second of cycle of osimertinib, TTE is optional except for patients with pre-existing risk factors as clinically indicated. .  
16PET-CT and brain MRI (standard of care procedures) must be done within 60 days of C1D1 as part of inclusion criteria (see Section 3.3.1)
17 During the first year after the EOT visit, assessment of survival status and subsequent care for NSCLC will occur every 3 months. From the first year following EOT visit up to the 5 years post-surgery, assessment of survival status and subsequent therapies will occur every 6 months via telephone or routine clinic visits.  
18 LTFU imaging will be performed every 6 months as standard of care. LTFU may be performed with greater frequency per the investigator's discretion or local institutional requirements 19 Urinalysis and pregnancy test are optional at C1D28 or as clinically indicated.  
| ECOG Performance Status Scale                                                                                                                                  | Karnofsky Performance Scale        |                                                                          |                                                                          |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|--------------------------------------------------------------------------|--------------------------------------------------------------------------|
| Grade                                                                                                                                                          | Descriptions                       | Percent                                                                  | Description                                                              |
| 0                                                                                                                                                              | Normal activity                    | 100                                                                      | Normal, no complaints, no evidence  of disease                           |
| Fully active, able to carry on all  pre-disease performance without                                                                                            | 90                                 | Able to carry on normal activity;                                        |                                                                          |
| restriction                                                                                                                                                    | minor signs or symptoms of disease |                                                                          |                                                                          |
| 1                                                                                                                                                              | Symptoms, but ambulatory           | 80                                                                       | Normal activity with effort; some  signs or symptoms of disease          |
| 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) | 70                                 | Cares for self, unable to carry on  normal activity or to do active work |                                                                          |
| 2                                                                                                                                                              | In bed <50% of the time            | 60                                                                       | Requires occasional assistance, but  is able to care for most of his/her |
| Ambulatory and capable of all                                                                                                                                  | needs                              |                                                                          |                                                                          |
| self-care, but unable to carry out  any work activities Up and about more than 50% of  waking hours                                                            | 50                                 | Requires considerable assistance  and frequent medical care              |                                                                          |
| 3                                                                                                                                                              | In bed >50% of the time            | 40                                                                       | Disabled, requires special care and  assistance                          |
| Capable of only limited self- care,  confined to bed or chair more than                                                                                        | 30                                 | Severely disabled, hospitalization                                       |                                                                          |
| 50% of waking hours                                                                                                                                            | indicated Death not imminent       |                                                                          |                                                                          |
| 4                                                                                                                                                              | 100% bedridden                     | 20                                                                       | Very sick, hospitalization indicated                                     |
| Completely disabled                                                                                                                                            | Death not imminent                 |                                                                          |                                                                          |
| Cannot carry on any self-care                                                                                                                                  | 10                                 | Moribund, fatal processes                                                |                                                                          |
| Totally confined to bed or chair                                                                                                                               | progressing rapidly                |                                                                          |                                                                          |
| 5                                                                                                                                                              | Dead                               | 0                                                                        | Dead                                                                     |
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appendix 2 performance status criteria

The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for all HDFCCC institutional clinical trials. A summary of DSMC activities for this trial includes:  
Semiannual auditing (depending on accrual). Review of serious adverse events.  
Minimum of a biennial regulatory auditing visit.
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monitoring and reporting guidelines

The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the trial and for auditing its safety and progress at all participating sites. The Study Chair will conduct continuous review of data and participant safety at monthly UCSF Site Committee meetings. The discussions are documented in the UCSF Site Committee meeting minutes. All institutional Phase II or III therapeutic trials are designated with a moderate risk assessment. The data is audited by a DSMC Monitor/Auditor on a semiannual basis with a random selection of twenty percent of the participants (or at least three participants if the calculated value is less than three). The DSMC Monitor/Auditor will audit a maximum of 5 cycles of treatment in the participants selected for review or until the selected participants discontinue study participation or the trial is closed with the IRB. Additionally, the assigned DSMC Monitor/Auditor will review no more than 10 total participant charts during the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to the study team within 20 business days after the monitoring visit is complete for the PI and the study team to resolve all action items from this report within 20 business days. An abbreviated regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) will occur at each participant monitoring review; however, a full regulatory review will occur on a biennially basis by the DSMC for regulatory compliance. The participating site's source documents are audited remotely via either review of redacted source documents downloaded by the site into the CRA console of OnCore and/or via access to the site's electronic medical records. The DSMC Monitor/Auditor will audit no more than three participant charts at each participating site during the course of auditing this trial. Auditing of all enrolled participants in these trials will be complete after 20% of enrolled participants have been audited through five cycles of treatment. However, regulatory reviews of the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by the IRB.
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multicenter communication

The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate monthly conference calls with the participating sites. The following issues will be discussed as appropriate:  
Enrollment information. Adverse events (i.e., new adverse events and updates on unresolved adverse events and new safety information).  
Protocol Violations.  
Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The data (i.e., copies of source documents) from the participating sites will be downloaded into the PC console of OnCore prior to the remote monitoring visits in order for the DSMC to monitor the participating site's compliance with the protocol and applicable FDA regulations.
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review and oversight requirements adverse

All Grade 3-5 adverse events (AEs), regardless of being unexpected or considered to be associated with the use of the study drug will be entered into OnCore®, UCSF's Clinical Trial Management System. Adverse events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the National Cancer Institute. Adverse events are further given an assignment of attribution or relationship to the investigational agent(s) or study procedure. Attribution categories are:  
**Definite** - The adverse event is clearly related to the investigational agent(s) or study procedure.  
**Probable** - The adverse event is likely related to the investigational agent(s) or study procedure.  
**Possible** - The adverse event may be related to the investigational agent(s) or study procedure.  
**Unrelated** - the adverse event is clearly not related to the investigational agent(s)
or study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the UCSF Site Committee meetings. All adverse events entered into OnCore® will be reviewed on a monthly basis at the UCSF Coordinating Center Site Committee meetings. All grade 3-5 adverse events must be reported to the UCSF Coordinating Center by the participating sites within 10 business days of becoming aware of the event or during the next scheduled monthly conference call, whichever is sooner. The UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and attribution assignment from the UCSF Coordinating Center and the participating sites.
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serious adverse event reporting

By definition, an adverse event is defined as a serious adverse event (SAE) according to the following criteria:  
Death. Life-threatening (i.e., results in an immediate risk of death).  
Requires inpatient hospitalization or prolongation of existing hospitalization.  
Permanent or significant disability/incapacity.  
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that suggests a significant hazard, contraindication, side effect, or precaution that may require medical or surgical intervention to prevent one of the outcomes listed above.  
Event occurring in a gene therapy study.  
Event that changes the risk/benefit ratio of a study.  
Any other event the Principal Investigator judges to be serious or which would suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials conducted under an investigational new drug (IND) application, the SAE will be reported in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med Watch form. UCSF IRB website for guidance in reporting serious adverse events: https://irb.ucsf.edu/adverse-event Med Watch forms and information: www.fda.gov/medwatch/getforms.htm All Serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB guidelines) via iRIS®. All SAEs, whether expected or unexpected, must be reported to the UCSF Coordinating Center within one business days of becoming aware of the event. The SAEs are reviewed and audited by the UCSF Data and Safety Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which take place every six weeks. The date the SAE was sent to all required reporting agencies will be documented in OnCore®. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be possibly, probably, or definitely related either to the investigational drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the assigned designee must be notified within 1 business day from the participating site(s) and the Study Chair must then notify the DSMC Chair or Vice Chair and the DSMC Director within 1 business day of this notification.
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review of adverse event rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF Coordinating Center is responsible for notifying the DSMC Chair (or Vice Chair) and the DSMC Director at the time the increased rate is identified via a report.  
The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert.  
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified within one business day and the IRB must be notified within their reporting guidelines. Data and Safety Monitoring Committee Contacts:  
  
San Francisco, CA 94158
John McAdams (DSMC Director)  
  
UCSF HDFCCC  
  
  
San Francisco, CA 94143
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appendix 4 ucsf policy/procedure for

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the HDFCCC where the PI holds the IND.
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background

The ICH-GCP Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful management of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
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procedures 1. hdfccc essential regulatory

Package Insert (if the study drug is commercial) or Investigator Brochure PRC-approved protocols, protocol amendments and Summary of Changes (SOC) Patient handouts Screening/enrollment log DSMC monitoring reports OnCore® CRF completion manual
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documents filed in regulatory binder

Completed FDA 1572 document with PI's signature For all PIs and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency Licenses, and Staff Training Documents (i.e., Collaborative Institute Training Initiative (CITI), etc.)
Site Initiation Visit (SIV) minutes and correspondence with participating site(s). As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center SAE reports to IRB and sponsor.  
MedWatch reporting to FDA and sponsor Delegation of Authority Form
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documents filed in iris

IRB approvals for initial submission of application, all modifications, and continuing annual renewals Current and prior approved protocol versions with signed protocol signature page(s)
IRB approval letters and ICF(s)
Current and prior versions of the Investigator Brochure (IB).  
SAE Reporting Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting fax documentation  
Drug Destruction SOP For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
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2. additional essential documents for

IRB approval letters, IRB roster, ICF, and HIPAA Consent Form for the Participating Site(s)
For all PIs and Sub-Investigators listed on the 1572 at the Participating Site(s) - Financial Disclosure Forms, CVs, MD Licenses, and Staff Training documents (i.e. CITI, etc.) (for IND Application)
SIV minutes and correspondence with Participating Site(s). As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center for the Participating Site(s)
Protocol Violations and SPE reports to IRB with supporting fax documentation for Participating Site(s)
Drug Destruction SOP for the Participating Site(s)
DSMC monitoring reports for the Participating Site(s)
For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating Site(s)
Copy of the DSMP Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if an outside CRO is used for the study)
SAE forms submitted to both the IRB and the sponsor for the Participating Site(s)
27 April 2012
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appendix 5 required regulatory documents

Directions:
1) Fax the documents listed below to the UCSF Coordinating center at 415-514-6995 or 2) Scan the documents and upload to OnCore® and create a Note to File for the on-site Regulatory binder to indicate where these documents may be found
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1572

PI and Sub investigators: CV and Medical license Financial disclosure form NIH or CITI human subject protection training certification Laboratories CLIA and CAP CV of Lab Director and Lab Licenses Laboratory reference ranges
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local irb

IRB Approval letter Reviewed/Approved documents Protocol version date: __________
Informed consent version date: __________
Investigator Brochure version date: __________  
HIPAA
Current IRB Roster
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other

Delegation of Authority Log Include NIH or CITI human subject protection training certificates or GCP training certification Pharmacy Drug destruction SOP and Policy Protocol signature page Executed sub contract  
| Appendix 6 Prohibited Medications Drug Trade name (if applicable) Aclarubicin  Aliskiren  Amiodarone  Anagrelide  Arsenic trioxide  Astemizole  Azithromycin bepridil  Carbamazepine  Chloroquine  Chlorpromazine  Cilostazol  Ciprofloxacin Cisapride  Citalopram  Clarithromycin Cocaine Dabigatran Daunorubicin  Digoxin  Disopyramide Norpace  Dofetilide Tikosyn  Domperidone  Dronedarone  Donepezil  Droperidol  Doxorubicin  Erythromycin  Escitalopram Flecainide  Fluconazole  Flecainide  Gatifloxacin Phase II - Osimertinib   | Page 80 of 85   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|  
| Version date: 04/12/2022                                                                                                                                                                                                                          | Protocol CC#: 17658   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|
| Grepafloxacin  Halofantrine  Haloperidol  Ibogaine  Ibutilide                                                                                                                                                                                     | Corvert               |
| Levofloxacin Levomepromazine  Levomethadyl                                                                                                                                                                                                        | Orlaam                |
| Levosulpiride  Mesoridazine  Methadone  Moxifloxacin  Ondansetron  Oxaliplatin  Papaverine hydrochloride Pentamidine  Phenobarbital  Phenobarbitone  Phenytoin                                                                                    | Dilantin              |
| Pimozide  Probucol  Procainamide  Propofol  Quinidine  Rifabutin  Rifampicin  Rifapentin  Rosuvastatin  Roxithromycin  Sevoflurane Sotalol  Sparfloxacin  St John's Wort  Sulfasalazine  Sulpiride Sultopride  Terfenadine Phase II - Osimertinib | Page 81 of 85         |  
| Version date: 04/12/2022               | Protocol CC#: 17658   |
|----------------------------------------|-----------------------|
| Terlipressin  Terodiline  Thioridazine | Mellaril              |
| Topotecan  Vandetanib                  |                       |
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appendix 7 actions required in

This Appendix describes the process to be followed in order to identify and appropriately report cases of Hy's Law. It is not intended to be a comprehensive guide to the management of elevated liver biochemistries. Specific guidance on the managing of liver abnormalities can be found in Section 5.3.1 of the protocol. During the course of the study, the Investigator will remain vigilant for increases in liver biochemistry. The Investigator is responsible for determining whether a patient meets potential Hy's Law (PHL) criteria at any point during the study. The Investigator participates, together with Sponsor clinical project representatives, in review and assessment of cases meeting PHL criteria to agree whether Hy's Law (HL) criteria are met. HL criteria are met if there is no alternative explanation for the elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review and assessment in line with standard safety reporting processes.
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definitions potential hy's law (phl)

Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal (ULN) **together with** total bilirubin (TBL) ≥ 2xULN at any point during the study following the start of study medication irrespective of an increase in Alkaline Phosphatase (ALP).
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hy's law (hl)

AST or ALT ≥ 3x ULN **together with** TBL ≥ 2xULN, where no other reason, other than the IMP, can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral hepatitis, another drug. For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e. on the same day) the elevation in TBL, but there is no specified timeframe within which the elevations in transaminases and TBL must occur.
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identification of potential hy's law

In order to identify cases of PHL, it is important to perform a comprehensive review of laboratory data for any patient who meets any of the following identification criteria in isolation or in combination:
ALT ≥ 3xULN
AST ≥ 3xULN
TBL ≥ 2xULN
The Investigator will without delay review each new laboratory report and if the identification criteria are met, the investigator will: Determine whether the patient meets PHL criteria (see Definitions within this Appendix for definition) by reviewing laboratory reports from all previous visits Promptly enter the laboratory data into the laboratory CRF
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follow-up potential hy's law criteria

If the patient does not meet PHL criteria, the Investigator will: Perform follow-up on subsequent laboratory results according to the guidance provided in the Clinical Study Protocol.
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potential hy's law criteria met

If the patient does meet PHL criteria, the Investigator will: Determine whether PHL criteria were met at any study visit prior to starting study treatment Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms and signs return to normal or baseline levels, or as long as medically indicated Investigate the etiology of the event and perform diagnostic investigations. Complete the three Liver CRF Modules as information becomes available If at any time the PHL case meets serious criteria, report it as an SAE using standard reporting procedures
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review and assessment of potential

The instructions in this Section should be followed for all cases where PHL criteria are met. No later than 3 weeks after the biochemistry abnormality was initially detected, Investigator reviews available data and agrees on whether there is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP. According to the outcome of the review and assessment, the Investigator will follow the instructions below. If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a determination of whether the alternative explanation is an AE will be made and subsequently whether the AE meets the criteria for a SAE: If the alternative explanation is **not** an AE, record the alternative explanation on the appropriate CRF
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly If it is agreed that there is no explanation that would explain the ALT or AST and TBL
elevations other than the IMP:
Report an SAE (report term 'Hy's Law') according to standard processes.  
The 'Medically Important' serious criterion should be used if no other serious criteria apply
As there is no alternative explanation for the HL case, a causality assessment of 'related' should be assigned. If there is an unavoidable delay of over 3 weeks, in obtaining the information necessary to assess whether or not the case meets the criteria for HL, then it is assumed that there is no alternative explanation until such time as an informed decision can be made:  
Report an SAE (report term 'Potential Hy's Law') applying serious criteria and causality assessment as per above Continue follow-up and review according to agreed plan. Once the necessary supplementary information is obtained, repeat the review and assessment to determine whether HL criteria are met. Update the SAE report according to the outcome of the review, amending the reported term if an alternative explanation for the liver biochemistry elevations is determined
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actions required for repeat episodes

This section is applicable when a patient meets PHL criteria on study treatment and has already met PHL criteria at a previous on study treatment visit. The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is based on the nature of the alternative cause identified for the previous occurrence. The Investigator should determine the cause for the previous occurrence of PHL criteria being met and answer the following question:  
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the disease under study (e.g. chronic or progressing malignant disease, severe infection or liver disease), or did the patient meet PHL criteria prior to starting study treatment and at their first on study treatment visit.  
If No: follow the process described in Potential Hy's Law Criteria met of this Appendix
If Yes: Determine if there has been a significant change in the patient's condition compared with when PHL criteria were previously met If there is no significant change no action is required  
If there is a significant change follow the process described above in this Appendix
A 'significant' change in the patient's condition refers to a clinically relevant change in any of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation or in combination, or a clinically relevant change in associated symptoms. The determination of whether there has been a significant change will be at the discretion of the Investigator.