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| Sponsor: Funding  Source: Protocol  Source: Duke  IRB#:   |
|-----------------------------------------------------------|  
Title: Single arm phase 2 trial of atezolizumab andbevacizumabin Epidermal Growth Factor Receptor (*EGFR*) mutant non‐small cell lung cancer in patients with progressive disease afterreceiving **osimertinib**
[Genentech Protocol Number: ML41358]
Thoracic Oncology Program (TOP) Protocol Number: TOP 1901 Principal Investigator Thomas Stinchcombe,MD
DUMC 3198 25178 Morris Building Durham, NC 27710 Telephone: 919‐681‐9509 Fax: 919‐684‐5163 Email address: Thomas.stinchcombe@duke.edu  
| PI - Duke Cancer Institute  Thomas Stinchcombe PI ‐ Duke Cancer Institute  Pro00103723   |
|------------------------------------------------------------------------------------------|
| Principal Investigator                                                                   |  
Sub‐Investigator(s)
Neal Ready MD, PhD
Jeffrey Clarke MD
Jeffrey Crawford MD
ScottAntonia,MD,PhD
Jennifer TenhoverANP
Yeshu ConnANP
Susan BlackwellMHS,PA‐C
Jeana SchneiderMHS,PA‐C
Deborah BallardANP
Statisticians Xiaofei, Wang PhD
Department of Biostatistics & Bioinformatics Duke University Medical Center xiaofei.wang@duke.edu  
Ben Neely, MS  
Senior Biostatistician  
Duke Cancer Institute ben.neely@duke.edu  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 Version 1, 09Oct2019
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lead study coordinator

Carol Alonso MSN, RN
Thoracic Oncology Fax: 919.684.8926 carol.alonso@duke.edu Regulatory Coordinator Eun Young Song Candice Singletary Lucas David Regulatory Coordinators Thoracic Oncology Research Program Duke Cancer Institute Hock Plaza, Room 8089 2424 Erwin Road Durham, NC 27705
(919) 668-1069 E-mail: eunyoung@neuro.duke.edu Data Management Thoracic Oncology Clinical Trials Room 00541, Duke South Duke Cancer Institute Durham, NC
Original version: 10/9/2019 Amended version 1:
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901
statement of compliance and signature
lead study coordinator

Title: Single arm phase 2 trial of atezolizumab and bevacizumab in Epidermal Growth Factor Receptor (*EGFR*) mutant non‐small cell lung cancer in patients with progressive disease after receiving osimertinib
[Genentech Protocol Number: ML41358]
Thoracic Oncology Program (TOP) Protocol Number: TOP 1901 This study will be conducted in compliance with the protocol approved by the Institutional Review Boards of Duke University Health System, and external sites according to Good Clinical Practice standards. No deviation from the protocol will be implemented without the prior review and approval of the IRB except where it may be necessary to eliminate an immediate hazard to a research subject. In such case, the deviation will be reported to the IRB as soon as possible. The signature below constitutes the approval (by the PI) of this protocol and the attachments, and provides the necessary assurances that this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to local and state legal and regulatory requirements and applicable U.S. federal regulations and ICHguideline Duke Sponsor Investigator: Thomas Stinchcombe, MD Duke University Thoracic Oncology Program Thomas Stinchcombe, MD, DukeSponsor Investigator Date Site Principal Investigator Date  
| 1     | TABLE OF CONTENTS                                               | 4   |
|-------|-----------------------------------------------------------------|-----|
| 2     | LISTOF ABBREVIATIONS                                            | 6   |
| 3     | PROTOCOL SYNOPSIS ANDSUMMARY                                    | 8   |
| 3.1   | Design and Procedure                                            | 10  |
| 3.2   | Objectives and endpoints                                        | 10  |
| 3.3   | Subject eligibility                                             | 11  |
| 3.4   | Registration Procedure                                          | 14  |
| 3.5   | Duration ofstudy                                                | 14  |
| 4     | STUDY SCHEMA                                                    | 14  |
| 5     | STUDY THERAPY                                                   | 15  |
| 5.1   | Atezolizumab background                                         | 15  |
| 5.1.1 | Pre‐clinical experience                                         | 15  |
| 5.1.2 | Clinical experience                                             | 16  |
| 5.2   | Bevacizumab background                                          | 18  |
| 5.2.1 | Preclinical experience                                          | 18  |
| 5.2.2 | Clinical experience                                             | 19  |
| 6     | CLINICAL MANAGEMENT OF STUDYTHERAPY                             | 23  |
| 6.1   | Discontinuation for adverse events                              | 23  |
| 6.2   | Management ofatezolizumab adverseevents                         | 23  |
| 6.2.1 | Dose modifications                                              | 23  |
| 6.2.2 | Management ofatezolizumab adverseevents                         | 23  |
| 6.3   | Management of bevacizumabadverse events                         | 30  |
| 6.3.1 | Dose modifications                                              | 30  |
| 6.3.2 | Management of bevacizumab‐relatedadverse events                 | 30  |
| 6.4   | Management of bevacizumabadverse events                         | 33  |
| 6.5   | Rationale for Selection of Dose, Regimen,and Treatment Duration | 34  |
| 7     | RATIONALE FOR TRANSLATIONAL MEDICINE STUDIES                    | 34  |
| 8     | EARLY STUDY TERMINATION                                         | 38  |  
| 9      | STUDY THERAPIESPHARMACYMANAGEMENT          | 38   |
|--------|--------------------------------------------|------|
| 9.1    | Atezolizumab and bevacizumab               | 38   |
| 9.2    | Packagingand Labeling                      | 39   |
| 9.3    | Supply, Receipt,and Storage                | 39   |
| 9.4    | Dispensingand Preparation                  | 39   |
| 9.5    | Complianceand Accountability               | 39   |
| 9.6    | Disposal and Destruction                   | 39   |
| 10     | SCREENINGANDON‐STUDY TESTSAND PROCEDURES   | 39   |
| 10.1   | Schedule of time and events table(Table9)  | 40   |
| 10.2   | Screening Examination                      | 42   |
| 10.3   | On studytreatmentperiod                    | 42   |
| 10.4   | End of Study Treatment                     | 43   |
| 10.5   | Follow‐up Period                           | 43   |
| 10.6   | End of Study                               | 43   |
| 10.7   | Early Withdrawal of Subject(s)             | 43   |
| 10.7.1 | Criteria for EarlyWithdrawal               | 43   |
| 10.7.2 | Follow‐up Requirements for EarlyWithdrawal | 44   |
| 10.7.3 | Replacement of EarlyWithdrawal(s)          | 44   |
| 11     | SAFETY MONITORING AND REPORTING            | 44   |
| 11.1   | Adverse Events                             | 44   |
| 11.2   | Serious Adverse Events                     | 45   |
| 11.3   | Adverse Events of Special Interest         | 47   |
| 11.4   | Safety OversightCommittee (SOC)            | 49   |
| 11.5   | Quality control andassurance               | 50   |
| 11.6   | Data Managementand Processing              | 52   |
| 12     | STATISTICAL METHODS ANDDATA ANALYSIS       | 53   |
| 13     | ADMINISTRATIVE AND ETHICAL CONSIDERATIONS  | 55   |
| 14     | REFERENCES                                 | 59   |
| 15     | APPENDICES                                 | 62   |
statement of compliance and signature
2 list ofabbreviations

| AE                                                                                                                                          | AdverseEvent                              |              |
|---------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|--------------|
| ACTH                                                                                                                                        | Adrenocorticotropic hormone               |              |
| ALT                                                                                                                                         | AlanineAminotransferase                   |              |
| ALC                                                                                                                                         | AbsoluteLymphocyteCount                   |              |
| AST                                                                                                                                         | AspartateAminotransferase                 |              |
| BAL                                                                                                                                         | Bronchoscopic alveolarlavage              |              |
| BUN                                                                                                                                         | Blood UreaNitrogen                        |              |
| CBC                                                                                                                                         | Complete BloodCount                       |              |
| CHF                                                                                                                                         | CongestiveHeart Failure                   |              |
| CMP                                                                                                                                         | Comprehensive Metabolic Panel             |              |
| CNS                                                                                                                                         | Central Nervous System                    |              |
| CR                                                                                                                                          | CompleteResponse                          |              |
| CT                                                                                                                                          | Computed Tomography                       |              |
| CTCAE                                                                                                                                       | CommonTerminologyCriteriaforAdverseEvents |              |
| DIPC                                                                                                                                        | DukeImmuneProfilingCore                   |              |
| DLT                                                                                                                                         | Dose Limiting Toxicity                    |              |
| DSMB                                                                                                                                        | Data and Safety Monitoring Board          |              |
| ECOG                                                                                                                                        | Eastern Cooperative Oncology Group        |              |
| ECMO                                                                                                                                        | Extracorporealmembraneoxygenation         |              |
| EGFR                                                                                                                                        | Epidermal Growth Factor Receptor          |              |
| H&P                                                                                                                                         | History& PhysicalExam                     |              |
| HRPP                                                                                                                                        | HumanResearch ProtectionsProgram          |              |
| IHC                                                                                                                                         | Immunohistochemistry                      |              |
| IV(or iv)                                                                                                                                   | Intravenously                             |              |
| IVIG                                                                                                                                        | intravenousimmunoglobulin                 |              |
| LFT                                                                                                                                         | Liver functiontest                        |              |
| MDSC                                                                                                                                        | Myeloidderivedsuppressor cells            |              |
| MRI                                                                                                                                         | Magnetic resonanceimaging                 |              |
| MTD                                                                                                                                         | MaximumTolerated Dose                     |              |
| NCI                                                                                                                                         | National Cancer Institute                 |              |
| NSCLC                                                                                                                                       | Non‐SmallCell LungCancer                  |              |
| ORR                                                                                                                                         | Overall ResponseRate                      |              |
| OS                                                                                                                                          | Overall Survival                          |              |
| PBMCs                                                                                                                                       | PeripheralBlood Mononuclear Cells         |              |
| PD                                                                                                                                          | ProgressiveDisease                        | CONFIDENTIAL |
| The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is |                                           |              |  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 6  
PFS Progression FreeSurvival  
PK Pharmacokinetic  
p.o. per os/bymouth/orally PR Partial Response  
SD StableDisease  
| PRES   | Posterior ReversibleEncephalopathySyndrome   |
|--------|----------------------------------------------|
| RECIST | Response Evaluation Criteria in Solid Tumors |
| SGOT   | SerumGlutamicOxaloaceticTransaminase         |
| SOP    | Standard OperatingProcedure                  |
| SPGT   | SerumGlutamicPyruvicTransaminase             |  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 7  
TKI TyrosineKinaseInhibitor  
UPC Urineprotein:creatinine  
| TSH   | Thyroid stimulatinghormone   |
|-------|------------------------------|  
VAD Ventricularassistdevice  
WBC WhiteBloodCells  
WHO World HealthOrganization  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 8
3 protocol synopsis and research
2 list ofabbreviations

Synopsis: This single arm, open label, phase 2 study will prospectively investigate the activity of the combination atezolizumab and bevacizumab in patients with stage 4 epidermal growth factor receptor (*EGFR*) mutant non‐small cell lung cancer (NSCLC) who have progressed after osimertinib. The purpose of the phase 2 is to determine if further investigation of the combination in a phase 3 trial is warranted Primary Objectives: To assess the Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 as assessed by investigator
3 protocol synopsis and research
hypotheses

The combination of bevacizumab and atezolizumab will have activity in *EGFR* mutant NSCLC in patients who have experienced disease progression on osimertinib. This study will obtain preliminary data to assist in determining if a larger prospective clinical trial should be pursued.
3 protocol synopsis and research
disease background

For patients NSCLC with an activating epidermal growth factor receptor (*EGFR)* mutation, defined as exon 19 deletion or exon 21 L858R point mutation, osimertinib is the standard of care in the United States.2 The median PFS observed with osimertinib is approximately 19 months, and at the time of disease progression multiple mechanisms of resistance have been detected.3 Current studies are investigating targeted therapies or combination of targeted therapies for specific mechanisms of resistance. Currently, a post‐osimertinib targeted therapy is not available. In subset analyses of phase 3 trials of single immunotherapy compared to single agent chemotherapy the PFS and OS
in patients with known *EGFR* mutant NSCLC were similar, and the ORR is approximately 5%.4‐7 Even in patients with an *EGFR* mutant NSCLC and high PD‐L1 score single agent immunotherapy has limited activity.8 Patients with *EGFR*
mutant NSCLC were excluded from the phase 2 and phase 3 trials of carboplatin, pemetrexed, and pembrolizumab so the activity of this combination has not been established.9,10 The standard therapy is a platinum‐based  
chemotherapy doublet which results in an objective response rate (ORR) of approximately 30% and a median progression‐free survival (PFS) of approximately 5 months.11 Preclinical data suggest inhibition of angiogenesis may overcome primary and acquired resistance to EGFR tyrosine kinase inhibitors.12,13 Previous clinical studies have revealed an improvement in PFS in treatment naïve patients with EGFR mutant NSCLC with the combination of erlotinib and bevacizumab compared to erlotinib alone.14,15 There is an interest in combining angiogenesis with immunotherapy based on preclinical models which suggest synergism between anti‐angiogenic therapy andimmunotherapy.16‐18 A recent phase 3 trial of carboplatin, paclitaxel, bevacizumab alone or with atezolizumab enrolled patients with *EGFR*
mutant NSCLC who had previously received an EGFR TKI.19,20 In a subset analysis of 59 patients with activating *EGFR*
mutations, patients assigned to the atezolizumab‐containing arm compared to standard arm had an improvement in progression‐free PFS (HR of 0.41, 95% confidence interval (CI) 0.22 to 0.87; median PFS of 10.3 and 6.1 months, respectively). In contrast the combination of carboplatin, paclitaxel and atezolizumab compared to carboplatin, paclitaxel and bevacizumab in the same trial did not reveal an improvement in PFS in the *EGFR* mutant NSCLC (HR of 1.01, 95% CI 0.61‐1.70; median of 6.0 and 6.1, respectively. In patients with an activating *EGFR* mutation when carboplatin, paclitaxel, bevacizumab, and atezolizumab wascompared to carboplatin, paclitaxel and bevacizumab the overall survival (OS) favored the 4‐drug combination (HR of .31, 95% CI 0.11 to 0.83; median non‐evaluable and 17.5 months, respectively). In the similar analysis of carboplatin, paclitaxel and atezolizumab compared to carboplatin, paclitaxel and bevacizumab a difference in OS was not observed (HR of 0.90, 95% CI 0.47 to 1.74; median 21.2 and 17.5 months, respectively). A different phase 3 trial of carboplatin and nab‐paclitaxel alone or with atezolizumab in patients with in patients with an *EGFR* or anaplastic lymphoma kinase rearrangement did not reveal an improvement PFS (HR of 0.75, 95% CI: 0.36 to 1.54; median 7.0 and 6.0 months) or OS (HR of 0.98, 95% CI 0.41 to 2.31; median 14.4 and 10 months, respectively).21 These subset analyses suggests the benefit was related to the combination of atezolizumab and bevacizumab since the same benefit was not observed in the comparison of chemotherapy and atezolizumab compared to chemotherapy alone or with bevacizumab.
3 protocol synopsis and research
3.1 design and procedure

The primaryobjective of this single‐arm phase II trial is to determine ORR, defined as all patients with a confirmed partial or complete response as assessed by investigator using RECIST 1.1, in patients with stage 4 NSCLC patients with *EGFR* mutations and who have progressed on osimertinib. Secondary objectives include
(1) evaluation of progression‐free survival; (2) overall survival; and (3) adverse events due to the protocol treatments.  
| Abbreviated Title           | TOP 1901                                                                                                                                                     |
|-----------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Trial Phase                 | II                                                                                                                                                           |
| Clinical Indication         | Stage IV NSCLC with EGFR mutation (exon 19 or exon 21 L858R) with progressive disease on osimertinib                                                         |
| Trial Type                  | Therapeutic treatment                                                                                                                                        |
| Type of control             | Not applicable‐single arm study                                                                                                                              |
| Route of administration     | IV every 3 weeks                                                                                                                                             |
| Trial Blinding              | Unblinded, open‐label                                                                                                                                        |
| Study Treatment Group       | Single Arm Atezolizumab 1200 mg IV every 3 weeks and bevacizumab 15 mg/kg IV every 3 weeks (1 cycle=3 weeks)                                                 |
| Number of trial subjects    | 39                                                                                                                                                           |
| Estimated enrollment period | Approximately 20‐41 months; first patient in Fourth Quarter 2019.                                                                                            |
| Estimated duration of trial | Estimated at 5 yearsfromthefirstpatientinto lastsubject'sfinal 2 year follow‐up                                                                              |
| Duration of Participation   | Active study treatment until progressionor study treatment not tolerated followedfor overallsurvivalfor amaximumof2 years after  completion ofstudy therapy. |  
3.2 Objectives and Endpoints  
| Objective   | Endpoint                                                               | Analysis                                                                         |                |
|-------------|------------------------------------------------------------------------|----------------------------------------------------------------------------------|----------------|
| Primary     | Objective response rate                                                | Patients experiencing a confirmed  partial or complete response using RECIST 1.1 | See Section 12 |
| Key         | Progression‐free survival                                              | Time from startingstudytherapy until                                             |                |
| Secondary   | disease progressionusing RECIST 1.1  or death (whichever occurs first) | See Section 12                                                                   |                |  
| Other                                 | Safety                                                   | Common Terminology Criteria for  Adverse Events (CTCAE ) 4.03 to assess   |                |
|---------------------------------------|----------------------------------------------------------|---------------------------------------------------------------------------|----------------|
| Secondary                             | treatment related adverseevents                          | See Section 12                                                            |                |
| Other                                 | Overall survival                                         | Time from study starting study therapy                                    | See Section 12 |
| Secondary                             | until deathor maximum of 2 years after  study completion |                                                                           |                |
| Exploratory                           | Investigation of immune  and angiogenesis                | Exploratory analysis based on ORR and                                     | See Section 12 |
| PFS observed on the studytherapy      |                                                          |                                                                           |                |
| markers and association with response |                                                          |                                                                           |                |  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 13
3 protocol synopsis and research
3.3 subject eligibility

The following guidelines are to assist physicians in selecting patients from whom protocol therapy is safe and appropriate. Physicians should consider the risks and benefits of any therapy, and therefore only enroll patients for whom this study treatment is appropriate. For entry into the study, the following criteria MUST be met.  
Patients are eligible to be included in the study only if they meet all of the following criteria.
3 protocol synopsis and research
inclusion criteria

1. Age ≥18years  
2. Histologic documentation of primary lung carcinoma, non‐squamous histology with *EGFR* exon deletion 19 or exon 21 L858R mutation.
Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory. The laboratory report from the commercial laboratories report the specific mutations detected, and the method of detecting the exon 19 and exon 21 L858R point mutations must be available. Both circulating tumor DNA and tumor testing are acceptable 3. Stage IV disease according to the 8th Edition of the American Joint Committee on Cancer staging system 4. Disease progression on osimertinib1 5. ECOG Performance Status 0 or 1 (appendix 1)
6. Measureable disease as defined by RECIST 1.1 (appendix2)
7. The following laboratory values obtained ≤ 28 days prior to starting study therapy a. ANC ≥ 1, 500 / mm3 b. Platelet count, ≥ 100,000 /mm3 c. Hemoglobin ≥ 9.0 g /dL  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 14 d. Total bilirubin ≤ 1.5 x upper limit of normal(ULN)
e. SGOT (AST) and SGPT (ALT) ≤2.5 x ULN in patients without liver or bone metastases; < 5 xULN
in patients with liver or bone metastases.  
f. Cockcroft‐Gault calculated creatinine clearance of ≥ 45 ml/min (appendix 3) or creatinine≤1.5 x ULN
g. Urine protein/creatinine (UPC) ratio ≤1.  
1 No limit to the number of prior lines of therapy. Osimertinib does not have to be most recent therapy prior to this study.  
There is no w ashout time period betw een prior therapy and initiating study treatment.  
8. Negative pregnancy test done ≤7 days (or per institutional policy) prior to start of study therapy, for women of childbearing potential only. Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test of must have evidence of non‐child bearing potential by fulfilling one of the following criteria atscreening:
a. Post‐menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonaltreatments; b. Women under 50 years of age would be considered post‐menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and LH
and FSH levels in the post‐menopausal range for theinstitution; c. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tuballigation.  
9. Male subjects should be willing to use barrier contraception.  
10. Provide informedwrittenconsent Patients will be excluded from the study if they meet any of the following criteria:
3 protocol synopsis and research
exclusion criteria

1. Mixed, non‐small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component. 2. Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception 3. Other active malignancy ≤ 2 years prior to study cycle 1 day 1 of study therapy. EXCEPTIONS: Non‐ melanotic skin cancer or carcinoma‐in‐situ of the cervix, or adequately treated stage I or II cancer. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (i.e.  
hormonal therapy) for their cancer.  
4. History of myocardial infarction or other evidence of arterial thrombotic disease (angina),
symptomatic congestive heart failure (New York Heart Association ≥ grade 2), unstable angina pectoris, or ventricular arrhythmia with ≤ 6months 5. History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months priorto study cycle 1 day 1 of study therapy.  
6. History of bleeding diathesis or coagulopathy.  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 17 7. Inadequately controlled hypertension (systolic blood pressure of >160 mmHg or diastolic pressure
>100 mmHg on anti‐hypertensive medications). Note: History of hypertensive crisis or hypertensive encephalopathy not allowed.  
8. Serious non‐healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days or core biopsy ≤ 7 days prior to starting therapy 9. History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess ≤6months prior to study cycle 1 day 1 of study therapy.  
10. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.  
11. History of hemoptysis ≥ grade 2 (defined as bright red blood of at least 2.5 mL) ≤ 3 months prior to cycle 1 day 1 of study therapy.  
12. Symptomatic untreated brain metastases which is defined as persistent neurological symptoms or requiring ongoing use of steroids. Asymptomatic untreated brain metastases are allowed if ≤ 1cm 13. Significant vascular disease (e.g. aortic aneurysm surgical repair or recent peripheral arterial thrombosis) ≤6 months prior to starting study therapy 14. Radiotherapy to any site for any reason ≤ 14 days prior to study cycle 1 day 1 of study therapy.  
15. Pre‐existing and clinically active interstitial lungdisease 16. Autoimmune condition requiring ongoing or intermittent systemic treatment. Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent)
or other immunosuppressive medications within 14 days of study treatment initiation. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.  
Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.  
17. Prior therapy with anti‐PD‐1 or anti‐PD‐L1immunotherapy, 18. Prisoners, participants who are involuntarily incarcerated, or participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease)illness
3 protocol synopsis and research
protocol eligibility waivers

No waivers of inclusion or exclusion criteria will be granted. All prospective patients must meet all entry criteria prior to enrollment in the study. If there are any questions regarding the interpretation of an eligibility criterion for a potential patient, contact the principal investigator to discuss the potential patient to confirm eligibility.
3 protocol synopsis and research
3.4 registration procedure

Patient registration for all patients signing informed consent will be completed through the Duke Cancer Institute (DCI) Clinical Research Unit (CRU) into EPIC and ONCORE systems within 1 business day of obtaining consent. Patients will be enrolled only after all pre‐treatment evaluations are completed and all eligibility criteria are met.
3 protocol synopsis and research
registration for outside sites

All patients signing informed consent at outside sites must be registered with Duke (including screen failures‐
indicate screen failure status on last page of eligibility checklist). The following documents are to be completed by the investigator and/or designee and faxed to (919)‐684‐8926 or scanned/emailed to the Thoracic Oncology Protocol Office (Thoracic‐multisite@dm.duke.edu): All supporting documents should be sentde‐identified.  
- TOP 1703 Eligibility Checklist with supporting source documents
- Signed Informed Consent
3 protocol synopsis and research
3.5 duration ofstudy

All patients will be followed for disease progression and death (whichever occurs first) from the date that the subjects were enrolled (cycle1 day 1) on study. Patients will remain on study until disease progression, unacceptable adverse event or withdrawal of consent. Patient discontinuing study therapy for reasons other than disease progression will be followed for disease progression. Once patients are no longer on study therapy, they will be followed for OS for a maximum 2 years from discontinuation of study therapy. Follow‐
up for OS can be through review of medical records or contacting patient and does require visit to the study center.  
  
Study Treatment  
  
  
  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 21
3 protocol synopsis and research
5 studytherapy 5.1 atezolizumab background

Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD L1 and inhibits the interaction between PD‐L1 and its receptors, PD‐1 and B7‐1 (also known as CD80), both of which function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD L1 binding by atezolizumab has been shown to enhance the magnitude and quality of tumor specific T cell responses, resulting in improved anti‐tumor activity.22,23 Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc effector function and associated antibody‐mediated clearance of activatedeffector T cells.  
Atezolizumab shows anti‐tumor activity in both nonclinical models and cancer patients and is being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in combination with chemotherapy, targeted therapy, and cancer immunotherapy. Atezolizumab is approved in the United States for the treatment of patients with locally advanced or metastatic urothelial carcinoma who fit the following criteria: 1) are not eligible for cisplatin‐ containing chemotherapy and whose tumors express PD‐L1 (PD‐L1 stained tumor‐ infiltrating immune cells [IC] covering ≥ 5% of the tumor area), as determined by an FDA‐ approved test, or 2) are not eligible for any platinum‐containing chemotherapy regardless of PD‐L1 status, or 3) have disease progression during or following any platinum‐containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy. Atezolizumab is also approved the treatment of previously treated locally advanced or metastatic NSCLC and in combination with carboplatin, paclitaxel and bevacizumab in patients with metastatic non‐ small cell lung cancer with non‐squamous histology Atezolizumab has been generally well tolerated. Adverse events with potentially immune‐ related causes consistent with an immunotherapeutic agent, including rash, influenza‐like illness endocrinopathies, hepatitis or transaminitis, pneumonitis colitis, and myasthenia gravis, have been observed (see Atezolizumab Investigator's Brochure for detailed safety results). To date, these events have been manageable with treatment or interruption of atezolizumab treatment.
3 protocol synopsis and research
5.1.1 pre-clinical

Exposure to atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg, including the fixed dose of 1200 mg administered every 3 weeks (q3w). On the basis of a population pharmacokinetic (popPK) analysis that included 472 patients in the dose range of 1 mg/kg to 20 mg/kg, the typical population clearance (CL) was 0.20 L/day, the volume of distribution at steady state (Vss) was 6.9 L,
and the terminal half‐life (t1/2) was 27 days. The popPK analysis suggested that steady state was obtained after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. The systemic accumulation in area under the concentration‐time curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin) was 1.91, 1.46, and 2.75‐fold, respectively.  
Based on an analysis of exposure‐safety and exposure‐efficacy data, the following factors had no clinically relevant effect: age (21‐89 years), body weight, sex, positive ADA status, albumin levels, tumor burden, region or ethnicity, renal impairment, mild hepatic impairment, level of PD‐L1 expression, or Eastern Cooperative Oncology Group (ECOG) status.
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reproductive and developmental toxicity

Reproductive and developmental toxicity studies with atezolizumab have not been conducted. The PD‐
L1/PD‐1 signaling pathway is well established as essential in maternal/fetal tolerance and embryo‐ fetal survival during gestation. Administration of atezolizumab is expected to have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo‐lethality.
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5.1.2 clinical experience

As of the CCOD of this IB update (17 May 2018) > 16,000 patients with solid tumors or hematologic malignancies have received atezolizumab as a single agent or in combination with cytotoxic chemotherapy and/or targeted therapy through participation in a clinical trial. Please refer to atezolizumab IB for additional details Safety findings of single‐agent atezolizumab across multiple tumor types in the clinical development program are consistent with the known mechanism of action of atezolizumab and the underlying disease.  
Overall, treatment with atezolizumab is well tolerated with a manageable adverse event profile. Currently, no maximum tolerated dose, no dose‐limiting toxicities (DLTs), and no clear dose‐ relatedtrends in the incidence of adverse events (AEs) have been determined. Among 3075 patients treated with single‐agent atezolizumab for whom pooled safety data are available, the most commonly reported AEs (> 10%) include fatigue, decreased appetite, cough, nausea, dyspnea, constipation, diarrhea, pyrexia, vomiting, arthralgia, back pain, asthenia, anemia, pruritus, rash, headache, and peripheral edema.  
The AEs observed with atezolizumab in combination with chemotherapy and/or targeted therapies are consistent with the known risks of the individual study treatment. Systemic immune activation, characterized by anexcessive immune response, is a potentialrisk associated with atezolizumabwhen used in combination with another immunomodulatingcompound. Atezolizumab‐related AEs were comparable between patients who received atezolizumab monotherapy and those who were treated with atezolizumab in combination with targeted therapy and/or chemotherapy. There are no atezolizumab‐related AEs that are exacerbated when used in combination with other agents.  
Immune‐related AEs are consistent with the role of the PD‐L1/PD‐1 pathway in regulating peripheral tolerance. Given the mechanism of action of atezolizumab, events associated with inflammation and/or immune‐related AEs are closely monitored during the atezolizumab clinical program. As of this IB update, immune‐related AEs associated with atezolizumab include pneumonitis, hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain‐Barré syndrome, myasthenic syndrome/myasthenia gravis, meningoencephalitis, myocarditis and nephritis.  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 25 In the overall population, Grade 3 AEs were reported by 24.3% of patients and Grade 4 by 6.1% of patients.  
The most common (> 2% of patients) events being dyspnea (3.7%), anemia (5.1%), fatigue (3.5%), asthenia
(2%), UTI (2.3%), hyponatremia (3.1%), and pneumonia (2.6%). The overall incidence of Grade 5 AEs occurring within 30 days of last study drug intake or prior to initiation of non‐protocol therapy was 3.9% (121/3075). Grade 5 AEs were reported in a variety of System Organ Classes (SOCs), and the following events were reported for more than 1 patient: pneumonia (12), death (19),
disease progression (3), myocardial infarction (2), cardiac arrest (5), sepsis (8), sudden death (3),septic shock
(5), respiratory failure (5), lung infection (2),cardiac failure (3), pulmonary embolism (2), pneumonia aspiration (2), respiratory distress (2) and pulmonary sepsis (2),
cerebrovascular accident (2), ischemic stroke (2), cerebral hemorrhage (2), hepatic failure (2) and embolism
(2). Eleven events were considered by the investigator as treatment related; one case each of constrictive pericarditis, cardiac failure, pneumonia, death, intestinal perforation, TEN, general physical condition abnormal, pulmonary hypertension, respiratory failure, hepatic failure and sepsis.
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hepatic impairment

No dedicated studies of atezolizumab have been conducted in patients with hepatic impairment. Ina popPK analysis, there were no clinically important differences in the clearance of atezolizumab between patients withmild hepatic impairment (bilirubin ≤ ULN andAST > ULN or bilirubin > 1.0 to 1.5 X ULN and any AST [n =
71]) and normal hepatic function (bilirubin and AST ≤ ULN [n = 401]). No data were available in patientswith either moderate or severe hepatic impairment. The effect of moderate (bilirubin > 1.5 to 3 × ULN and any AST)orsevere(bilirubin> 3 × ULN and anyAST) hepatic impairment on the pharmacokinetics of atezolizumab is unknown. Hepatic impairment was defined by the National CancerInstitute criteria of hepatic dysfunction
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renal impairment

No dedicated studies of atezolizumab have been conducted in patients with renal impairment. In a popPK
analysis, no clinically important differences in the clearance of atezolizumab were found in patients with mild (eGFR 60‐89 mL/min/1.73 m2; n = 208) or moderate (eGFR 30‐59 mL/min/1.73 m2; n = 116) renal impairment compared with patientswith normalrenal function (eGFR ≥ 90 mL/min/1.73 m2; n = 140). Only a few patients had severe renal impairment (eGFR 15‐29 mL/min/1.73 m2; n = 8).
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concomitant use with other medications

Because antibodies are cleared principally by catabolism (i.e., cleavage to small peptides and amino acids),
atezolizumab is not expected to show pharmacokinetic interactions with other drugs, and is therefore not expected to interact with other drugs through protein binding, effects on cytochrome P450 activity, renal excretion or competition for common drug transporter proteins.  
Please refer to the atezolizumab IB for additional details.  
Bevacizumab is classified as an Anti‐VEGF Monoclonal Antibody and a Vascular Endothelial Growth Factor
(VEGF) Inhibitor. Bevacizumab is a recombinant, humanized monoclonal immunoglobulin G1 (IgG1) antibody which binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors, Flt‐1 and KDR. VEGF binding initiates angiogenesis (endothelial proliferation and the formation of new blood vessels). The inhibition of microvascular growth is believed to retard the growth of all tissues (including metastatic tissue).  
The initial development program included studies sponsored and conducted by Genentech Inc. and F. Hoffmann‐La Roche Ltd., as well as the National Cancer Institute (NCI) in the United States. On the basis of these studies, bevacizumab received Marketing Authorization in > 100 countries (including the United States and the European Union) for the treatment of patients with metastatic carcinoma of the colon or rectum. Subsequently, Marketing Authorization has also been received worldwide for other indications (e.g. unresectable, locally advanced, recurrent or metastatic non‐squamous NSCLC; locally recurrent or metastatic breast cancer; advanced and/or metastatic renal cell carcinoma; epithelial ovarian, fallopian tube or primary peritoneal cancer; malignant glioma [World Health Organization; WHOGrade IV glioblastoma],
and cervical cancer).
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5.2.1 preclinical

Bevacizumab is a recombinant humanized anti‐VEGF monoclonal antibody composed of human IgG1 framework regions and antigen‐binding, complementarity‐determining regions from a murine monoclonal antibody (muMAb VEGF A4.6.1). Approximately 93% of the amino‐acid sequence, including most of the antibody framework, is derived from human IgG1, and approximately 7% of the sequence is derived from the murine antibody
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pregnancy

Angiogenesis has been shown to be critically important to fetal development. The inhibition of angiogenesis following administration of bevacizumab could result in an adverse outcome of pregnancy.  
There are no adequate and well‐controlled studies in pregnant women. IgGs are known to cross the placental barrier, and bevacizumab may inhibit angiogenesis in the fetus. In the post‐ marketing setting, cases of fetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed. Therefore, bevacizumab should not be used during pregnancy. In women of childbearing potential and male partners of such women, appropriate contraceptive measures should be used during bevacizumab therapy.  
Based on pharmacokinetic considerations, contraceptive measuresshould be used for at least 6 months following the last dose of bevacizumab.  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 28
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pharmacokinetics

The pharmacokinetics of bevacizumab waswell described by a biphasic concentration‐time profile that exhibits dose–proportional exposure (two‐compartment, linear, PK model) at doses of 1 mg/kg/week to 10 mg/kg/week, which includes the clinical doses of 2.5 to 5.0 mg/kg/week administered at 2‐ to 3‐week intervals (Q2W‐Q3W). For a typical patient, bevacizumab pharmacokinetics was characterized with a slow clearance (Cl = 0.22 L/day) and a volume of distribution that approximates the plasma volume (Vd = 3.28 L), resulting in long systemic persistence (elimination half‐ life [t1/2,elimination] of 3‐4 weeks) with a predicted time to steady state of 100 days.  
The pharmacokinetics of bevacizumab in pediatric patients was characterized using a comprehensive PopPK
model that was developed using data from 152 patients across four pediatric studies who were administered doses of 5 to 15 mg/kg every 2 to 3 weeks. Generally; pediatric pharmacokinetics was comparable to adult pharmacokinetics when normalized by body weight with a slow CL, a limited Vd, and a long serum terminal half‐life (t1/2; approximately 21 days). On the basis of model predictions, bevacizumab exposure trended lower as body weight decreased. No additional PK‐associated covariates with significant impact on bevacizumab exposure were observed for the pediatric patients other than those already known for adult patients (body weight, sex, and albumin levels) with primary CNS tumors found to be a specific covariate in the pediatric PopPK model. Age was not associated with bevacizumabpharmacokinetics when body weight wastakeninto account.
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concomitant therapy

The co‐administration of bevacizumab with various chemotherapeutic and other anti‐cancer agents resulted in similar values of CL and volume of distribution for the central compartment (Vc) for bevacizumab. The peripheral volume (Vp) was found to be smaller when bevacizumab was administered alone or with interferon (IFN) alfa‐2a compared with bevacizumab administered with other chemotherapeutic agents. Those results suggest that exposure to bevacizumab is not affected by concomitant dosing with doxorubicin, capecitabine, 5‐fluorouracil (5‐FU)/leucovorin (LV), 5‐
FU/LV/irinotecan (IFL), erlotinib, carboplatin, cisplatin, oxaliplatin; paclitaxel, gemcitabine, temozolomide
(TMZ), or IFN alfa‐2a.  
Accumulating data do not suggest that bevacizumab affects disposition of anti‐neoplastic agents.
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hepatic and renal impairment

The safety and efficacy of bevacizumab has not been studied in patients with renal or with hepatic impairment
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safety

Clinical experience with bevacizumab has shown significant AEs associated with its use. Patients particularly vulnerable to significant AEs, such as those with recent pulmonary hemorrhage/hemoptysis or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding, have been excluded from the study. Study patients will be assessed by prior medical history, physical examinations, monitoring of vital signs, performance statusevaluations, hematology and chemistry laboratory testing, and urinalyses.  
•Hypertension will be monitored through routine evaluation of blood pressure prior to each bevacizumab treatment. Optimal control of blood pressure according to standard public health guidelines is recommended for patients on treatment with or without bevacizumab. - Proteinuria will be monitored by urine protein:creatinine (UPC) ratio or dipstick at least every 6 weeks. - If patients on treatment with bevacizumab require elective major surgery, it is recommended that bevacizumab be held for 4‐8 weeks prior to the surgical procedure. Patients undergoing a major surgical procedure should not begin/restart bevacizumab until 4 weeks after that procedure (in the case of high risk procedures such as liver resection, thoracotomy, or neurosurgery, it is recommended that chemotherapy be restarted no earlier than 6 week and bevacizumab no earlier than 8 week after surgery Hypertension: An increased incidence of hypertension (all grades) of up to 42.1% has been observed in patients treatedwith bevacizumab compared to up to 14% in the comparator arm. In clinical trials across all indications the overall incidence of NCI‐CTC Grade 3 and 4 hypertension in patients receiving bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of bevacizumab‐treated patients, compared to up to 0.2% of patients treated with the same chemotherapy alone. Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal. The risk of bevacizumab‐associated hypertension did not correlate with the patients' baseline characteristics, underlying disease or concomitant therapy.  
Analyses of the clinical safety data suggest that the occurrence of hypertension with bevacizumab therapy is likely to be dose‐dependent. Monitor blood pressure every two to three weeks during treatment with bevacizumab. Treat with appropriate anti‐hypertensives such as angiotensin‐ converting enzyme inhibitors, diuretics and calcium‐channel blockers and monitor blood pressure regularly.  
Continue to monitor blood pressure at regular intervals in patients with bevacizumab ‐ induced or –
exacerbated hypertension after discontinuation of bevacizumab.  
Temporary interruption of bevacizumab therapy is recommended in patients with hypertension requiring medical therapy until adequate control is achieved. Bevacizumab should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy. Bevacizumabshould be permanently discontinued in patients who develop hypertensive crisis or hypertensive encephalopathy.  
Proteinuria: In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients receiving bevacizumab. Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome. Grade 3 proteinuria was reported in up to 8.1% of treated patients.  
Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. In the event of Grade 4 proteinuria Bevacizumab treatment should be permanently discontinued. The proteinuria seen in bevacizumab clinical trials wasnot associated with renal impairment and rarely required permanent discontinuation of bevacizumabtherapy.  
Analyses of the clinical safety data suggest that the occurrence of proteinuria with bevacizumab therapy is likely to be dose‐dependent. Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with bevacizumab. There is evidence suggesting that Grade 1 proteinuria may be related to bevacizumab dose. Testing for proteinuria is recommended prior to start of bevacizumab therapy. In most clinical studies urine protein levels of
≥2g/24h led to the holding of bevacizumab until recovery to <2g/24h.  
Wound healing complications: Bevacizumab may adversely affect the wound healing process. Serious wound healing complications with a fatal outcome have been reported. Necrotizing fasciitis including fatal cases, has rarely been reported in patients treated with Bevacizumab; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Bevacizumab therapy should be discontinued in patients who develop necrotizing fasciitis, and appropriate treatment should be promptly initiated. As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days prior to starting bevacizumab treatment were excluded from participation in Phase III
trials.  
Hemorrhage: In clinical trials across all indications the overall incidence of NCI‐CTC Grade 3‐5 bleeding events ranged from 0.4% to 6.9% in bevacizumab‐treated patients, compared to 0 to 4.5% of patients in the chemotherapy control group. The hemorrhagic events that have been observed in bevacizumab clinical studies were predominantly tumor‐ associated hemorrhage (see below) and minor mucocutaneous hemorrhage (e.g.epistaxis). Bevacizumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding during Bevacizumab therapy.  
Tumor‐Associated Hemorrhage: Major or massive pulmonary hemorrhage or hemoptysis has been observed primarily in patients with NSCLC. Possible risk factors include squamous cell histology, treatment with anti‐rheumatic/anti‐inflammatory drugs, treatment with anticoagulants, prior radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central tumor location and cavitation of tumors prior to or during therapy. The only variables that showed statistically significant correlations with bleeding were bevacizumab therapy and squamous cell histology. Patients with NSCLC
of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent studies, while patients with unknown tumor histology were included. In patients with NSCLC excluding predominant squamous histology, all grade events were seen with a frequency of up to 9% when treatedwith bevacizumab plus chemotherapy compared with 5% in the patients treatedwith chemotherapy alone. Grade 3‐5 events have been observed in up to 2.3% of patients treated with bevacizumab plus chemotherapy as compared with <1% with chemotherapy alone. Major or massive pulmonary hemorrhage/hemoptysis can occur suddenly and up to two thirds of the serious pulmonary hemorrhages resulted in a fatal outcome.  
Patientswith non–small cell lung cancer treatedwith Bevacizumab may be at risk for serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/ haemoptysis (>1/2 teaspoon red blood) should not be treated with Bevacizumab. Of patients experiencing pulmonary hemorrhages requiring medical intervention, many had cavitation and/or necrosis of the tumor, either preexisting or developing during bevacizumab therapy. Patients developing lung cavitation on treatment should be assessed by the treating physician for risk‐benefit.  
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 34 In Study E4599, in which squamous cell carcinoma was excluded, the rate of any type of Grade ≥ 3 hemorrhage was 1.0% in the control arm (carboplatin and paclitaxel) versus 4.1% in the carboplatin and paclitaxel+ bevacizumabarm.  
Brain metastases: The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not been prospectively evaluated in randomized clinical studies. In an exploratory retrospective analysis of data from 13 completed randomized trials in patients with various tumor types, 3 patients out of 91 (3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated with bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In two subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 CNS hemorrhage was reported.  
Posterior Reversible Encephalopathy Syndrome (PRES): PRES is a rare neurologic disorder that can present with the following signs and symptoms (among others): seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. Brain imaging is mandatory to confirm the diagnosis of PRES. Two confirmed cases (0.8%) of PRES have been reported in one clinical study. Symptoms usually resolve or improve within days, although some patients have experienced neurologic sequelae. In patients who develop PRES, treatment of specific symptoms, including control of hypertension, is recommended along with discontinuation of bevacizumab. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known.
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refer to the bevacizumab investigator's

| Agent                                                                                                                                                       | Premedications               | Dose      | Route                   | Schedule   | Cycle length   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|-----------|-------------------------|------------|----------------|
| Atezolizumab                                                                                                                                                | Per institutional            | 1200 mg   | IV over 60 minutes for  | Day 1      | Every 21       |
| practice                                                                                                                                                    | first infusion, and if first | days      |                         |            |                |
| infusion is tolerated all subsequent infusions can be used infused over 30 minutes or per institutional practice                                            |                              |           |                         |            |                |
| Bevacizumab                                                                                                                                                 | Per institutional            | 15 mg/kg* | IV over 90 minutes (1st | Day 1      | Every 21       |
| practice                                                                                                                                                    | infusion), if the first      | days      |                         |            |                |
| infusion is tolerated (2nd infusion) over 60 minutes andif 2nd infusion is tolerated all subsequent infusions over 30 minutes or per institutional practice |                              |           |                         |            |                |
| * The doseofbevacizumabwillbebased on thepatient'sweightatscreeningandwillremainthesamethroughoutthe                                                        |                              |           |                         |            |                |  
* The doseofbevacizumabwillbebased on thepatient'sweightatscreeningandwillremainthesamethroughoutthe study unlessthepatient'sweightchangesby >10%.If weightchanges>10%thendosewill berecalculated based on weighton day oftreatment 6.1 Discontinuation for adverse events If one of the study agents is permanently discontinued related to an adverse event than the study therapy should be discontinued.  
If the atezolizumab or bevacizumab is held for > 12 weeks the patient should discontinued from study therapy (both drugs).  
Patients may continue to receive one study agent if the second agent is temporarily being held for adverse event (i.e. patient can continue to receive bevacizumab if atezolizumab is being held related to adverse event).
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6.2.1 dosemodification and delays

Dosemodification e of atezolizumabisnot permitted. Dosedelaysare permitted for maximumof ≤ 12 weeks.  
If study therapy cannot be resumed > 12 weeks study therapy (both agents) should be discontinued. Reasons for dose delays, the supportive measures taken and the outcomes will be documented in the patient's chart and recorded on the eCRF.  
6.2.2 Management ofimmune related adverse events The management of more common specific adverse events associated with atezolizumab are outlined Adverse events related to immune‐related pulmonary, hepatic, gastrointestinal, endocrine, dermatologic are outline below. The primary management is dose delay, use of prednisone when indicated, and appropriate supportive care.  
Although most immune‐mediated adverse events observed with immunomodulatory agents have been mild and self‐limiting, such events should be recognized early and treated promptly to avoid potential major complications. Atezolizumab should be permanently discontinued in patientswith life‐ threatening immune‐
mediatedadverse events.
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additional information is available in

Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with the administration of atezolizumab. Patients will be assessed for pulmonary signs and symptoms throughout the study and will also have CT scans of the chest performed at every tumor assessment. Management guidelines for pulmonary events are provided in table 1.  
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension  
| Event            | Management                                                                                                                    |                                                                                        |
|------------------|-------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------|
| Pulmonary event, | -                                                                                                                             | Continueatezolizumab andmonitor closely.                                               |
| Grade 1          | -                                                                                                                             | Re‐evaluateon serial imaging.                                                          |
| -                | Consider patientreferralto pulmonary specialist.                                                                              |                                                                                        |
| Pulmonary event, | -                                                                                                                             | Withholdatezolizumab forup to 12 weeks after eventonset.a                              |
| Grade 2          | -                                                                                                                             | Referpatienttopulmonaryandinfectiousdiseasespecialistsandconsider  bronchoscopy orBAL. |
| -                | Initiate treatmentwith 1‐2 mg/kg/day oralprednisoneorequivalent.                                                              |                                                                                        |
| -                | If eventresolvestoGrade 1 or better,resumeatezolizumab.b                                                                      |                                                                                        |
| -                | If eventdoes notresolvetoGrade 1 or better whilewithholding atezolizumab for > 12 weeks, permanently discontinue atezolizumab |                                                                                        |
| -                | For recurrentevents,treatas a Grade 3 or 4 event.                                                                             |                                                                                        |  
| Pulmonary event,                                                                               | -                                                                                                              | Permanently discontinueatezolizumab   |
|------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|---------------------------------------|
| Grade 3 or 4                                                                                   | -                                                                                                              | Bronchoscopyor BALisrecommended.      |
| -                                                                                              | Initiate treatmentwith 1‐2mg/kg/day oralprednisoneor equivalent.                                               |                                       |
| -                                                                                              | If eventdoes notimprovewithin 48hoursafterinitiatingcorticosteroids,consider  addinganimmunosuppressive agent. |                                       |
| -                                                                                              | If eventresolvestoGrade1 or better,taper corticosteroidsover ≥1 month.                                         |                                       |
| BAL=bronchoscopic alveolarlavage; a Atezolizumabmay bewithheld fora maximumof ≤12 weekstoallow |                                                                                                                |                                       |  
BAL=bronchoscopic alveolarlavage; a Atezolizumabmay bewithheld fora maximumof ≤12 weekstoallow for corticosteroids(if initiated)tobereducedto ≤10 mg/day oralprednisoneor equivalent.Ifstudy therapyis delayed > 12 weeks then studytherapy (bothagents) should be discontinued; b If corticosteroids have been initiated,theymustbetapered over ≥1 month to ≤10 mg/day oral prednisoneor equivalentbefore atezolizumab canbe resumed
3 protocol synopsis and research
hepatic events

Immune‐related hepatitis has been associated with the administration of atezolizumab. Eligible patients must have adequate liver function, as manifested by measurements of total bilirubin and hepatic transaminases. Liver function will be monitored throughout study treatment. Management guidelines for hepatic events are provided in table 2. Patients with right upper‐quadrant abdominal pain and/or unexplained nausea or vomiting should have LFTs performed immediately and reviewedbefore administration of the next dose of study drug.  
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic etiologies should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, and biliary tree should be performed to rule out neoplastic or other causes for the increased LFTs  
| Event          | Management                                                                                                                                                                                                                                                                                                                                                                                                              |                                                         |
|----------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|
| Hepatic event, | -                                                                                                                                                                                                                                                                                                                                                                                                                       | Continueatezolizumab.                                   |
| Grade 1        | -                                                                                                                                                                                                                                                                                                                                                                                                                       | Monitor LFTs until valuesresolveto within normallimits. |
| Hepatic event, | All events:                                                                                                                                                                                                                                                                                                                                                                                                             |                                                         |
| Grade 2        | Monitor LFTs more frequently until return to baseline values. Events of > 5 days' duration: - Withhold atezolizumabforup to 12 weeksaftereventonset.a  - Initiate treatmentwith 1‐2 mg/kg/dayoral prednisoneor  equivalent. - If eventresolvestoGrade 1 orbetter,resume  atezolizumab.b  - If eventdoes notresolvetoGrade 1 orbetter whilewithholding  atezolizumab for > 12 weeks,permanently discontinue atezolizumab |                                                         |  
  
- Permanently discontinueatezolizumab   
a Atezolizumabmay be withheld for a maximumof ≤ 12 weeks to allow for corticosteroids(if initiated)to be reduced to ≤10 mg/day oral prednisoneorequivalent.Ifstudytherapy is delayed >12weeksthenstudytherapy
(both agents) should be discontinued; b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisoneor equivalentbeforeatezolizumabcan beresumed
3 protocol synopsis and research
gastrointestinal events

Immune‐related colitis has been associated with the administration of atezolizumab. Management guidelines for diarrhea or colitis are provided in Table 3.  
All events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies. For events of significant duration or magnitude or associated with signs of systemic inflammation or acute‐
phase reactants (e.g., increased CRP, platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 3 to 5 specimens for standard paraffin block to checkfor inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  
| Event                         | Management                                                                                                                                     |                                                           |
|-------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------|
| -                             | Continueatezolizumab.                                                                                                                          |                                                           |
| Diarrhea or  colitis, Grade 1 | -                                                                                                                                              | Initiate symptomatictreatment.                            |
| -                             | Endoscopy isrecommended ifsymptomspersistfor > 7days.                                                                                          |                                                           |
| -                             | Monitor closely.                                                                                                                               |                                                           |
| -                             | Withholdatezolizumab forup to 12 weeks after eventonset.a                                                                                      |                                                           |
| Diarrhea or  colitis, Grade 2 | -                                                                                                                                              | Initiate symptomatictreatment.                            |
| -                             | PatientreferraltoGI specialistisrecommended.                                                                                                   |                                                           |
| -                             | Forrecurrentevents or eventsthatpersist > 5 days, initiatetreatmentwith 1‐  2 mg/kg/day oral prednisoneorequivalent.                           |                                                           |
| -                             | If eventresolvestoGrade 1 or better,resumeatezolizumab.b                                                                                       |                                                           |
| -                             | If eventdoes notresolvetoGrade 1 or better whilewithholding atezolizumab for > 12 weeks, permanently discontinue atezolizumab                  |                                                           |
| Diarrhea or  colitis, Grade 3 | -                                                                                                                                              | Withholdatezolizumab forup to 12 weeks after eventonset.a |
| -                             | Referpatienttogastrointestinalspecialistforevaluationand  confirmatorybiopsy.                                                                  |                                                           |
| -                             | Initiatetreatmentwith1‐2 mg/kg/day IVmethylprednisoloneor equivalent  and convertto 1‐2 mg/kg/day oralprednisoneor equivalentupon improvement. |                                                           |
| -                             | If eventresolvestoGrade 1 or better,resumeatezolizumab.b                                                                                       |                                                           |
| -                             | If eventdoes notresolvetoGrade 1 or better whilewithholding atezolizumab for > 12 weeks, permanently discontinue atezolizumab                  |                                                           |  
Table 3: Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)  
| -                             | Permanently discontinueatezolizumab                                                                                                         |                                                                              |
|-------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|
| Diarrhea or  colitis, Grade 4 | -                                                                                                                                           | Referpatienttogastrointestinalspecialistforevaluation andconfirmationbiopsy. |
| -                             | Initiatetreatmentwith1‐2mg/kg/day IVmethylprednisoloneor equivalentand  convertto1‐2 mg/kg/day oral prednisoneor equivalentuponimprovement. |                                                                              |
| -                             | If eventdoes notimprovewithin 48hoursafterinitiatingcorticosteroids,  consideradding an immunosuppressiveagent.                             |                                                                              |
| -                             | If eventresolvestoGrade1 orbetter,taper corticosteroidsover ≥1 month.                                                                       |                                                                              |  
a Atezolizumab maybe withheld for a maximum of ≤ 12 weeks to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. If study therapy is delayed > 12 weeks then study therapy (both agents) should be discontinued; b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed
3 protocol synopsis and research
endocrine events

Thyroid disorders, adrenal insufficiency, diabetes mellitus and pituitary disorders have been associated with the administration of atezolizumab. Management guidelines for endocrine events are provided in table 4. Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, constipation, or mental status changes should be investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies, as well as for hyponatremia or hyperkalemia. The patient should be referred to an endocrinologist if an endocrinopathy is suspected. Thyroid‐ stimulating hormone (TSH) and free T3 and T4 levels should be measured to determine whether thyroid abnormalities are present. Pituitary hormone levels and function tests (e.g. TSH, growth hormone, luteinizing hormone, follicle‐ stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.  
| Event                                                            | Management                                                                    |                                                    |
|------------------------------------------------------------------|-------------------------------------------------------------------------------|----------------------------------------------------|
| -                                                                | Continueatezolizumab.                                                         |                                                    |
| Asymptomatic  hypothyroidism                                     | -                                                                             | Initiate treatmentwith thyroid replacementhormone. |
| -                                                                | Monitor TSH                                                                   |                                                    |
| Symptomatic hypothyroidism                                       | -                                                                             | Withholdatezolizumab.                              |
| -                                                                | Initiate treatmentwith thyroid replacementhormone.                            |                                                    |
| -                                                                | Monitor TSHweekly.                                                            |                                                    |
| -                                                                | Consider patientreferralto endocrinologist.                                   |                                                    |
| -                                                                | Resumeatezolizumabwhen symptomsarecontrolledand  thyroid functionisimproving. |                                                    |
| Asymptomatic                                                     | TSH ≥ 0.1 mU/L and < 0.5 mU/L:                                                |                                                    |
| hyperthyroidism                                                  | -                                                                             | Continueatezolizumab.                              |
| -                                                                | Monitor TSHevery 4 weeks.                                                     |                                                    |
| TSH < 0.1mU/L - Follow guidelinesforsymptomatic hyperthyroidism. |                                                                               |                                                    |
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table 4 management guidelines for

| Symptomatic hyperthyroidism   | -                                                                                      | Withholdatezolizumab.   |
|-------------------------------|----------------------------------------------------------------------------------------|-------------------------|
| -                             | Initiatetreatmentwithanti‐thyroiddrugsuchasmethimazoleor  carbimazoleas needed.        |                         |
| -                             | Consider patientreferralto endocrinologist.                                            |                         |
| -                             | Resumeatezolizumabwhensymptomsarecontrolledand  thyroid functionisimproving.           |                         |
| -                             | Permanentlydiscontinueatezolizumabforlife‐threatening  immune‐related hyperthyroidism. |                         |  
| Symptomatic adrenal  insufficiency,   | -                                                                                                                                                                     | Withholdatezolizumab forup to 12 weeks afterevent a   |
|---------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|
| Grade 2‐4                             | onset.                                                                                                                                                                |                                                       |
| -                                     | Refer patientto endocrinologist.                                                                                                                                      |                                                       |
| -                                     | Performappropriateimaging.                                                                                                                                            |                                                       |
| -                                     | Initiate treatment with 1‐2 mg/kg/day IV methylprednisolone or  equivalent and convert to 1‐2 mg/kg/day oral prednisone or  equivalent uponimprovement.               |                                                       |
| -                                     | If eventresolvestoGrade1 orbetter andpatientisstableon  replacementtherapy,resumeatezolizumab.b                                                                       |                                                       |
| -                                     | If eventdoes notresolvetoGrade 1 or better or patientis  notstable on replacementtherapywhilewithholding atezolizumabfor>12weeks,permanentlydiscontinue  atezolizumab |                                                       |
| Hyperglycemia Grade 1 or 2            | -                                                                                                                                                                     | Continueatezolizumab.                                 |
| -                                     | Initiate treatmentwith insulinif needed.                                                                                                                              |                                                       |
| -                                     | Monitor forglucosecontrol.                                                                                                                                            |                                                       |
| Hyperglycemia, Grade 3 or 4           | -                                                                                                                                                                     | Withholdatezolizumab.                                 |
| -                                     | Initiate treatmentwith insulin.                                                                                                                                       |                                                       |
| -                                     | Monitor forglucosecontrol.                                                                                                                                            |                                                       |
| -                                     | Resumeatezolizumabwhensymptomsresolveandglucoselevels  arestable.                                                                                                     |                                                       |
| Hyperglycemia, Grade 3 or 4           | -                                                                                                                                                                     | Withholdatezolizumab.                                 |
| -                                     | Initiate treatmentwith insulin.                                                                                                                                       |                                                       |
| -                                     | Monitor forglucosecontrol.                                                                                                                                            |                                                       |
| -                                     | Resumeatezolizumabwhensymptomsresolveandglucoselevels  arestable.                                                                                                     |                                                       |  
| Hypophysitis (pan‐          | -                                                                                                                                                 | Withholdatezolizumab forup to 12 weeks after eventonset. a   |
|-----------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|
| hypopituitarism), Grade 2‐3 | -                                                                                                                                                 | Refer patientto endocrinologist.                             |
| -                           | Performbrain MRI(pituitaryprotocol).                                                                                                              |                                                              |
| -                           | Initiatetreatmentwith1‐2mg/kg/day IVmethylprednisoloneor  equivalent and convert to 1‐2 mg/kg/dayoral prednisone or  equivalent uponimprovement.a |                                                              |
| -                           | Initiatehormonereplacementtherapyif clinically indicated.                                                                                         |                                                              |
| -                           | If eventresolvestoGrade1 or better,resumeatezolizumab. b                                                                                          |                                                              |
| -                           | If eventdoes notresolve toGrade 1 or better whilewithholding  atezolizumab for>12 weeks,permanently discontinue atezolizumab                      |                                                              |
| -                           | For recurrenthypophysitis,treatas a Grade4 event.                                                                                                 |                                                              |  
MRI = magnetic resonance imaging; TSH = thyroid‐stimulating hormone, IV = intravenous a Atezolizumab may be withheld for a maximum of ≤12 weeks to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. If study therapy is delayed > 12 weeks then study therapy (both agents) should be discontinued b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed
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dermatologic events

Treatment‐emergent rash has been associated with atezolizumab. The majority of cases of rash were mild in severity and self‐limited, with or without pruritus. A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should be considered unless contraindicated. Management guidelines for dermatologic events are provided in table 5.  
| Event                                                                                                                      | Management                                                                                                                             |                                                                                                    |
|----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|
| -                                                                                                                          | Continueatezolizumab.                                                                                                                  |                                                                                                    |
| Dermatologicevent, Grade 1 (<10%BSA)                                                                                       | -                                                                                                                                      | Considertreatmentwithtopical corticosteroidsand/orothersymptomatic  therapy (e.g.,antihistamines). |
| Dermatologic event,                                                                                                        | -                                                                                                                                      | Continueatezolizumab.                                                                              |
| Grade 2 (10‐30%BSA)                                                                                                        | -                                                                                                                                      | Consider patientreferralto dermatologist.                                                          |
| -                                                                                                                          | Initiate treatmentwith topical corticosteroids.                                                                                        |                                                                                                    |
| -                                                                                                                          | Consider treatmentwith higher‐potency topicalcorticosteroidsif event  does notimprove                                                  |                                                                                                    |
| Dermatologic event,                                                                                                        | -                                                                                                                                      | Withholdatezolizumab forup to 12 weeks after eventonset.a                                          |
| Grade 3 (>30% BSA)                                                                                                         | -                                                                                                                                      | Refer patientto dermatologist.                                                                     |
| -                                                                                                                          | Initiate treatmentwith 10 mg/dayoral prednisoneor equivalent, increasingdoseto1‐2mg/kg/day if eventdoes notimprovewithin 48‐72  hours. |                                                                                                    |
| -                                                                                                                          | If eventresolvestoGrade 1 or better,resumeatezolizumab.b                                                                               |                                                                                                    |
| -                                                                                                                          | If eventdoes notresolve toGrade 1 or better whilewithholding  atezolizumab for > 12 weeks,permanently discontinue atezolizumab         |                                                                                                    |
| Dermatologic                                                                                                               | -                                                                                                                                      | Permanentlydiscontinueatezolizumabandcontactprincipal                                              |
| event, Grade 4                                                                                                             | investigator                                                                                                                           |                                                                                                    |
| a Atezolizumab may be withheld for a maximum of 12 weeks to allow for corticosteroids (if initiated) to be reduced to ≤ 10 |                                                                                                                                        |                                                                                                    |  
Table 5: Management Guidelines for Dermatologic Events a Atezolizumab may be withheld for a maximum of 12 weeks to allow for corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. If study therapy is delayed > 12 weeks then study therapy (both agents) should be discontinued; b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed
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6.3.2 management of bevacizumab-related adverse

The management of more common specific adverse events associated with bevacizumab are outlined below. To summarize, bevacizumab should be held temporarily or permanently discontinued in patients (as per the clinical judgment of the treating physician) experiencing any of the following events:
- Febrile grade 4 neutropenia and/or grade 4 thrombocytopenia regardless of the  
relationship to treatment (hold treatmenttemporarily)
- Grade ≥ 2 fistula (hold temporarily or permanently discontinue)
- GI perforation (permanentlydiscontinue)
- Major surgery or wound healing complications (hold temporarily or permanently discontinue)
- Medically significant hypertension not controlled with antihypertensive therapy, hypertensive crisis or hypertensive encephalopathy (permanentlydiscontinue)
- Grade ≥ 3 left ventricular dysfunction (CHF) (permanentlydiscontinue)
- Nephrotic syndrome (permanentlydiscontinue)
- Arterial thrombosis/embolism (any grade) (permanently discontinue) - Grade ≥ 3 venous thrombosis/embolism (hold temporarily orpermanently
discontinue for grade 4)
- CNS bleeding (any grade) or ≥ grade 3 bleeding of any kind(permanently discontinue)  
- Grade ≥ 2 hemoptysis (permanently discontinue)
- Hypersensitivity/allergic reactions related to bevacizumab (permanently discontinue)
- PRES (or RPLS) (permanently discontinue)
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additional information is available in

required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 48  
| NCI CTCAE  v. 4.03                                                                                       | Urinalysis                                                                                                                                                                                                                                       | Treatment Action                                         |
|----------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------|
| Grade 1                                                                                                  | Urine protein creatinine                                                                                                                                                                                                                         | No bevacizumab dose modification                         |
| ratio ≤ 1.0                                                                                              |                                                                                                                                                                                                                                                  |                                                          |
| Grade 2                                                                                                  | Urine protein creatinine                                                                                                                                                                                                                         | For urine protein/creatinine ratio > 1.0 to <2.0 monitor |
| ratio> 1.0 to 3.4)                                                                                       | urine protein/creatinine ratio with each cycle Suspend bevacizumab for urine protein /creatinine  ratio ≥ 2.0. Resume bevacizumab when urine  protein/creatinine ratio is < 2. Permanently  discontinue study therapy if therapy held > 12 weeks |                                                          |
| Grade 3                                                                                                  | Urine protein/creatinine                                                                                                                                                                                                                         | Suspend bevacizumab.                                     |
| ratio ≥3.5                                                                                               | Resumebevacizumabwhenurine/proteincreatinine  ratio < 2.0                                                                                                                                                                                        |                                                          |
| Nephrotic syndrome                                                                                       | Permanently discontinue bevacizumab                                                                                                                                                                                                              |                                                          |
| UPC ratio ofspoturineis an estimationofthe24 urineprotein excretion. A UPC ratioof 1 isroughlyequivalent |                                                                                                                                                                                                                                                  |                                                          |  
UPC ratio ofspoturineis an estimationofthe24 urineprotein excretion. A UPC ratioof 1 isroughlyequivalent  
to a 24‐hoururineprotein of 1 g.UPC ratio is calculated usingofthefollowing formulas:  
[urineprotein]/[urinecreatinine]‐if both proteinand creatinineare reportedinmg/dL [(urineprotein) x 0.0088]/[urinecreatinine]ifurine creatinineisreported in mmol/L.  
Bevacizumab maybe held for a maximum of 12 weeks. If study therapy delayed> 12 weeks then study therapy (both agents) shouldbe discontinued.
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arterial thrombosis/embolism

Bevacizumab should be discontinued in patients who develop arterial thromboembolic events.
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venous thrombosis/embolism

Bevacizumab should be held in patients developing a grade 3 thrombosis/embolism. Bevacizumab may be resumed once the patient is adequately anti‐coagulated and on a stable level of anticoagulation for at least 2 weeks prior to restarting study drug treatment. Patients on heparin treatment should have an aPTT
between 1.5‐2.5 x ULN (or patient value before starting heparin treatment). Patients on coumadin derivativesshould have an INR between 2.0 and 3.0 assessed in two consecutive measurements 1‐4 days apart. Patients on full dose low molecular weight heparins should receive the appropriate dose based on the weight of the patient according to package insert.  
An increased risk of venous thromboembolic events and bleeding in patients receiving anti‐ coagulation therapy after first venous thromboembolic event while receiving bevacizumab has been observed.  
In the event of recurrent grade 3 thrombosis/embolism, the patient should be discontinued from bevacizumab.  
Bevacizumab should be discontinued in patients with life‐threatening (grade 4) pulmonary embolism.  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 50
3 protocol synopsis and research
hemorrhage

An increased incidence of bleeding events was observed in study patients treated with bevacizumab as compared to control treatment arms. The hemorrhagic events observed in bevacizumab studies were predominantly tumour‐associated hemorrhage and minor mucocutaneous hemorrhage.  
Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS hemorrhage in such patient has not been prospectively evaluated in randomized clinical studies.  
Bevacizumab should be permanently discontinued for:  
- grade 3 or 4 bleeding of any kind
- any grade of CNS bleeding. Patients should be monitored for signs and symptoms of CNS bleeding\
- grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL bright red blood per episode).
If hemorrhagic complications occur in patients on full dose anti‐coagulation therapy, permanently discontinue bevacizumab treatment and follow guidelines of the treating institution. Standard procedures such as antagonisation with protamin or vitamin K and infusion of vitamin K dependent factors should be considered dependent on the severity of the bleeding
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posterior reversible encephalopathy syndrome (pres/rpls)

There have been rare reports of patients treated with bevacizumab developing signs and symptoms that are consistent with PRES, a rare neurological disorder. PRES is also known as reversible posterior leukoencephalopathy syndrome or RPLS). PRES can present with following signs and symptoms among others:
seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES,
treatment of specific symptoms including control of hypertension is recommended along with discontinuation of bevacizumab. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES is not known. Adequate brain imaging using MRI must be performed as a follow‐up measurement for patients withPRES.
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gastrointestinal perforation

Bevacizumab should be permanently discontinued in patients who develop GI perforation.  
Fistula Bevacizumab use has been associated with serious cases of fistulae including events resulting in death.  
Fistulae within the GI tract or GI tract and skin are common in patients with mCRC and ovarian cancer, but are uncommon or rare in other indications. Other fistulae (e.g. tracheoesophageal, bronchopleural, urogenital, biliary) have been reported uncommonly in bevacizumab clinical trials patients and in post‐
marketingreports.  
1. Temporarily discontinue bevacizumab in patients with grade 2 or 3 non‐tracheoesophageal fistula until resolution to ≤ grade 1.  
2. Permanently discontinue bevacizumab in patients with tracheoesophageal fistula or any grade 4fistula.  
Limited information is available on the continued use of bevacizumab in patients with other fistulae. In cases of internal fistula not arising in the GI tract, discontinuation of bevacizumab should be considered.
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wound healing complications

In patients who experience wound healing complications during bevacizumab treatment, bevacizumab should be withheld until the wound is fully healed. If the wound does not fully heal despite withholding treatment, should be permanentlydiscontinued.  
Bevacizumab therapy should be withheld for an interval of at least two half‐lives (approximately six weeks)
before conducting major elective surgery. Emergency surgery should be performed as appropriate without delay after a careful risk‐benefit assessment.
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hypertension

In most cases hypertension is controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient. Bevacizumab should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy.
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congestive heart failure (chf)

Bevacizumab should be permanently discontinued in patients with ≥ grade 3 CHF.
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6.4 concomitant medications

Use of the following concomitant therapies is prohibited as described below:
1. Concomitant therapy intended for the treatment of cancer (including, but not limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), whether health authority‐approved or experimental, is prohibited during study treatment, until the patient has discontinued study treatment 2. Investigational therapy (other than protocol‐mandated study treatment) is prohibited within 14 days prior to initiation of study treatment and during studytreatment.  
3. Live, attenuated vaccines are prohibited within 4 weeks prior to initiation of study treatment, during treatment with atezolizumab, and for 5 months after the last dose of atezolizumab.  
4. Systemic immunostimulatory agents (including, but not limited to, interferons and IL 2) are prohibited within 4 weeks or five half‐lives of the drug (whichever is longer) prior to initiation of study treatment and during study treatment because these agents could potentially increase the risk for autoimmune conditions when given in combination with atezolizumab.  
5. Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited during study treatment because these agents could potentially alter the efficacy and safetyof atezolizumab.
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6.5 rationale for selection of

Atezolizumab will be administered at a fixed dose of 1200 mg every 3 weeks (1200 mg on Day 1 of each 21‐
day cycle), which is the approved dosage for atezolizumab (see U.S. Package Insert). Bevacizumab will be administered at 15 mg/kg every 3 weeks which is the approved dose for bevacizumab (see US package insert). The doses and schedule of bevacizumab and atezolizumab were investigated in the phase 3 trial in combination with carboplatin and paclitaxel which lead to FDA approval of carboplatin, paclitaxel, bevacizumab and atezolizumab
3 protocol synopsis and research
7 rational for translational medicine

The translational medicine researchproposed below representsideas based upon the state of the field to date.  
However, the exact correlative research that will be done may be modified based upon the best science at the time these assays are ready to be performed. The specific cell surface markers, genes, and proteins that may be assayed for are suggested below, but as the immune checkpoint and specifically knowledge around the PD‐1/PD‐L1 axis expands in the upcoming years, these specifics may be modified to provide the most useful data. At this time, we are capable of conducting all proposed assays, but external collaborations would be welcome. Given the small sample size of the trial the proposed analyses will be considered exploratory.
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tumor samples

Pre‐treatment tumor samples ≤ 60 days after disease progression on osimertinib and before day 1 of study therapy (if available) will be used. There are no specific requirements associated with the type of biopsy. IHC
for expression of proteins that may be associated with sensitivity or resistance to atezolizumab, including but not limited to immune cell populations including CD3, CD4, CD8, Treg, Th17 T‐cells and monocyte/macrophage and neutrophil populations, as well as immune and tumor cell expression of PD‐1, and PD‐L1 and PD‐L2, respectively. In addition, if sufficient tumor tissue exists, we will isolate tumor‐derived RNA and/or DNA for downstream analyses. While NGS analyses may not be possible due to input limitations, focused RT‐PCR or ddPCR assays may be employed to evaluate specific gene expression levels or known mutations orindels.
3 protocol synopsis and research
circulating immune cell analysis

Two fifteen color polychromatic flow cytometry panels will be used to analyze changes in the immune cell subtypes that are expected to be altered by treatment (please see lab manual for additional details). The 13‐
color base panelstoidentify immune cell types andrelatedmarkersare listed in Table 7 (lymphoid) and Table 8 (myeloid). The lymphoid panel focuses on T‐cell activation, maturation, regulation, and exhaustion. The myeloid panel focuses on myeloid derived suppressor cells (MDSC), M1/M2 polarization, and dendritic cells (DC, pDC). The markersincluded in each respective panel have been reported to be of value in the context of prognostic or predictive immune markers in cancer studies.24‐26 While the majority of immune markers reported are associated with the tumor microenvironment, measurement of peripheral MDSCs has been associated with progression free survival in the context of neoadjuvant ipilimumab therapy for melanoma.  
The two additional markers for eachpanel are included to include novel markersbased on literature current at the time of funding as well as scientific data supporting the use for each additional marker. Data will be analyzed using novel computational methods developed at Duke that can be used to identify multi‐
dimensional populations and evaluate changes in these populations across treatment.27,28 Patient samples will be analyzed at baseline (cycle 1 day 1), at time of first imaging, and at the time of disease progression.  
All immune cell correlates will be performed in collaboration with the Duke Immune Profiling Core (DIPC)
laboratory under the direction of Dr. Kent J. Weinhold. The DIPC represents one of a limited few facilities nationwide offering highly standardized/validated assays for polyfunctional T‐cell analysis. The DIPC works directly with Duke CFAR/GAP Quality Assurance Program to ensure that all assays are performed in compliance with Good Clinical Laboratory Practice Guidelines.29 The DIPC has participated in/currently participates in regular proficiency testing and standardization programs including the NIAID/DAIDS
Immunology Quality Assessment Proficiency Program (26+ yrs), CDC Model Performance Evaluation Program T‐Lymphocyte Immunophenotyping (14+ yrs), NIH/NIAID‐ SeraCare Bioservices & BD Biosciences ICS Quality Assessment Program (6+ yrs), NIH/NIAID‐BD Biosciences CFSE Standardization Working Group (3.5 yrs), and Cancer Vaccine Consortium Proficiency Panel Program (ICS & CFSE, 6+ yrs). Currently, the DIPC
leads the Flow Cytometry External Quality Assurance Program for the NIH/NIAID/DAIDS sponsored External Quality Assurance Program Oversight Laboratory (EQAPOL) contract EQAPOL evaluates polychromatic antigen‐specific flow cytometry methods, such intracellular staining (ICS) and T‐ follicular helper assays. The DIPC has clearly focused its efforts on the development of and continued refinement of polychromatic flow cytometry‐based readout aimed at assessing phenotypic and functional reactivities, including intracellular cytokine staining and degranulation within a broad range of phenotypically‐defined T‐ cell populations.  
Moreover, this Core is constantly developing new assays for novel immunologic endpoints
(http://sciences.surgery.duke.edu/research/institutes‐and‐labs/weinhold‐lab) such as polychromatic ICS assays, lymphocyte activation/maturation, and T‐cell regulation.30‐32 Collaboration with this core will leverage the unique experience of this facility as it applies to analysis of specimens derived from patients with solid tumors. This will include studies requiring the analysis of immunological reactivity in vivo and immune response in vitro. Cells to be used in flow‐based assays will be obtained from individual patient's acid citrate dextrose anti‐coagulated fresh whole blood that has been processed to isolate PBMC, cryopreserved, and stored in LN2 freezers for batch processing. Cell thawing and overnight resting will be performed for all flow cytometry assays according to standardized and optimized standard operating procedures (SOPs). After the overnight rest, cells will be counted, assessed for viability and recovery, then aliquoted for flow cytometry assays. Flow cytometry assays will be performed following standardized/optimized SOPs. For efficiency and to minimize assay variability, all visits from a single patient will be assayed in the same batch. To assess variability across assays, cells from a normal donor (drawn, processed and cryopreserved from a single visit), will be used as a control across all assaybatches Table 7: Markers for Lymphoid Cells to be Evaluated. Lymphoid markers that may be detected by flow cytometry are shown. There will also be 2 additional markers included to be determined. The final panels will be determined based upon the best science at the time these analyses are performed.  
| Marker                       | Stain         | Purpose                                                                       |
|------------------------------|---------------|-------------------------------------------------------------------------------|
| Fixable Live/Dead Cell Stain | Surface       | Dead cell exclusion                                                           |
| CD3                          | Intracellular | T cells                                                                       |
| CD4                          | Intracellular | Helper T cells                                                                |
| CD45RO                       | Surface       | Maturation                                                                    |
| CD38                         | Surface       | Activation                                                                    |
| CD278 (ICOS)                 | Surface       | Activation                                                                    |
| FoxP3                        | Intranuclear  | Regulation                                                                    |
| CD25                         | Surface       | Regulation, Activation                                                        |
| Tim‐3                        | Surface       | Regulation, Activation                                                        |
| CD152 (CTLA‐4)               | Intracellular | Regulation                                                                    |
| IDO                          | Intracellular | Apoptosis, Regulation (tryptophanase)                                         |
| CD223 (LAG‐3)                | Surface       | Exhaustion                                                                    |
| CD279 (PD‐1)                 | Surface       | Exhaustion                                                                    |
| Additional Marker #1         | TBD           | TBD based on most recent literature or scientific results at time of analysis |
| Additional Marker #2         | TBD           | TBDbased onmostrecentliteratureorscientificresults attimeof  analysis         |  
Table 8: Markers for Myeloid Cells to be evaluated. Myeloid markers that may be detected by flow cytometry are shown. There will also be 2 additional markers included to be determined. The final panels will be determined based upon the best science at the time these analyses are performed.  
| Marker                       | Stain         | Purpose                                                                       |
|------------------------------|---------------|-------------------------------------------------------------------------------|
| Fixable Live/Dead Cell Stain | Surface       | Dead cell exclusion                                                           |
| Lineage (CD3, CD14, CD16,    | Surface       | Exclusion gate to identify MDSC                                               |
| CD56, CD19, CD20) CD11b      | Surface       | MDSC                                                                          |
| CD33                         | Surface       | MDSC                                                                          |
| HLA‐DR                       | Surface       | MDSC, DC                                                                      |
| CD123                        | Surface       | DC                                                                            |
| CD11c                        | Surface       | DC                                                                            |
| CD304 (BDCA‐4)               | Surface       | pDC (neuropilin‐1)                                                            |
| CD86                         | Surface       | M1 (co‐stimulatory for T cell activation)                                     |
| CD163                        | Surface       | M2a, activation(hemoglobin‐haptoglobin scavenger receptor)                    |
| CD206                        | Surface       | M2a (mannose receptor)                                                        |
| CD16                         | Surface       | M1 (FcγRIII)                                                                  |
| CD68                         | Intracellular | M1 (macrosalin)                                                               |
| Additional Marker #1         | TBD           | TBDbased onmostrecentliteratureorscientificresults attimeof  analysis         |
| Additional Marker #2         | TBD           | TBD based on most recent literature or scientific results at time of analysis |
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circulating protein analysis

Plasma samples will be obtained from all subjects at baseline (cycle 1 day 1), at first imaging, and at disease progression on study therapy. Plasma will be isolated within 2 hours of collection and stored at ‐80°C until analyzed. The Duke Phase I Biomarker Laboratory under the direction of Dr. Andrew Nixon has developed a multiplex ELISA approach to analyze 24 inflammatory and angiogenic growth factors(termedthe Angiome)
in less than1.0 ml of plasma. Coefficients of variation for all analytesare
<10%. Our group has pioneered the analysis of blood‐ based inflammatory and angiogenesis factors and is one of the largest and most experienced academic laboratories in the world at performing multiplex protein analyses in cancer patients on clinical trials. We have applied our Angiome multiplex array to dozens of Phase I‐III studies conducted by the National Cancer Institute's early and late stage clinical trials networks (ET‐CTN and NCTN), pharma, biotech, and other investigator‐initiated trials that we have organized.33‐35 The Angiome multiplex array (Table 9) has already gone through a rigorous evaluation to ensure data quality and last year, we were approved by the NCI Biomarker Review Committee (BRC) to incorporate our Angiome panel as an *integrated biomarker* in more than 14 trials, including the ongoing NRG studies, GY‐004 and GY‐ 005, evaluating the combination of cedarinib andolaparib.  
Fortheproposed study, analytelevels atbaselineand changesin analytelevelsalong thecontinuumofcarewill be correlated with clinicaloutcome(ORR,PFS,OS).In addition,longitudinal samples will be evaluated for key pharmacodynamic changesthatoccur in responsetotherapy.In addition toperformingtheAngiomeanalysis, plasmawillalsobeevaluatedby ELISAfor proteinmarkersthatmaybeassociated with sensitivityor resistance to atezolizumab.Thesemay includemeasurementofsolublecheckpoints(i.e.,PD1, PDL1,PDL2) as well asCRP
and other markersofinflammation,includingbutnotlimited toIFNγ,IL1β, IL4, IL6,IL7,IL10,IL12,IL17A,IL17E,
and IL23.
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8 early studytermination

This study can be terminated at any time for any reason by the PI‐sponsor. If this occurs, all subjects on study should be notified as soon as possible.
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9.1 atezolizumab and bevacizumab

The atezolizumab1200mg drug productwill be supplied. . Eur. Type 1 glassvial asacolorlesstoslightly yellow, sterile, preservative‐free clear liquid solution intended for IV administration. The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than the stated volume to enable delivery of the entire 20‐mL volume.  
Bevacizumab drug product will be supplied. Bevacizumab is manufactured by recombinant DNA technology, using a genetically engineered Chinese hamster ovary (CHO) cell line. The protein is purified from the cellculture medium by routine methods of column chromatography and filtration. The final product is tested for quality, identity, safety, purity, potency, strength, and excipient/chemical composition according to International Conference on Harmonisation (ICH) guidelines. The purity of bevacizumab is >
95%.Bevacizumabmaybe supplied in 6‐cc (100‐mg) and 20‐ cc (400‐mg) glass vials containing 4 mL or 16 mL
of bevacizumab, respectively (all at 25 mg/mL). Vials contain bevacizumab with phosphate, trehalose, polysorbate 20, andsterile waterfor injection (SWFI). Vials containno preservative and are suitable for single use only
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9.2 packaging and labeling

Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory guidelines.  
The labels will fulfill Good Manufacturing Practice Annex 13 requirements for labeling. The label will include the Name of the Sponsor, Study Code, For Clinical trial use only and /or any other market specific requirements. All study drugs should be kept in a secure place under appropriate storage conditions. The investigational product label on the pack specifies the appropriatestorage.
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9.3 supply receipt and storage

Atezolizumab and bevacizumab will be provided by Genentech/Roche free of charge and will be ordered through the research pharmacy. Both atezolizumab and bevacizumab receipt and storage should be per standard institutional practice and consistent with the package insert.
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9.4 dispensing and preparation

The atezolizumab and bevacizumab will be prepared and dispense as per package insert and institutional practice Please refer to the atezolizumab and bevacizumab package inserts and IB for additional details.
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9.5 compliance andaccountability

The investigator, or a responsible party designated by the investigator, should maintain a careful record of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability form. (Refer tothe NCI Investigator's Handbook for Procedures for Drug Accountability and Storage.)
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9.6 disposal anddestruction

Unused atezolizumab and bevacizumab will returned to the research pharmacy for disposal as per institutional standards.
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10 screeningand on-study tests and

Both atezolizumab and bevacizumab are approved for the treatment of NSCLC. The time and events table reflectsstandard of care testing associated with each of the agents, and imaging for response is performed at intervals and using modalities consistent with standard of care. Investigators can perform additional testing if in his or her clinical judgement it is indicated.  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 64  
| Active Monitoring Phase Re-staging every  3 cycles for 17                                     |                                                                |                         |    |
|-----------------------------------------------------------------------------------------------|----------------------------------------------------------------|-------------------------|----|
| Screening                                                                                     | cycles (1 year)  fromcycle 1 day  1 then every 6  cycles until | End of treatment (EOT)  |    |
| ≤ 28 days prior  to startingstudy  therapy5                                                   | Day 1 of  each  cycle14                                        | (28 days after the last |    |
| Tests and Procedures                                                                          | treatment) 4                                                   |                         |    |
| disease                                                                                       |                                                                |                         |    |
| progression                                                                                   |                                                                |                         |    |
| Informed Consent                                                                              | X                                                              |                         |    |
| Inclusion/Exclusion                                                                           | X                                                              |                         |    |
| Demography & Medical History  including prior therapies and                                   | X                                                              |                         |    |
| smoking history Local documentation of EGFR  exon 19 deletion or exon 21 L858R  and histology | X                                                              |                         |    |
| ECOG PS                                                                                       | X                                                              | X                       | X  |
| Physical Exam including weight,                                                               | X                                                              | X                       | X  |
| blood pressure, temp, P, O2 sat5 Adverse event assessment                                     | X                                                              | X9                      | X  |
| Prior/concomitant medications                                                                 | X                                                              | X                       | X  |
| Urine protein creatinine ratio                                                                | X                                                              | X12                     | X  |
| Hematology: CBC/ differential8                                                                | X                                                              | X8                      |    |
| PT/INR, PTT6                                                                                  | X6                                                             |                         |    |
| Chemistry: SGOT (AST), SGPT                                                                   | X 7                                                            | X                       |    |
| (ALT), alk phos, T. bili, creatinine                                                          | X                                                              |                         |    |
| TSH10                                                                                         | X                                                              | X10                     |    |
| Tumor measurement 3                                                                           | X                                                              | X3                      | X  |
| MRI or CT scan of brain11                                                                     | X                                                              | X11                     |    |
| Pregnancy test1                                                                               | X1                                                             | X1                      |    |
| CONFIDENTIAL                                                                                  |                                                                |                         |    |  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 65  
| Research Blood sample2          | X2   | X   |
|---------------------------------|------|-----|
| Tissue sample (if available) 13 | X    |     |  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 66 1. For women of childbearing potential only. Must be done ≤ 7 days prior to starting therapy. Then day 1 of each cycle or per institutional guidelines 2. Research blood sample should be drawn at 3 time points: *baseline (cycle 1 day 1), at time of first* imaging (9 weeks), and at time of disease progression on study therapy. Kits are required for this collection. Research blood sample to be drawn prior to treatment. Samples should be drawn at time of disease progression if disease occurs on a visit not associated with planned tumorimaging 3. Patients should undergo imaging with CT chest and abdomen for disease progression every 3 cycles for the initial 17 cycles (1 year) then every 6 cycles until disease progression. Tumor measurements should be done < 28 days prior to starting study therapy. Patients who discontinue study therapy prior to disease progression should be followed with imaging until disease progression. The schedule of follow‐up imaging is at the discretion of physician, but an interval of 6 to 12 weeks is recommended 4. All patients (including those who have left the study because of progressive disease, unacceptable toxicity, patient refusal, investigator's decision to remove patient, etc.) should have an end of treatment visit. However, if it is not feasible due to decline in performance status, patient has initiated another therapy, or patients is being treated at another center patient can be exempted for the visit. This study visit can occur +/‐ 3 days due to patient convenience andtravel 5. Baseline/screening assessments are to be performed ≤ 28 days prior to starting study therapy unless otherwise specified.  
6. PT/INR, PTT required at baseline 7. Only SGOT (AST), SGPT (ALT), alk phos, T. bili, and creatinine checked on Day 1 of each cycle forfirst 4 cycles, and then every other cycle. More intensive monitoring per investigator discretion or institutional practice.  
8. CBC required at baseline then day 1 of cycles 1‐4, then every other cycle and as clinically indicated, at the discretion of the investigator or institutionalpractice.  
9. Prior to subsequent cycle.  
10. TSH should be check every 3 cycles. Additional testing at the discretion of the investigator or per institutionalstandard 11. MRI is the preferred test for imaging for brain metastases, CT scan with contrast is acceptable for patients who are unable or intolerant of undergoing MRI of the brain. Patients must have either MRI or CT scan prior to starting study therapy. MRI and CT scans should be done < 28 days prior to start of study therapy. Patients with untreated brain metastases should undergo repeat imaging every 12 weeks or sooner if clinically indicated to assess disease status. Patients without brain metastases or treated brain metastases can undergo repeat imaging at the discretion of the investigator or per institutional practice 12. Urine protein/creatinine ratio should be checked on every 3 cycles.  
13. Biopsy tissue obtained < 60 days after disease progression on osimertinib and before day 1 of study therapy (if available). There are nospecific requirementsrelatedtothe biopsy 14. The study visits can occur +/‐ 3 days to accommodate holidays, travelschedule, family events, etc.  
as necessary
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10.2 screening examination

The following procedures and tests are to be performed < 28 days prior to starting study therapy to confirm eligibility (unless otherwise specified). Baseline and Cycle 1 Day 1 procedures may be completed on the same day, however, screening assessments to confirm eligibility MUST have already been determined. Informed consent is to be obtained before any screening procedures are performed. If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, these may be used for screening purposes with consent of patient. Refer to Time and events table fordetails.  
1. Informed consent 2. Review of past medical history and previous therapies for NSCLC
3. Eligibility criteria review(Inclusion/exclusion) 4. Baseline characteristics, smokinghistory 5. A directed physical examination will be performed at the visit with vital signs including pulse, blood pressure, temperature, oxygen saturation, weight 6. ECOG Performance status 7. Routine blood work (CBC, chemistries) and PT/INR and PTT as clinically indicated 8. Urine protein/creatinine ratio 9. Thyroid stimulating hormone 10. Pregnancy test ifapplicable 11. Tumor Histology 12. *EGFR* mutation status 13. Review of baseline sign/symptoms 14. Review of concomitant medications 15. Disease assessment: Brain MRI, CT scan of chest andabdomen 10.3On study treatment period: Day of each cycle as noted in time and events table 1. Review of interval medical history, concomitant medications and assessment of performance status 2. A directed physical examination will be performed at the visit with vital signs including pulse, blood pressure, temperature, oxygen saturation,weight 3. Laboratory: chemistry, and hematology. 4. Thyroid stimulating hormone every 3 cycles. Additional testing as clinically indicated or as per institutional standard 5. Urine protein/creatinine ratio every 3 cycles. 6. MRI ofthe brain to be performed with every 12 weeks in patientswith known and untreated brain metastases to assess for intracranial disease progression. Patients without brain metastases or treated brain metastases will undergo repeat brain imaging as clinically indicated or per institutional standard.  
7. CT Chest/abdomen every 3 cycles for the first 17 cycles (approximately 1 year) and then every 6 cycles until disease progression.  
8. Adverse event assessment 9. Pregnancy test (ifapplicable)  
10. Research blood sample baseline (cycle 1day 1), at time of first imaging (9 weeks) and at time of disease progression on study therapy in providedkits 11. Research blood sample at time of disease progression in provided kit
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 69 1. Review of interval medical history since the last visit and assessment of performance status 2. A directed physical examination will be performed at the visit with vital signs including pulse, blood pressure, temperature, oxygen saturation,weight 3. Laboratory: chemistry andhematology
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10.5 follow-up period

After discontinuing study therapy patients will be followed for overall survival every 3 months by telephone or review of medical records until death or a maximum of 2 years from completion of study therapy.  
Subsequent therapy and survival status will be documented. If molecular testing performed (e.g. molecular testing of tumor biopsy or circulating tumor DNA) as part of standard of care the results of the testing will be recorded if available.  
Patients who discontinue therapy for reasons other than disease progression will be followed for disease progression even if patient starts on new treatment. The imaging schedule is at the discretion of the treating physician, but the recommended interval is every 6 to 12 weeks. For patients not returning to the treatment center the assessment of disease progression will be based on interpretation of radiographic report by the investigator. Investigators should report SAE's that are attributed to the study treatment for 100 days after the last dose of study therapy.
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10.6 end ofstudy

The end of study will be defined as the time at which all patients have discontinued study therapy and study report is accepted for publication.
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10.7 early withdrawal of subject(s)

Subjects may voluntarily withdraw from the study at any time. The PI may also withdraw a subject from the study at any time based on his/her discretion. Reasons for PI‐initiated withdrawal may include, but is not limited to the following:
− Subject or legal representative withdrawsconsent
− Confirmed radiographic disease progression − There is toxicity deemed by the investigator or subject to beunacceptable
− Concurrent illness that prevents further administration of treatment
− The subject, for any reason, requires treatment with another systemic agent potentially effective for treatment of the study indication. In this case, discontinuation from the study occurs immediately upon introduction of the new agent
− Noncompliance with trial treatment or procedurerequirements  
− Abnormal laboratory values
− Abnormal test procedure results
− Protocol deviation
− Administrative issues
− Pregnancy − Subject is lost tofollow‐up − The investigator for any reason, stops the study
− Termination of the study by Genentech/Roche
− If the atezolizumab is held for ≥ 12 weeks the patient should discontinued fromstudy therapy. If the bevacizumab is held ≥ 12 weeks the patient should discontinue study therapy.
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10.7.2 follow-up requirementsfor early withdrawal

Patients who do not start study drug will not have any study follow‐up requirements. Patients who discontinue therapy for reasons other than disease progression will be followed for disease progression every 6‐12 weeks at the discretion of the treating physician. Once patient stops study therapy they will be followed for overall survival every 3 months by telephone or by review of medical records for a maximum of 2years.
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10.7.3 replacement of early withdrawal(s)

Patients who do not start study drug will be replaced and will be considered non‐evaluable. They will be classified as "consented but not treated."
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11 safety monitoring and reporting

The PI is responsible for the identification and documentation of adverse events and serious adverse events, as defined below. At each study visit, the PI or designee must assess, through non‐suggestive inquiries of the subject or evaluation of study assessments, whether an AE or SAE has occurred. Adverse events that are judged to be Serious Adverse Events by the institutional PI are to be reported to the Duke Cancer Institute Safety Desk for Reporting Procedures for Adverse Events and Serious Adverse Events by ParticipatingSites.
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11.1 adverse events

An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and which does not necessarily have a causal relationship with this treatment. For this protocol, the definition of AE also includes worsening of any pre‐existing medical condition. An AE can therefore be any unfavorable and unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to use of the study drug. Abnormal laboratory, physical exam, or vital sign findings without clinical significance (based on the provider judgment) should not be recorded asAEs AEs will be documented from the date of first dose of study drug through 28days after the last dose of study drug. All grade 1‐5 AEs as well as special reporting circumstances, such as exposure via a parent during pregnancy or breast feeding, overdose, medication error, misuse, abuse, off‐label use or occupational exposure must be recorded in theCRF.  
AEs will be assessed according to the CTCAE version 4.03. If CTCAE grading does not exist for an AE, the severity of the AE will be graded as mild (1), moderate (2), severe (3), life‐threatening (4), or fatal (5).  
Attribution of AEs will be indicated as follows:
− Definite: The AE is clearly related to the studydrug
− Probably: The AE is likely related to the study drug − Possible: The AE may be related to the studydrug − Unlikely: The AE is doubtfully related to the study drug
− Unrelated: The AE is clearly NOT relatedto the study drug
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reporting of aes

All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity case report forms. AEs reported through expedited processes (e.g., reported tothe IRB, FDA, etc.) must also be reported in routine study data submissions. Abnormal laboratory results are to be recorded as AEs if any of the following conditions are met:
- The abnormal laboratory value leads to a therapeutic intervention (e.g. corrective therapy). - The abnormal laboratory value is considered to be clinically significant by the Investigator. - Any lab test result that is clinically significant or meets the definition of an SAE.  
- Any laboratory test result abnormality that requiredthe subject to have study treatment discontinued or interrupted
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11.2 serious adverseevents

A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose:
1) Results in death (i.e., the AE actually causes or leads to death).  
2) Is life‐threatening (i.e., in the opinion of the Investigator, the AE places the subject at immediate risk of death; it does not include a reaction that, had it occurred in a more severe form, might have caused death).  
3) Requires inpatient hospitalization or results in prolongation of an existing hospitalization.  
4) Results in persistent or significant disability or incapacity. (Note: The term "disability" refers to events that result in a substantial disruption of a subject's ability to conduct normal life function.)
5) Is a congenital anomaly or birth defect in a neonate/infant born to a mother exposed to the study therapy 6) Is an important medical event (Note: The term "important medical event" refers to an event that, based upon appropriate medical judgment, may not be immediately life‐threatening or result in death or hospitalization, but may jeopardize the subject or require intervention to prevent one of the other serious outcomes listed under the definition of SAE. Examples of important medical events include intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; or development of product dependency or product abuse.)
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methods and timing for assessing

The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during the study are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).
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adverse event reporting period

The study period during which AE's and SAEs and/or follow up to SAEs including death due to any cause other than progression of the cancer under study, that occurs from the date of the first dose of study drug through 28 days following the last dose of study drugs (atezolizumab and bevacizumab), whether or not related to study drug(s), must be recorded on the CRF and must be reported within 24 hours to DCI Safety Desk and within 2 working days to supporting companies. After the 28 day period, investigators should report SAE's that are attributed to the study treatment for 100 days after the last dose of study therapy.  
All SAEs must be followed until resolution, return to baseline condition, or stabilization. Any SAEs that are ongoing at the time the clinical database is closed will be reported to supporting companies as unresolved.  
All adverse events (AEs)/Serious Adverse Events (SAE's), AEs of Special Interest (AESIs), Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from the Study for the Product will be sent to DCI Safety Desk. Events which are unequivocally due to disease progression should not be reported as an AE during the study.  
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered an SAE
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assessment of adverse events

All AEs and SAEs whether volunteered by the subject, discovered by study personnel during questioning, or detected through physical examination, laboratory test, or other means will be reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if applicable,suspected relationship to the atezolizumab and bevacizumab (see following guidance), and actions taken. To ensure consistency of AE and SAE causality assessments, investigators should apply the following general guideline:
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yes (definite probably possible unlikely)

There is a plausible temporal relationship between the onset of the AE and administration of the atezolizumab and bevacizumab, and the AE cannot be readily explained by the subject's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to the atezolizumab and bevacizumab or with similar treatments; and/or the AE abates or resolves upon discontinuation of the atezolizumab and bevacizumab or dose reduction and, if applicable, reappears upon re- challenge.
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no (not related)

Evidence exists that the AE has an etiology other than the atezolizumab and bevacizumab (e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to atezolizumab and bevacizumab administration (e.g., cancer diagnosed 2 days after first dose of study drug). Expected adverse events are those adverse events that are listed or characterized in the Package Insert (P.I) or current Investigator Brochure (I.B). Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This includes adverse events for which the specificity or severity is not consistent with the description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis.
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procedures for eliciting recording and

Eliciting Adverse Events A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. Examples of non-directive questions include:
- "How have you felt since your last clinical visit?"
- "Have you had any new or changed health problems since you were last here?" Specific Instructions for Recording Adverse Events Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid colloquialisms and abbreviations.  
a. Diagnosis vs. Signs and Symptoms If known at the time of reporting, a diagnosis should be reported rather than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report the information that is currently available. If a diagnosis is subsequently established, it should be reported as follow-up information.
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b. deaths

All deaths that occur during the protocol-specified AE reporting period, with the exception of disease progression, will be reported to the appropriate parties. When recording a death, the event or condition that caused or  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 76 contributed to the fatal outcome should be reported as the single medical concept. If the cause of death is unknown and cannot be ascertained at the time of reporting, report "Unexplained Death".
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c. preexisting medical conditions

A preexisting medical condition is one that is present at the start of the study. Such conditions should be reported as medical and surgical history. A preexisting medical condition should be re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or character of the condition worsens during the study.  
When reporting such events, it is important to convey the concept that the preexisting condition has changed by including applicable descriptors (e.g., "more frequent headaches").
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d. hospitalizations for medical or

Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE.  
If a subject is hospitalized to undergo a medical or surgical procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, should be reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass surgery, record the heart condition that necessitated the bypass as the SAE. Hospitalizations for the following reasons do not require reporting:
- Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for preexisting conditions
- Hospitalization for < 24 hours (observation admissions)  
` - Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study o  
- Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study
e. Assessment of Severity of Adverse Events The adverse event severity grading scale for the NCI CTCAE version 4.03 will be used for assessing adverse event severity. Below Table should be used for assessing severity for adverse events that are not specifically listed in the NCI CTCAE.
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adverse event severity grading scale

Grade Severity  
| 1                                                                                     | Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or  intervention not indicated                            |              |           |                 |            |            |             |                   |
|---------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|--------------|-----------|-----------------|------------|------------|-------------|-------------------|
| 2                                                                                     | Moderate; minimal, local, or non-invasive intervention indicated; or limiting  age-appropriate instrumental activities of daily living a |              |           |                 |            |            |             |                   |
| 3                                                                                     | Severe                                                                                                                                   | or           | medically | significant,    | but        | not        | immediately | life-threatening; |
| hospitalization                                                                       | or                                                                                                                                       | prolongation | of        | hospitalization | indicated; | disabling; | or          |                   |
| limiting self-care activities of daily living b,c                                     |                                                                                                                                          |              |           |                 |            |            |             |                   |
| 4                                                                                     | Life-threatening consequences or urgent intervention indicated d                                                                         |              |           |                 |            |            |             |                   |
| 5                                                                                     | Death related to adverse event d                                                                                                         |              |           |                 |            |            |             |                   |
| NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. |                                                                                                                                          |              |           |                 |            |            |             |                   |  
Note: Based on the most recent version of NCI CTCAE (v 4.03)  
a. Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.  
b. Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, and taking medications, as performed by patients who are not bedridden.  
c. If an event is assessed as a "significant medical event," it must be reported as a serious adverse event d. Grade 5 events must be reported as serious adverse events
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f. pregnancy

If a female subject or female partner of a male study subject becomes pregnant while receiving the study drug or within 6 months after the last dose of study drug, a report should be completed and expeditiously submitted to Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female subject exposed to the study drug should be reported as an SAE.
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reporting of saes

SAEs, deaths, and grade 4 unknown reactions or unexpected events that occur in the course of any patient's treatment on study (from the time of enrollment) or within 28 days following cessation of study treatment are reportable. All sites will complete DCI SAE Report Form and Page 1 of the DCI Safety Review Form. Sub‐sites will submit both forms to the DCI Safety Desk (Fax \#: 919‐681‐9357 or email dcccsafe@dm.duke.edu) and to the Lead PI, Dr. Stinchcombe Fax: 919‐684‐5163 and Thoracic‐ multisite@dm.duke.edu).  
Note: It is imperative that initial SAE reports are submitted as soon as possible (within 24 hours of knowledge of the event) with available information to the DCI Safety Desk. Missing and/or clarified event information may be provided in a follow‐up report.  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 79  
If the safety desk cannot be reached within 24 hours, the Duke PI, Dr. Thomas
Stinchcombe,should be contacted (thomas.stinchcombe@duke.edu, Pager (919)
970- 2829, Office: (919) 681- 9509.
The initial report for each SAE or death should include at minimum the following information:  
- protocol (TOP 1901)
- patient initials, study identification number, sex, age
- date the event occurred - description of the event - study drug name(s)
- dose level and cycle number at the time the event occurred
- description of the patient's condition
- indication whether the patient remains onstudy - event causality or causalrelationship - responsible investigator name and contact details
De‐identified source documentation (i.e. admission notes, discharge notes, applicable laboratory results, radiology/diagnostic testing results, etc.) must be sent with the DCI SAE Report Form. Follow‐ up information including severity, action taken, concomitant medications, and outcome should be communicated to DCI
Safety Desk as soon as possible using the same formsmentioned above.
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reporting to regulatory authorities ethics

SAE Reporting Procedure for Lead PI and DCI Safety Desk Duke as the lead center is responsible for reporting the serious adverse event to the FDA in accordance with 21CFR 312.32. Any SAE that is possibly related and unexpected must be submitted to the FDA. This will be done by DCI Safety Desk and/or coordinate with study team regulatory coordinator.
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reporting saes at participating institutions

Each site is responsible for reporting unexpected and/or serious adverse events to their individual IRB
according to their institutional guidelines.  
Expedited Reporting Procedure for Duke Cancer Institute (Coordinating Center)
Duke Cancer Institute as the coordinating center for this study is responsible for reporting SAEs to the FDA
in accordance with 21CFR 312.32. Any SAE that is possibly related and unexpected must be submitted to the FDA. If the SAE meets criteria for reporting to the FDA, the DCI Safety Desk will complete the Form FDA
3500A (MedWatch) and send to the Principal Investigator and the Sponsor that are noted above. This submission of the Form FDA 3500A to the FDA will be completed by the designee.  
- All unexpected, drug related SAEs that are fatal or life‐threatening will be reported to the FDA
by phone or fax within 7 calendar days of initial receipt of the information and will provide a complete report within 8 days of the initial report submission (by calendar day15).  
And Duke Cancer Institute will be responsible for the distribution of safety information to Site IRB: The Duke Safety Desk will complete Form 3500A (21CFR 312.32) as needed.  
Duke Safety Desk Contact Information: DCI Safety Desk: Fax (919) 681-9357; email dcccsafe@dm.duke.edu.  
With a copy being sent to: (919) 660-9246 or (insert coordinator email here) External Site(s): Refer to Study Manual For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: (888) 835-2555 Fax: (650) 225-4682 or (650) 225-4630
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reporting saes to genentech

The Duke Safety Desk will be responsible for reporting Adverse Events (AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE) originating from the Study for the Product.  
Investigators/Duke Safety Desk must report all the above mentioned single case reports adequately to Genentech within the timelines described below. The completed MedWatch reporting forms should be faxed/emailed immediately upon completion to Genentech at the following contacts:
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints should be sent to:
Fax: 650-238-6067 Email: usds_aereporting-d@gene.com It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or without an AE)
originating from the study. These single case reports will be exchanged between the parties as outlined below so that regulatory obligations are met.
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sadrs

Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen (15)
calendar days of the awareness date.
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other saes

Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty (30)
calendar days of the awareness date.
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aesis

AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date.
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special situation reports pregnancy reports

While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined herein, any reports of pregnancy (including pregnancy occurring in the partner of a male study subject), where the fetus may have been exposed to the Product, shall be transmitted to Genentech within thirty (30) calendar days of the awareness date. Pregnancies will be followed up until the outcome of the pregnancy is known, whenever possible, based upon due diligence taken to obtain the follow-up information.
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pregnancies in female partners of

Male patients will be instructed through the Informed Consent Form to immediately inform the investigator if their partner becomes pregnant during the study or within 30 days after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form should be completed and submitted to Genentech within thirty (30) calendar days of the awareness date.  
- Other Special Situation Reports In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations Reports should be collected even in the absence of an Adverse Event and transmitted to Genentech within thirty (30)
calendar days:
- Data related to the Product usage during breastfeeding - Data related to overdose, abuse, misuse or medication error (including potentially exposed or intercepted medication errors)  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 83
- In addition, reasonable attempts should be made to obtain and submit the age or age group of the patient, in order to be able to identify potential safety signals specific to a particular population
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product complaints

All Product Complaints (with or without an AE) shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date.  
A Product Complaint is defined as any written or oral information received from a complainant that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, effectiveness, or performance of a product after it has been released and distributed to the commercial market or clinical trial.
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case transmission verification of single

The Investigator-Sponsor agrees to conduct the Case Transmission verification to ensure that all single case reports have been adequately received by Genentech via Investigator-Sponsor emailing Genentech a Quarterly line-listing documenting single case reports sent by Investigator-Sponsor to Genentech in the preceding time period.  
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed time period. Confirmation of receipt should be received within the time period mutually agreed upon.  
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case basis until satisfactory resolution. The sponsor shall receive reconciliation guidance documents within the 'Activation Package'.  
Following Case Transmission Verification, single case reports which have not been received by Genentech shall be forwarded by Investigator-Sponsor to Genentech within five (5) calendar days from request by Genentech.  
At the end of the study, a final cumulative Case Transmission Verification report will be sent to Genentech
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duke safety desk contact information

DCI Safety Desk: Fax (919) 681‐9357; email dcccsafe@dm.duke.edu.  
With a copy being sent to: Dr. Stinchcombe fax (919) 660‐9246 and scanned to Thoracic‐multisite@dm.duke.edu External Site(s): Refer to *Safety packet*
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11.3 adverse events of special

AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor is required. Such an event might require further investigation in order to characterize and understand it. Depending on the nature of the event, rapid communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted. The following AEs are considered of special interest and must be reported to the Genentech Drug Safety expeditiously, irrespective of regulatory seriousness criteria:
Immediately upon awareness of an AESI, the Investigator (or designee) completes the **DCI SAE Report**
Form and **Page 1 of the DCI Safety Review Form** and will submit both forms within 24 hours of knowledge of the event to DCI Safety Desk (contact information is above). Note: It is imperative that initial AESI reports are submitted as soon as possible (within 24 hours of knowledge of the event) with available information to the DCI Safety Desk. Missing and/or clarified event information may be provided in a follow‐up report.  
De‐identified source documentation (i.e. admission notes, discharge notes, applicable laboratory results, radiology/diagnostic testing results, etc.) must be sent with the DCI SAE Report Form.  
Follow‐up information including severity, action taken, concomitant medications, and outcome should be communicated to DCI Safety Desk as soon as possible using the same forms mentioned above.
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eci reporting procedure for dci

The Lead PI will review the report form with accompanying source document, complete Page 2 of the DCI
Safety Review Form and promptly submit it to the DCI Safety Desk.  
Within two business days of receipt, the DCI Safety Desk will also submit the SAE report form and other relevant safety information to the following supporting company:
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events of special interest are

- Cases of potential drug‐induced liver injury that include an elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law and based on the following observations:
- Treatment‐emergent ALT or AST > 3 x ULN (or > 3 X baseline value in disease states where LFTs may be elevated at baseline) in combination with total bilirubin > 2 X ULN (of which ≥ 35% is direct bilirubin)
- Treatment‐emergent ALT or AST > 3 X ULN (or > 3 x baseline value in disease states where LFTs may be elevated at baseline) in combination with clinicaljaundice
- Suspected transmission of an infectious agent by the study treatment, as:
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non‐pathogenic, is considered an infectious agent. A transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection in a patient exposed to a medicinal product. This term applies only when a contamination of study treatment issuspected.  
•Systemic lupus erythematosus
- Events suggestive of hypersensitivity, infusion‐related reactions, cytokine release syndrome, macrophage activating syndrome, hemophagocytic lymphohistiocytosis •Nephritis
•Ocular toxicities (e.g. uveitis, retinitis, opticneuritis)
•Grade ≥ 2 cardiac disorders (e.g. atrial fibrillation, myocarditis, pericarditis)
•Vasculitis
•Autoimmune hemolytic anemia
•Severe cutaneous reactions (e.g., Stevens‐Johnson syndrome, dermatitis bullous, toxic epidermal necrolysis)
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development safety update report

Duke Cancer Institute, as the Sponsor of the Study, will be responsible for the preparation of their own Development Safety Update Report (DSUR) for the Study and for the submission of the report to the regulatory authorities and Ethics Committees of the concerned Member States, where applicable. Duke Cancer Institute, agrees to share a copy of their own DSUR with Genentech as soon as reasonably possible after completion.  
Genentech agrees to forward to Duke Cancer Institute an executive summary of the Genentech DSUR upon request.  
Furthermore, Genentech agrees that Duke Cancer Institute may cross-reference the executive summary of the Genentech/Roche DSUR, as applicable
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other reports

Events which are unequivocally due to disease progression should not be reported as an AE during the study. Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered an SAE.  
11.4 Safety Oversight Committee (SOC)
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor‐
investigator phase I and II, therapeutic interventional studies that do not have an independent Data Safety Monitoring Board (DSMB). These reviews occur at a minimum annually and more frequently for the high risk studies. The SOC safety reviews include review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, reference literature, and interim analyses as provided by the sponsor‐
investigator. The SOC, at a convened meeting, assigns a rating of satisfactory when adequate accrual with lack of excessive toxicity is present. The SOC in concert with the DCI Monitoring Team oversees the conduct of DUHS cancer‐related, sponsor‐investigator greater‐than‐minimal‐risk intervention studies that do not have an external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in accordance with the protocol, standing operating procedures (SOPs), Good Clinical Practice
(GCP), and applicable regulatory requirements.
11. 5 quality control and
assurance monitoring

This clinical research study will be monitored both internally by the PI, and institutionally by the Duke Cancer Institute (DCI). In terms of internal review the PI will continuously monitor and tabulate adverse events. Appropriate reporting to the Duke University Medical Center IRB will be made. If an unexpected frequency of Grade III or IV
events occur, depending on their nature, action appropriate to the nature and frequency of these adverse events will be taken. This may require a protocol amendment, dose de‐escalation, or potentially closure of the study. The PI of this study will also continuously monitor the conduct, data, and safety of this study to ensure that:
- Interim analyses occur asscheduled; - Stopping rules for toxicity and/or response are met;
- Risk/benefit ratio is not altered to the detriment of the subjects; - Appropriate internal monitoring of AEs and outcomes is done;
- Over‐accrual does not occur; - Under‐accrual is addressed with appropriate amendmentsor actions;
- Data are being appropriately collected in a reasonably timely manner.  
DCI Protocol Review and Monitoring systems (PRMS) review of this protocol begins with an initial review by the Cancer Protocol Committee (CPC). CPC new protocol review focuses on scientific relevance, study design, adequacy of biostatistical input, protocol prioritization, feasibility of completing the study within a reasonable time frame and risk assessment of the trial. The PI will abide by CPC assessment of the level of risk, which will determine the intensity of subsequent DCI monitoring. CPC also conducts annual scientific progress reviews on protocols that are open to enrollment and focus on protocol prioritization, accrual and scientific progress.  
These reviews are conducted at the time of IRB annual renewals and documentation of all CPC reviews will be maintained in eIRB/iRIS systems. A determination for the degree of monitoring conducted by the DCI monitoring team is made at the time of initial CPC approval to commensurate with the type and level of intervention, phase, endpoints, degree of risk, size and complexity of the protocol. A formal, independent monitoring will be conducted by the DCI monitoring team according to the risk level and monitoring plan assigned by the CPC until the study is closed to enrollment or subjects are no longer receiving study drug or other interventions that are more than minimal risk.  
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns. Monitoring visits may also be initiated upon request by DUHS and DCI
Leadership, CPC, SOC, a sponsor, an investigator, or the IRB.  
The DCI monitoring team reviews the adequacy of informed consent, enrollment of eligible patients, implementation of protocol‐specified procedures and treatment, adequacy of data collection, and appropriateness of adverse event  
monitoring and reporting. The DCI monitoring team presents final monitoring reports to the DCI Safety Oversight Committee (SOC) highlighting safety concerns and unresolved issues. The SOC, at a convened meeting, assigns an overall rating of satisfactory, marginal, or unsatisfactory to reflect the overall quality of data, regulatory, consent, eligibility, study conduct and AE reporting. Corrective action plans (CAPs) are developed, implemented, and evaluated as indicated. The SOC will notify the sponsor‐investigator and DUHS IRB when significant safety concerns are identified.  
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, the Principal Investigator, or the IRB. All study documents must be made available upon request to the DCI
Monitoring Team and other authorized regulatory authorities, including but not limited to the National Institute of Health, National Cancer Institute, and the FDA. Every reasonable effort will be made to maintain confidentiality during study monitoring.  
Please refer to the study specific external site monitoring plan for monitoring sites external to the Duke University HeathSystem.
11. 5 quality control and
audits

The Duke School of Medicine Office of Audit, Risk and Compliance (OARC) may conduct confidential audits to evaluate compliance with the protocol and the principles of GCP. The PI agrees to allow the OARC
auditor(s) direct access to all relevant documents and to allocate his/her time and the time of the study team to the OARC auditor(s) in order to discuss findings and any relevant issues.  
OARC audits are designed to protect the rights and well‐being of human research subjects. OARC audits may be routine or directed (for cause). Routine audits are selected based upon risk metrics generally geared towards high subject enrollment, studies with limited oversight or monitoring, Investigator initiated Investigational Drugs or Devices, federally‐funded studies, high degree of risk (based upon adverse events, type of study, or vulnerable populations), Phase I studies, or studies that involve Medicare populations.  
Directed audits occur at the directive of the IRB or an authorized Institutional Official. OARC audits examine research studies/clinical trials methodology, processes and systems to assess whether the research is conducted according to the protocol approved by the DUHSIRB. The primary purpose of the audit/review is to verify that the standards for safety of human subjects in clinical trials and the quality of data produced by the clinical trial research are met. The audit/review will serve as a quality assurance measure, internal to the institution. Additional goals of such audits are to detect both random and systemic errors occurring during the conduct of clinical research and to emphasize "best practices" in the research/clinical trialsenvironment
11. 5 quality control and
data and safety monitoring

Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan.
11. 5 quality control and
case report forms (crfs)

The electronic CRF will be the primary data collection document for the study. The CRFs will be updated within two weeks of acquisition of new source data. The electronic records of subject data will be maintained using a dedicated database (Medidata Rave and/or Redcap) which is housed in an encrypted and password protected DCI file server. Access to electronic databases will be limited to the PI and designated stud staff listed on key personnel. Subject data may be stored temporarily on encrypted and password‐protected portable memory devices such as flash drives and external hard drives, but only when absolutely necessary. Data stored on portable memory deviced will be de‐ identified. Subject data will be deleted from the portable memory device at the earliest opportunity. The security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine. Only approved study staff, are permitted to make entries, changes, or corrections in the CRF.  
An audit trail will be maintained automatically by the electronic CRF management system (Medidata Rave and/or Redcap). Designated personnel will complete user training, as required or appropriate per regulations
11. 5 quality control and
data management procedures and data

Designated personnel using the electronic CRF will have access based on their specific roles in the protocol. Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted to the presence of data inconsistencies. Additionally, the data manager and study coordinator and/or PI will cross‐reference the data to verify accuracy. Missing or implausible data will be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of data, completion or confirmation that data is not available, etc.).  
The database will be reviewed and discussed prior to database closure, and will be closed only after resolution of all remaining queries. An audit trail will be kept of all subsequent changes to the data.
11. 5 quality control and
study closure

Following completion of the studies, the PI will be responsible for ensuring the following activities:  
- Data clarificationand/or resolution - Accounting, reconciliation, and destruction/return of used and unused studydrugs
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 91
- Review of site study records for completeness
- Shipment of all remaining laboratory samples to the designated laboratories Upon completion of the study, research records will be archived and handled per DUHS (or participating Institution's) HRPP policy.  
required to initiate the study, to conduct study‐related activities, or to comply with national, state, or local laws and regulations. Written authorization from the coordinating site and sponsor is required for disclosure otherwise.  
Protocol TOP 1901 92
11. 5 quality control and
12 statistical methods and data

All statistical analysis will be performed under the direction of the statistician designated in key personnel. Any data analysis carried out independently by the investigator must be approved by the statistician before publication or presentation. The primary objective of the single‐arm phase II trial is to determine objective response rate, defined as all patients with a confirmed partial or complete response as assessed by investigator using RECIST 1.1, among stage 4 NSCLC patients with EGFR mutations and who have progressed on osimertinib. Secondary objectives include (1) evaluation of progression‐free survival; (2) overall survival; and (3) adverse events due to the protocol treatments.  
Sample Size and Study Design The single‐arm phase II trial is designed to test the following hypothesis about the anti‐tumor activity of the experimental therapy:
H0: ORR <= 30% versus H1: ORR >= 50%,
where ORR is the true ORR for the experimental therapy. We will use Simon's minimax 2‐stage design to evaluate theORR.36 The 2‐stage designallow a futility test afterstage I patientshas been evaluated for tumor response. The specific design described below is also the design that yields the smallest maximum sample size under the null hypothesis (minimax) among all designs satisfying type I error rate of 0.10 and type II error rate of 0.10.  
Specifically, the first stage will enroll 28 patients. If there are 7 or fewer patients confirmed responders
(complete or partial response) among the 28 patients, the trial will be terminated; otherwise, the trial will move forward to enroll additional 11 patients. If 15 or fewer patients among the total of 39 patients are confirmed responders, the experimental therapy will be concluded as not worthy of further investigation; otherwise it will be conducted that the experimental therapy has sufficient activity worthy of further investigation. The above design has expected sample size 39 under the null hypothesis. The early stopping probability at stage I is 0.3648 under the null hypothesis. The actual type I and type II errorrates are 0.0943 and 0.0999,respectively.
11. 5 quality control and
statistical analysis methods

Patient characteristics at baseline will be summarized in tables. Categorical data will be summarized using frequency tables while summary statistics such as means, medians, standard deviation, range, etc. will be provided for continuous data.  
All enrolled patients, except for those withdrawn prior to study treatment or fail to receive study treatment for various reasons, will be included in the efficacy analysis. The primary endpoint will be objective response rate (ORR) per RECIST 1.1. Patients with confirmed partial or complete responses will be considered responders and patients without a confirmed partial or complete response will be considered non‐responders.  
Patients who stop therapy prior to confirmation of response per RECIST will be considered non‐responders.  
Patients who are not able to get radiographic assessment for all reasons will be considered non‐responders.  
At the end of the trial, the ORR will be estimated using the UMVUE method, and the p‐value and 95%
confidence interval willcalculated.37,38 Progression free survival (PFS) using RECIST 1.1 as assessed by the investigator. Progression will be defined as time from start of study therapy to disease progression or death (whichever occurs first). Patients who are not able to get radiographic assessment for all reasons will be considered disease progression at the time they discontinue protocol therapy for the PFS analysis. Patients who stop therapy for reasons other than disease progression will be followed for disease progression. Patients who have not experienced an event of interest by the time of analysis will be censored at the date they are last known to be alive and progression‐
free. Overall survival (OS) is defined as the time from start of study therapy to death from any cause, and patients who are alive at the time of analysis will be censored at the last date of contact. Time to event endpoints will be summarized using the method of Kaplan and Meier as well. The association of baseline covariates with time to event endpoints will be evaluated by multivariable Cox regression models. Potential baseline covariates to include in the models are smoking history, mutation subtype, gender, and performance status.  
The evaluation of safety using the AE using NCI CTCAE version 4.03. All patients who receive at least one dose of study treatment will be included in the safety analysis. The frequencies and percentage of treatment‐
related adverse events by type and gradewill be tabulated. Immune and angiogenesis biomarkers will be measured with the samples collected at baseline and during treatment. The changes (mean, SD, etc) of these biomarkers relative to baseline will be summarized by collection time. The trajectory of the changes and the effects of baseline risk factors on the trajectorywill be evaluated in linear mixedmodels. The measures at baseline and their changes during treatment relative to baseline will be correlatedwith clinical outcomes using logistic regression for ORR and Cox egression for PFS
and OS with starting time reset to collection time.
11. 5 quality control and
accrual and follow-up

Taking into 5% ineligibility/cancelation rate, we will enroll approximately 41 patients to have 39 evaluable patients for the efficacy analysis of the trial. At a rate of 1 to 2 patients per month, we expect that trial will take approximately 20‐41 months to reach its target of 39 evaluable patients if it will not be terminated earlier based on the planned interim analysis. All patients will be followed for disease progression from the date that the subjects started on the study until disease progressiony. Patients will be followed for overall survival until death or for a maximum 2 years from discontinuation of study therapy (whichever occurs first).
11. 5 quality control and
handling of missing values censoring

Ineligible subjects and subjects who do receive any study therapy will not be included in the efficacy analyses. Patients who receive at least one dose of the experimental therapy will be included in the safety analysis.
13 administrative and ethicalconsiderations
regulatory and ethical compliance

This protocol was designed and will be conducted and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable federal, state, and local regulations.