Clinical trial NCT02803203
Conditions: Non-small Cell Lung Cancer EGFR-mutant Lung Cancers
Keywords: Osimertinib bevacizumab metastatic 16-033
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2016-06-29; Completion date: 2022-03-01
Enrollment: 49 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test the safety of combining the drugs osimertinib and bevacizumab at different dose levels. The investigators want to find out what effects, good and/or bad, taking osimertinib and bevacizumab has on the patient and lung cancer. This study will try to find the best dose of osimertinib and bevacizumab given together that does not cause significant side effects. Once the investigators determine that combining osimertinib and bevacizumab is safe, they want to see if the combination is effective in treating lung cancers with the EGFR mutation.

Detailed description:

Arms: arm 1: Phase 1:

3+3 dose escalation design 2 dose levels Dose level -1: Osimertinib 40mg daily Maximum accrual = 12 Bevacizumab 15mg/kg q3 weeks Dose level 1: Osimertinib 80mg daily Bevacizumab 15mg/kg q3 Weeks

Phase 2:

Use MTD determined during phase 1
Interventions: intervention 1: osimertinib intervention 2: Bevacizumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-033 A(17) 
Approval date: 16-Dec-2020 
 
 
 
 
 
MSK PROTOCOL COVER SHEET 
 
A Phase 1/2 study of combination osimertinib and bevacizumab as treatment for patients with 
EGFR-mutant lung cancers 
Principal Investigator/Department: Helena Yu, MD/ Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
Page 1 of 47 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-033 A(17) 
Approval date: 16-Dec-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 5 of 47 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEM A .................................................................................................................................. 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................. 8 
3.0 
BACKGROUND AND RATIONALE ...................................................................................... 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................................. 9 
4.1 
Design .................................................................................................................. 9 
4.2 
Intervention ................................................................................................................. 10 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS ............................................................................ 11 
6.0 
CRITERIAFOR SUBJECT ELIGIBILITY ............................................................................... 12 
6.1 
Subject Inclusion Criteria ..................................................................................... 12 
6.2 
Subject Exclusion Criteria .................................................................................... 12 
7.0 
RECRUITMENT PLAN ........................................................................................................ 12 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 13 
9.0 
TREATMENT/INTERVENTION  PLAN ................................................................................. 14 
10.0 EVALUATION  DURING TREATMENT/INTERVENTION .................................................... 15 
11.0 TOXICITIES/SIDE EFFECTS ..................................................................................................... 16 
12.0 CRITERIAFOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 19 
13.0 CRITERIAFOR REMOVAL FROM STUDY ........................................................................ 21 
14.0 BIOSTATISTICS .................................................................................................................. 22 
15.0    RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES   24 
15.1 Research Participant Registration ....................................................................... 24 
15.2 Randomization ...................................................................................................... 25 
16.0 DAT A M ANAGEMENT ISSUES .......................................................................................... 25 
16.1 Quality Assurance ......................................................................................... 25 
16.2 Data and Safety Monitoring .................................................................................. 25 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................26 
17.1 Privacy ............................................................................................................. 27 
17.2 Serious Adverse Event (SAE) Reporting .......................................................... 27 
17.2.1    ................................................................................................................................... 
29 
18.0 INFORMED CONSENT PROCEDURES ................................................................................. 29 
19.0 REFERENCES ......................................................................................................................... 29 
20.0 APPENDICES ..................................................................................................................... 31 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-033 A(17) 
Approval date: 16-Dec-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 6 of 47 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title: A Phase 1/2 study of combination Osimertinib and bevacizumab as treatment for 
patients with EGFR-mutant lung cancers 
Study 
Objectives: 
Phase 1: 
Primary Objective:  To determine the maximum tolerated dose of combination 
Osimertinib and bevacizumab in patients with untreated EGFR-mutant lung cancers. 
Phase 2: 
Primary Objective:   Assess the progression-free survival at 12 months of combination 
Osimertinib and bevacizumab in patients with untreated EGFR-mutant lung cancers. 
Secondary Objectives: 1) Measure overall response rate (CR+PR), 2) measure 
progression-free survival 3)measure intracranial progression-free survival 4) measure 
overall survival 5) further define the toxicity profile of the combination 
Correlative Studies: 
Objectives: 1) to identify EGFR T790M in pre and post treatment samples and correlate 
with PFS on Osimertinib and bevacizumab 2) perform next-generation sequencing 
based mutation testing on tumors before treatment and at progression. 
Patient 
Population: 
Patients with locally advanced or metastatic lung adenocarcinomas with a confirmed 
EGFR mutation not yet treated with an EGFR TKI. 
Number of 
patients: 
Phase 1: Maximum of 12 patients 
Phase 2: Maximum of 46 patients (including 6  from the phase 1) 
Inclusion 
Criteria: 
All patients must have: 
• 
Written informed consent 
• 
Advanced biopsy-proven metastatic non-small cell lung cancer 
• 
Somatic activating mutation in EGFR 
• 
No prior treatment with an EGFR TKI. 
• 
No prior treatment with a VEGF inhibitor. 
• 
Measurable (RECIST 1.1) indicator lesion not previously irradiated 
• 
Karnofsky performance status (KPS) ≥ 70% 
• 
Age >18 years old 


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Exclusion 
Criteria: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-033 A(17) 
Approval date: 16-Dec-2020 
Patients are to be excluded from the study if they meet any of the following criteria: 
• Any contra-indications to bevacizumab as per the investigator’s discretion. 
Possible contra-indications include but are not limited to recent thromboembolic 
disease, severe uncontrolled hypertension (systolic blood pressure >180 mmHg 
and/or diastolic blood pressure > 120mmHg), cardiovascular disease, risk of 
bleeding, hemorrhagic brain metastases, history of severe proteinuria (urine 
dipstick ≥ 2+ or 24 hr urine > 2gm/24hr)) 
• Pregnant or lactating women 
• Any type of systemic anticancer therapy (chemotherapy or experimental drugs) 
within 2 weeks of starting treatment on protocol. 
• Any major surgery within 4 weeks of starting treatment on protocol. 
• Any radiotherapy within 1 week of starting treatment on protocol. 
• Any evidence of clinically significant interstitial lung disease 
• Any other condition that, in the opinion of the investigator, may compromise the 
safety of the patient, or would preclude the patient from successful completion 
Study drug: Osimertinib (also known as AZD9291)and bevacizumab 


 
 
 
Study 
Design: 
 
Phase 1: 
This portion of the study will assess whether combination Osimertinib and bevacizumab 
given at the doses below is safe and tolerable. Osimertinib and bevacizumab have non- 
overlapping toxicity profiles and we expect that we will be able to utilize the full doses of 
both agents. A 3+3 dose-escalation design will be utilized. 
 
Three patients will be enrolled at a dose level and assessed for dose limiting toxicities 
(DLTs) for 1 full cycle (21 days). Toxicity will be graded according to NCI CTCAE 
version 4. If 2 or more patients develop a DLT at dose level 1, we will de-escalate and 
utilize dose level -1.  If 2 or more patients develop a DLT at dose level -1, we will review 
toxicity and consider alternative dosing through a protocol amendment. 
 
The MTD (maximum tolerated dose)/recommended phase 2 dose will be the highest 
dose level at which <1 DLT is detected in the first cycle for 6 treated patients. If only 3 
patients are treated at a dose level being considered for the MTD, an additional 3 
patients will be enrolled. 
 
Table 1: Dose levels 
Dose level 
Osimertinib 
Bevacizumab 
-1 
40mg daily 
15mg/kg every 3 weeks 
1 
80mg daily 
15mg/kg every 3 weeks 
 
Phase 2: 
Once the phase 1 portion  of the study has been completed,  patients  will be 
enrolled  in the phase 2 portion  of the single-arm  study of Osimertinib  and 
bevacizumab.  A cycle will be 21 days  in length.  Osimertinib  will be dosed daily 
and bevacizumab  is dosed once every 3 weeks. Response to therapy  will  
initially  be assessed by interval  imaging  every 3 cycles of treatment  with CT 
scan of the chest/abdomen/pelvis  with response evaluated  by RECIST 1.1.   An 
additional  40 patients  (for a total  of 46) will be enrolled  at the MTD. The six 
patients  treated  at the MTD in the phase 1 will be included  in the phase 2 study. 
 
Correlative studies: 
Molecular  testing  will be performed  on archived  pre-treatment  tumor specimens. 
A rebiopsy at the time of clinical progression on EGFR TKI will not be mandated 
per protocol,  but is typically  done as per standard  of care. 
 
EGFR T790M  is routinely  identified  in tumor tissue by several  standard  methods 
including  a mass spectrometry  based mutation  platform  (Sequenom),  locked 
nucleic  acid based PCR sequencing  or by next  generation  sequencing.  Our 
next-generation  sequencing  based mutation  platform  (IMPACT)  will be 
performed  to compare the molecular  alterations  in pre and post treatment 
specimens. The sequencing  data will be analyzed  for base mutations, 
insertions,  deletions,  copy number alterations  and 
 
 
 
 
 
 
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1275 York Avenue 
New York, New York 10065 
 
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Memorial  Sloan Kettering Cancer Center 
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New York, New York 10065 
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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Phase 1: 
Primary Objective:  To determine the maximum tolerated dose of combination Osimertinib and 
bevacizumab in patients with untreated EGFR-mutant lung cancers. 
 
Phase 2: 
Primary Objective:   Assess the progression-free survival at 12 months of combination Osimertinib and 
bevacizumab in patients with untreated EGFR-mutant lung cancers. 
Sec ondary Objectives: 1) measure overall response rate (CR+PR), 2) measure progression-free 
survival 3) measure intracranial progression-free survival 4) measure overall survival 5) further define the 
toxicity profile of the combination 
 
Correlative Studies: 
Objectives: 1) to identify EGFR T790M in pre and post treatment samples 2) perform next- 
generation sequencing based mutation testing on tumors before treatment and at progression. 
 
3.0 
BACKGROUND AND RATION ALE 
 
EGFR-mutant lung cancers 
Twenty percent of patients with metastatic lung adenocarcinoma have somatic activating mutations in the 
epidermal growth factor receptor gene (EGFR). Patients with EGFR-mutant lung adenocarcinomas have a 
70% response rate to first-line EGFR-TKI therapy (erlotinib or afatinib) and a median progression-free 
survival of 9-12 months.(1) First-line EGFR TKI therapy is superior to cytotoxic chemotherapy and is 
recommended as first-line treatment for patients with EGFR-mutant 
lung cancers. All patients will develop resistance to EGFR TKI therapy and clinical progression. The 
majority of patients acquire a second mutation, EGFR T790M,  as their dominant mechanism of 
resistance.(2) 
 
Third-generation EGFR TKIs 
There are several EGFR T790M inhibitors in clinical development including Osimertinib.(3) These agents 
were initially tested in the acquired resistance setting, after progression on first-line, first- generation EGFR 
tyrosine kinase inhibitors. The overall response rate to Osimertinib in patients who harbor EGFR T790M in 
their lung cancers is 61% and the overall response rate in all patients was 
51%. Osimertinib inhibits mutant EGFR selectively over wild-type EGFR, and avoids significant wild- type 
EGFR toxicity. The most frequent adverse events seen with Osimertinib in the phase 1 study include 
diarrhea (47%), rash (40%), nausea (22%) and decreased appetite (21%). The side effect profile is mild 
and comparable to what is seen with erlotinib. Treatment with erlotinib in BR.21 had an adverse event 
profile (all grades) that included fatigue (79%), rash (76%), anorexia (69%), diarrhea (55%), and nausea 
(40%). In contrast, osimertinib had an adverse event profile (all grades) that included diarrhea (47%), rash 
(40%), nausea (22%), anorexia (21%), and fatigue (17%).  Osimertinib received accelerated approval in 
November 2015, for the treatment of patients with NSCLC with EGFR T790M mutation who have 
progressed on a previous EGFR TKI. The FDA approved dose of osimertinib is 80mg orally once daily. 
 
Due to its efficacy and tolerable side effect profile, Osimertinib is beginning evaluation as first-line therapy 
genomic  rearrangements  in all target  genes. 


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for patients with EGFR-mutant lung cancers (NCT02296125). FLAURA is a first 
line study randomizing patients to either Osimertinib versus erlotinib or gefitinib; the primary 
endpoint of the study is progression free survival. In addition, there was a first line cohort in the AURA study 
of patients who received osimertinib as first-line treatment for metastatic EGFR-mutant lung cancer. Interim 
data was presented at ASCO in 2015; 60 patients were treated. The overall response rate was 73%. The 
median progression-free survival was not yet reached, but 72% of patients (95% CI 55%-84%) were 
progression-free at 12 months. 
 
Use of VE GF inhibitors in lung canc ers 
Rational combinations of targeted therapies have been constantly assessed in order to improve patient 
outcomes. Pro-angiogenesis pathways have been an important therapeutic target as they 
are essential for tumor growth and metastases. The best characterized pro-angiogenesis pathway is 
vascular endothelial growth factor (VEGF) signaling pathway. Several studies have demonstrated 
improved overall survival with the addition of VEGF inhibitors to standard cytotoxic chemotherapies in 
non-small cell lung cancers.(4-6) Recent studies have combined VEGF inhibitors (bevacizumab, 
ramucirumab and nintedanib)  with first-line and second-line chemotherapy and demonstrated 
improvements in overall survival. Avastin is approved in non-small cell lung cancer for combination use 
with cytotoxic chemotherapy. The FDA approved dose of bevacizumab is 15mg/kg given once every 3 
weeks. 
 
Preliminary data/Feasibility 
EGFR TKI and bevac izumab 
The combination of erlotinib and bevacizumab was first-tested after progression on first-line platinum based 
therapy in molecularly unselected patients. These studies did not meet their primary endpoint 
but a subgroup analysis suggested that in patients with EGFR-mutant lung cancer, the combination 
of erlotinib and bevacizumab improved progression free survival compared to erlotinib alone (7, 8). Based 
on this data, a phase 2 study in Japan randomized untreated patients with EGFR-mutant lung 
cancers to erlotinib or erlotinib plus bevacizumab with a primary endpoint of progression-free 
survival (PFS). The median PFS was 16.0 months on the combination compared to 9.7 months with 
erlotinib alone, HR 0.54, 95% CI 0.36-0.79, p=0.0015(9). Higher incidences of hypertension, bleeding and 
proteinuria were seen in the patients that received bevacizumab and erlotinib compared to erlotinib alone. 
A separate single-arm phase 2 was conducted in Japan that assess the combination of gefitinib and 
bevacizumab as first-line therapy in patients with advanced NCLC harboring EGFR mutations(10). The 
objective response rate was 73.8% and the median PFS was 
14.4 months. The PFS on the study was 4 to 50 months longer with bevacizumab and gefitinib 
compared to historical EGFR TKI monotherapy(11-14). Both studies, erlotinib plus bevacizumab and 
gefitinib plus bevacizumab, treated patients with full, FDA-approved doses of both agents, in large 
part due to their non-overlapping toxicity profiles. 
 
Innovation 
First-line Osimertinib has the potential to extend progression free survival for patients with EGFR- mutant 
lung cancers. As the addition of bevacizumab to erlotinib or gefitinib appears to significantly improve 
outcomes, the intuitive next study is to combine Osimertinib and bevacizumab in the first- line setting. W e 
will perform a phase 1/2 to further assess toxicity and preliminary efficacy of osimertinib and bevacizumab 
in the first line setting in patients with EGFR mutant lung cancers. Due to largely non-overlapping toxicity 
profiles, we will treat patients and full, FDA-approved doses of both agents and allow for a step-down dose 
level -1 if the dose level 1 is not well tolerated. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 


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4.2 
Design 
 
This is a phase 1/2 single institution study of Osimertinib and bevacizumab in patients  with 
EGFR-mutant lung cancer. 
 
 
 
 
 
Key Eligibility 
Untreated Metastatic EGFR+ NSCLC 
No prior treatment with EGFR TKI 
No contraindications to bevacizumab 
 
 
Phase 1: 
3+3 dose escalation design 
2 dose levels 
Dose level -1: Osimertinib 40mg daily 
Maximum accrual = 12 
 
Bevacizumab 15mg/kg q3 weeks 
Dose level 1: Osimertinib 80mg daily 
Bevacizumab 15mg/kg q3 Weeks 
 
Phase 2: 
Use MTD determined during phase 1 
Primary endpoint: PFS @ 12 months 
Maximum accrual= 46 (including 6 from phase 1) 
 
 
 
4.3 
Intervention 
 
Phase 1: 
This portion of the study will assess whether combination Osimertinib and bevacizumab given at the 
doses below is safe and tolerable. Osimertinib and bevacizumab have non-overlapping toxicity 
profiles and we expect that we will be able to utilize the full doses of both agents. A 3+3 dose- 
escalation design will be utilized. 
 
Three patients will be enrolled at a dose level and assessedfor dose limiting toxicities (DLTs) for 1 
full cycle (21 days). Toxicity will be graded according to NCI CTCAE version 4. If 2 or more patients 
develop a DLT at dose level 1, we will de-escalate and utilize dose level -1. If 2 or more patients 
develop a DLT at dose level -1, we will review toxicity and consider alternative dosing through a 
protocol amendment. 


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The MTD (maximum tolerated dose)/recommended phase 2 dose will be the highest dose level at 
which <1 DLT is detected in the first cycle for 6 treated patients. If only 3 patients are treated at a 
dose level being considered for the MTD, an additional 3 patients will be enrolled. 
 
 
Table 1: Dose levels 
 
Dose level 
Osimertinib 
Bevacizumab 
-1 
40mg daily 
15mg/kg every 3 weeks 
1 
80mg daily 
15mg/kg every 3 weeks 
 
Phase 2: 
Once the phase 1 portion of the study has been completed, patients will be enrolled in the phase 2 
portion of the single-arm study of Osimertinib and bevacizumab. A cycle will be 21 days in length. 
Osimertinib will be dosed daily and bevacizumab is dosed once every 3 weeks. Response to therapy 
will initially be assessed by interval imaging every 3 cycles of treatment with CT scan of the 
chest/abdomen/pelvis with response evaluated by RECIST 1.1.  An additional 40 patients (for a total 
of 46) will be enrolled at the MTD. The six patients treated at the MTD in the phase 1 will be included 
in the phase 2 study. 
 
Correlative studies: 
Molecular  testing will be performed on archived pre-treatment tumor specimens. A rebiopsy at the 
time of clinical progression on EGFR TKI will not be mandated per protocol, but is typically done as 
per standard of care. 
 
EGFR T790M is routinely identified in tumor tissue by several standard methods including a mass 
spectrometry based mutation platform (Sequenom), locked nucleic acid based PCR sequencing or 
by next generation sequencing. Our next-generation sequencing based mutation platform (IMPACT) 
will be performed to compare the molecular alterations in pre and post treatment specimens. The 
sequencing data will be analyzed for base mutations, insertions, deletions, copy number alterations 
and genomic rearrangements in all target genes. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Osimertinib 
Osimertinib will be provided by Astra Zeneca. Osimertinib is a crystalline powder presented for oral 
administration as a beige, film- coated tablet containing either 40mg or 80mg of Osimertinib. 
Osimertinib beige film-coated tablets contain Osimertinib mesylate, mannitol, microcrystalline 
cellulose, low-substituted hydroxypropyl cellulose and sodium stearyl fumarate. Tablets will come in 
high-density polyethylene (HDPE) bottles with child-resistant closures. Tablets should be stored in 
their original packaging at room temperature. Osimertinib is administered as a once daily dose 
(fasting). Patients will be required to fast (can take with water only) for at least one hour prior to 
taking a dose until two hours post-dose. 


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5.2 Bevac izumab 
 
Bevacizumab will be supplied by Genentech. Bevacizumab is a humanized monoclonal antibody that 
binds all five isoforms of human VEGF. It is FDA approved for the treatment of metastatic non- 
squamous, non-small cell lung cancers. It is a recombinant human antibody consisting of 93% 
human and 7% murine amino acid sequences. Bevacizumab is supplied as a clear to slightly 
opalescent, sterile liquid ready for parenteral administration. Each 400mg (25mg/mL- 16 mL fill)  
glass vial contains bevacizumab with phosphate, trehalose, polysorbate 20 and sterile water for 
injection, USP. Bevacizumab should be stored in the refrigerator (2-8 degrees Celsius) and should 
be refrigerated until just prior to use. Bevacizumab is administered intravenously every 3 weeks. It 
can be given irrespective of fasting or fed state. Bevacizumab will be prepared and administered  
per institutional guidelines outlined in section 9.1.2. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 Subject Inclusion Criteria 
 
• 
Written informed consent 
• 
Advanced biopsy-proven metastatic non-small cell lung cancer 
• 
Somatic activating mutation in EGFR 
• 
No prior treatment with an EGFR TKI. 
• 
No prior treatment with a VEGF inhibitor. 
• 
Measurable (RECIST 1.1) indicator lesion not previously irradiated 
• 
Karnofsky performance status (KPS) ≥ 70% 
• 
Age >18 years old 
• 
Adequate organ function 
o AST, ALT < 3 x ULN 
o Total bilirubin < 1.5x ULN 
o Creatinine < 1.5x ULN OR calculated creatinine clearance > 60ml/min 
o Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 
o Hemoglobin≥8.0 g/dL 
o Platelets ≥100,000/mm3 
6.3 
Subject Exclusion Criteria 
 
• Any contra-indications to bevacizumab which include but are not limited to recent 
1. Any previous venous thromboembolism > NCI CTCAE Grade 3 
2. Severe uncontrolled hypertension (systolic blood pressure >150 mmHg and/or 
diastolic blood pressure >100mmHg) 
3. Cardiovascular disease including stroke of myocardial infarction <6 months prior to study 
enrollment, New York Heart Association Grade 2 or greater congestive heart failure, serious 
cardiac arrythmia uncontrolled by medication 
4. Hemorrhagic brain metastases. Asymptomatic  (not requiring  escalating  doses of 
steroids)  brain metastases are acceptable. 
5. History of severe proteinuria (urine dipstick ≥ 2+ or 24 hr urine > 2gm/24hr) 
6. Prior history of hypertensive crisis or hypertensive encephalopathy 
7. History of a central nervous system disease (e.g. seizures) unrelated to cancer unless 


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adequately treated with standard medical therapy 
8. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair) <6 months 
prior to study enrollment 
9. History of hemoptysis  (>1/2 teaspoon of bright red blood per episode) within the last 3 
months 
10. Evidence of a bleeding diathesis or significant coagulopathy (in the absence of 
therapeutic  anticoagulation) 
11. Current or recent (within 10 days of study drug start) use of aspirin (>325mg daily), 
clopidogrel (>75mg daily). 
12. Recent initiation of full dose oral or parental anticoagulants that have not been in place 
for at least 2 weeks. 
13. Tumor invading or abutting major blood vessels 
14. Tumor histology classified by squamous cell histology. 
15. Any history of abdominal fistula or GI perforation within 6 months of study enrollment 
 
• Pregnant or lactating women 
• Any type of systemic anticancer therapy (chemotherapy or experimental drugs) within 2 weeks 
of starting treatment on protocol. 
• Any radiotherapy within 1 week of starting treatment on protocol. 
• Any major surgery within 4 weeks of starting treatment on protocol. 
• Any evidence of clinically significant interstitial lung disease 
• Known hypersensitivity to any component of bevacizumab and osimertinib. 
 
 
7.0 
RECRUITMENT PLAN 
A member of the patient’s treatment team, the protocol investigator, or research team at Memorial 
Sloan Kettering Cancer Center will identify potential research participants. If the investigator is a part of the 
treatment team, s/he will screen the patient as to eligibility, and will discuss the study and the possibility of 
enrollment in the research study with the patient. The preliminary screen of eligibility 
will be confirmation for the diagnosis of the following: 
 
• 
Patientswith metastatic EGFR mutant lung cancers 
 
Potential subjects that meet these basic criteria will be referred by their treatment physician to the 
investigator, co-investigators, or research staff of the study. Minority and women are well represented in 
the thoracic oncology clinics, and we expect that they will be well represented in the trial accrual. The 
principal investigator, Dr. Helena Yu, will be available to all patients for further questions and information 
through a contact number which will be provided on the consent form itself. 
 
During the initial conversation between the investigator/research staff and the patient, the patient may be 
asked to provide certain health information that is necessary to the recruitment and enrollment process. The 
investigator/research staff may also review portions of their medical records at MSKCC in order to further 
assess eligibility. They will use the information provided by the patient and/or medical record to confirm that 
the patient is eligible and to contact the patient regarding study enrollment. If the patient turns out to be 
ineligible for the research study, the research staff will destroy all information collected on the patients  
during the initial conversation and medical records review, except for any information that must be 
maintained for screening log purposes. 


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All recruited patients will be under the care of attending medical oncologists of the MSKCC Thoracic 
Oncology Service. There will be no direct advertising for this study and participants will not be reimbursed 
for participation.  Patients will be accrued to this study without regard for gender or minority status. The 
study will be available to the public and the details of the inclusion criteria, exclusion criteria and study 
design will be posted at www.clinicaltrials.gov. 
 
8.1 
PRETREATMENT EVALU ATION 
 
The following tests must be completed within 28 days of started treatment on study unless otherwise noted. 
• 
Documented presence of the EGFR mutation within the patient’s tumor (no time window) 
• 
Medical history 
• 
Baseline tumor assessment with CT scan of the chest/abdomen/pelvis is preferred, or other 
comparable radiologic study (PET scan) can be utilized if adequate assessment of target lesions 
can be performed. Tumor burden measurable by RECIST 1.1 
• 
Baseline CNS assessment with contrast-enhanced MRI brain (or CT if MRI is 
contraindicated). This can be within 8 weeks of study start. 
• 
Physical examination, vital signs (pulse, blood pressure, temperature, respiratory rate) as well 
as weight. 
• 
12-lead electrocardiogram (ECG) (within 8 weeks of study start) 
• 
Performance status by KPS 
• 
Serum or urine pregnancy test (for premenopausal women with child-bearing potential) 
• 
Complete blood count with differential 
• 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, potassium, 
chloride, bicarbonate, calcium, total protein, albumin, serum bilirubin, alkaline phosphatase, 
ALT, AST) 
• 
Urinalysis, dipstick 
• 
EGFR T790M plasma blood test 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 Therapeutic Agents 
 
9.2.1 Therapeutic Agent –    Osimertinib 
Osimertinib will be provided by AstraZeneca. A pill diary will be used to track adherence. Osimertinib is 
administered daily, at approximately the same time of day every day. Osimertinib should be taken on an 
empty stomach (at least 1 hour before, or 2 hours after the ingestion of food). If the patient forgets to take 
his/her daily dose, he/she should take Osimertinib within 12 hours after the missed dose. If more than 12 
hours have elapsed, that day’s dose should be omitted, and the patients should continue treatment with the 
next scheduled dose. 
 
9.2.2 Therapeutic Agent –    Bevac izumab 
Bevacizumab will be provided by Genentech. Bevacizumab is administered intravenously every 3 
weeks (21 days) at the FDA approved dose level of 15 mg/kg. If an infusion is not tolerated well (ie. 


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Fever, chills) then the subsequent infusion(s) should be given over a prolonged infusion time (i.e. 60 – 
90 min). Premedications (ie. Acetaminophen, diphenhydramine, corticosteroids) may be given to 
prevent/reduce the incidence/severity of reactions; however routine prophylactic use of premedications 
is not recommended. 
 
9.2 Treatment arms 
All patients will receive daily Osimertinib and every 3 week bevacizumab in this single-arm study. 
 
9.3 Phase 1 study 
This portion of the study will assess whether combination Osimertinib and bevacizumab is safe and 
tolerable. The study will follow a standard 3+3 dose escalation trial design. Three to six patients will need to 
be enrolled at each dose level and assessed for DLT for 1 full cycle (21 days). Toxicity will be graded 
according to NCI CTCAE version 4.0. Patients who do not complete 21 days of treatment for reasons other 
than experiencing a DLT will be replaced. For the purposes of dose-escalation decisions, only DLTs 
occurring during the first cycle (21 days) will be considered. Patients in each cohort must complete the first 
3 weeks of study therapy prior to enrollment of subsequent cohorts. 
 
9.4 Dose-Limiting Toxicities 
The NCI Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE) will be used to grade 
toxicities during the trial. Dose-limiting toxicities (DLT’s) are defined as any of the following events occurring 
during the first cycle of treatment (i.e. 21 days) that are, in the opinion of the 
treating physician, possibly, probably, or definitely related to the investigational  regimen: 
• 
Death related to the investigational regimen 
• 
Hematologic toxicities including: 
o Grade 4 neutropenia lasting > 5 days 
o Grade 4 thrombocytopenia (<25,000/mm3) 
o Grade ≥ 3 thrombocytopenia with evidence of clinically significant bleeding 
o Grade 4 anemia 
• Non-hematologic  toxicities including: 
o Grade ≥ 3 AST, ALT, alkaline phosphatase or total bilirubin 
o Grade ≥ 3 diarrhea, nausea, vomiting that lasts > 72 hrs despite optimal maximal 
supportive care 
o Grade >3 rash that persists >7 days despite supportive medications 
o Grade >4 diarrhea, nausea or vomiting 
o Any other non-hematologic grade ≥ 3 major organ toxicity 
9.5 Phase 2 Study 
Once the phase 1 portion of the study has been completed, patients will be enrolled in the phase 2 
portion of the single-arm study of Osimertinib and bevacizumab in the treatment of patients with 
EGFR-mutant lung cancers.  Response to therapy will be assessed by interval imaging every 9 
weeks +/- 1 week (every 3 cycles) with CT scan of the chest/abdomen/pelvis with response 
evaluated by RECIST 1.1. A maximum of 46 patients will be enrolled during this portion of the study. 
This phase 2 total accrual will include six patients treated at the MTD in the phase 1. To reach the 
primary endpoint of the phase 2 study, 43 patients will need to be response evaluable. As a result, a 


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total of 46 patients will be enrolled to account for potential patient-drop out. 
9.6  Correlative Studies 
Molecular  testing will be performed on archived pre-treatment tumor specimens if available. A 
rebiopsy at the time of clinical progression on EGFR TKI will not be mandated per protocol, but is 
typically done as per standard of care. 
 
EGFR T790M is routinely identified in tumor tissue by several standard methods including a mass 
spectrometry based mutation platform (Sequenom), locked nucleic acid based PCR sequencing or 
by next generation sequencing. Our next-generation sequencing based mutation platform (IMPACT) 
will be performed to compare the molecular alterations in pre and post treatment specimens. The 
sequencing data will be analyzed for base mutations, insertions, deletions, copy number alterations 
and genomic rearrangements in all target genes. 
 
9.6.1 Optional Studies 
W e propose to an obtain biopsy in patients with metastatic EGFR-mutant lung cancer at initial    
clinical response at 4 weeks +/- 1 week on study. There will be an optional CT scan at 4 weeks to    
demonstrate response, and an optional biopsy of residual disease in patients w ithout disease 
progression on that initial scan. Patients that provide consent to the optional 4 week scan and 
biops y will allow us to better understand the molecular mechanisms underlying intrinsic and    
acquired resistance. W e will be performing IMPACT tes ting on these obtained samples, and     
compare to the pre-treatment and post-treatment tumor samples. 
 
9.7 Treatment Beyond Disease Progression 
 
Subjects will be permitted to continue study treatment beyond initial RECIST 1.1 defined PD, 
assessed by the investigator, as long as they meet the following criteria: 
• 
Investigator-assessed clinical benefit, and do not have rapid disease progression 
• 
Tolerance of study drug 
• 
Stable performance status 
• 
Subject provides written informed consent prior to receiving additional study treatment 
acknowledging the possibility of any reasonably foreseeable risk or discomforts, as well 
as the possibility of alternative treatment options. 
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. 
If the investigator feels that the subject continues to achieve clinical benefit by continuing treatment, 
the subject should remain on the trial and continue to receive monitoring according to the Study 
Calendar in Section 10.0.  A radiographic assessment should be performed at the next scheduled 
time point to determine whether there has been a decrease in the tumor size or continued 
progression of disease. 


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10.0 EVALU ATION DURING TREATMENT/INTERVENTION 
 
The table below outlines the schedule of assessments applied to patients. All assessments, 
including drug dosing, have a window of +/- 5 days for cycle 1, and +/- 7 days for cycle 2 and 
beyond unless otherwise noted. If the subject is unable to have a study assessment taken within 
the defined time window due to an event outside of his or her control (e.g. clinic closure, personal 
emergency, inclement weather, vacation) the assessment should be performed as close as 
possible to the required schedule, at which time the window clock will reset and the patient will have 
a +/- 7 day window from the date of their visit. Tumor assessments have a window of +/- 1 weeks. If 
an appropriate imaging study is done for an unrelated reason, it can be used for disease 
assessment if it falls within the appropriate time frame. Subjects will return to the study site within 
30 days after their last dose of Osimertinib and bevacizumab to complete end of study 
assessments outlined below. 
 
Study 
Assessments 
Screening 
Cycle 1 
Cycle 2+ 
At 
Progression/Off 
Study 
Day 
Within 4 weeks 
C1D1 
C1D8 
C2D1 + 
Informed Consent 
X 
Medical History 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
12-lead EKG 
X 
Tumor 
Assessment1,  8 
X 
X 
X 
Pregnancy Test6 
X 
X6 
CBC2 
X 
X 
X 
X 
CMP3 
X 
X 
X 
X 
Urinalysis, 
Dipstick5,10 
X 
X 


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IMPACT testing4 
X 
X
EGFR T790M 
testing7 
X 
X7 
Tumor Biopsy9 
(optional) 
X9 
X9 
 
1. CT chest/abdomen/pelvis with or without contrast (preferred and will be used for all subsequent scans after screening). CT 
will be done at screening, every 9 weeks (+/- 1 week) and at progression, or when patient com es off study. An MRI of the 
brain, or a comparable study, will be done every 18 weeks (+/- 1 weeks), unless patient is found to have brain metastases 
after baseline/FU 1 scans are completed. If brain metastases are found, the patient will have a brain MRI completed every 9 
weeks instead of every 18 weeks . Patients that do not have brain metastases will still require a brain MRI every 18 weeks on 
study. 
2. CBC- complete blood count with differential 
3. CMP-com prehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, bicarbonate, 
calcium, total protein, albumin, serum bilirubin, alkaline phosphatase, ALT, AST) 
4. IMPACT molecular profiling will be done on pre-treatment archived tissue if available. If a post-progression biopsyis performed 
as standard of care, IMPACT molecular results will be obtained. A post-progression biopsyis not mandatoryor included in the 
protocol. 
5. Urinalysis, dipstick will be done at screening and every 2 cycles to monitor for proteinuria. If urine protein (dipstick) is > 2+, then 
a 24 hour urine protein test will be administered. 
6. A urine pregnancy test will be done every 4 cycles for women of childbearing age . 
7. An EGFR T790M plasma blood test is to be completed at screening and at progression or off study . 
8. Optional tumor assessment scans will be completed 4 weeks post Cycle 1 Day 1 (+/- 14 day window) to determine initial clinical 
response. 
9. Optional tumor biopsywill be completed within 2 weeks (=/- 14 day window) post the optional 4 week tumor scan if initial 
clinical response is confirmed. Patient must consent to both optional assessments. Initial clinical response is defined as stable 
disease, a partial response or a complete response to treatment. 
10. Urinalysis, dipstick is not required for patients who have discontinued bevacizumab. 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Adverse events occurring in patients treated with Osimertinib and bevacizumab may be 1) 
overlapping toxicities seen in both agents; 2) toxicities typically associated with Osimertinib (i.e. 
rash, diarrhea) or 3) toxicities typically associated with bevacizumab (hypertension). However, 
toxicities with individual agents may be potentiated in the combination or unanticipated AEs may 
occur.  The dose modifications or discontinuations may involve one or both agents, and should be 
based on the nature, severity, and attributions of the AEs. Differentiation of the causative agent for 
adverse events for the purposes of dose modifications are at the discretion of the treating physician 
and/or principal investigator. General guidelines are provided below.. For safety and adverse event 
reporting, see Section 17.0. 
 
W hile AEs may be thought to be related to individual agents for purposes of dose modifications, all 
toxicities will be considered related to combination therapy for description of AE profile. 
 
11.1 Osimertinib Related Toxicities: 


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Toxicities with Osimertinib that are likely (>20%) include: 
• 
Rash 
• 
Diarrhea 
• 
Nausea 
• 
Decreased appetite 
• 
Dry skin 
 
 
Toxicities with Osimertinib that are less likely (<20%) include: 
• 
Itchy skin 
• 
Decreased energy 
• 
Nail changes 
• 
Mucositis 
• 
Constipation 
• 
Cough 
• 
Vomiting 
• 
Low red blood cell counts which can lead to fatigue 
• 
Shortness of breath 
• 
Upper respiratory tract infections 
• 
Headache 
 
Side effects of Osimertinib that are rare, but serious include: 
• 
Pneumonitis (inflammation of the lung). Fatal events of inflammation of lungs 
have been reported in patients taking Osimertinib. 
 
11.1 Bevacizumab Related Toxicities: 
 
Toxicities with Bevacizumab that are likely (>20%) include: 
• 
Mild to moderate increase in blood pressure 
• 
Protein in urine, which rarely leads to damage to the kidney 
• 
Shortness of breath 
• 
Nosebleeds 
• 
Headache 
• 
Loss of appetite 
• 
Sore mouth or throat 
• 
Constipation 
• 
Feeling tired 
• 
Diarrhea 
• 
Nausea and vomiting 
• 
Generalized pain and pain in the abdomen (belly) 
• 
Heartburn 
 
Toxicities with Bevacizumab that are less likely (<20%) include: 
• 
Mild to moderate decrease in blood pressure 
• 
Blood clots in veins or arteries, which may be life threatening 
• 
Mild to moderate bleeding in the tumor, stomach, intestines, vagina or lungs 


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• 
Reactions associated with bevacizumab infusion: chills, fever, rigors 
• 
Rash, skin ulcer, hives, welts or itching 
• 
Infection 
• 
Dizziness 
• 
Pains in the muscles and joints 
• 
Chest pain 
• 
Cough 
• 
Nasal stuffiness, sneezing, post nasal drip 
• 
Wheezing 
• 
Weight loss 
• 
Voice changes, hoarseness, laryngitis 
• 
Damage to the heart muscle resulting in decrease in heart function 
• 
Low white blood cell counts, which may make you more at risk for infection. 
 
 
Side effects of Bevacizumab that are rare, but serious include: 
• 
Problems with wound healing 
• 
Development of an abnormal opening (fistula) between the large intestine 
(bowel) and another organ, most commonly the bladder, uterus or vagina 
• 
Bowel perforation. This can occur when an opening forms in the bowel wall 
allowing bowel contents to spill into the abdomen. This is rare but often requires 
surgery and can be life-threatening and fatal. 
• 
Bowel anastomotic dehiscence: This is a breakdown in the surgical connection between 
two pieces of bowel in patients with prior history of bowel surgery. This is rare but often 
requires surgery and can be life-threatening and fatal 
• 
Severe allergic reactions that result in difficulty breathing or drop in blood pressure 
• 
Serious or fatal bleeding from the tumor, brain, gut or lungs 
• 
Heart problems, including irregular heartbeats, heart attack or heart failure 
• 
Reversible changes in the liver function 
• 
Nephrotic syndrome, a type of kidney disease caused by damage to the tiny blood 
vessels in the kidney 
• 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome. RPLS is a medical condition related to leakiness of 
blood vessels in the brain. This can cause confusion, blindness or vision changes, 
seizure and other symptoms. This condition is usually reversible. In rare cases it 
can be life threatening and may have a long term effect on brain function. 
 
11.2 Dose modifications will not be allowed for cycle 1 during the Phase 1 portion of the 
protocol in order to ensure accurate assessment of the MTD. General guidelines are below: 
 
Osimertinib Dose modifications (Cycle ≥2 only) 
Dose at time of toxicity 
Dose reduction levels 
80mg 
40mg 
40mg 
40mg every other day 
 
If a patient experiences a CTCAE grade 3 or higher and/or unacceptable toxicity (any grade), where 
the Investigator considers the AE to be associated with the study drug, dosing will be interrupted and 


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supportive therapy administered as required in accordance with local practice/guidelines. If the AE is 
clearly attributable to one drug and not the other, only the culprit drug will be held. If an AE is not 
clearly attributable to one drug, both drugs will be held until the AE resolves as specified below. 
 
If the toxicity resolves or reverts to ≤CTCAE grade 1 within 2 weeks of onset, study drug may be 
restarted at the same dose (starting dose) or reduced dose using the dose reduction in the table 
above. If restarting at the same dose level, patients should be closely monitored for 3 days following 
the restart of treatment. If within 3 days there is recurrence of same toxicity, a dose reduction should 
be considered at the Investigator’s  discretion. 
 
If the toxicity does not resolve to ≤CTCAE grade 1 after 2 weeks, then the patient should be 
withdrawn from the study treatment and observed until resolution of the toxicity. Resumption of the 
study drug at a lower dose would require discussion with the sponsor and Principal Investigator. If 
one drug is permanently discontinued, it is the treating physician’s discretion as to whether to 
continue the other drug as monotherapy. 
 
Patients who develop asymptomatic Gr. 3 or Gr. 4 lymphopenia without clinical correlate (eg. 
Opportunistic infection) may continue study treatment without interruption if approved by the 
treating physician. 
 
For any toxicity, supportive medications should be utilized. For example, for skin reactions, mild to 
moderate strength steroids creams, either topical or systemic antibiotics should be started, as seen 
appropriate by the investigator upon assessment of the skin reaction. For nausea/vomiting, anti- 
emetic therapy should be utilized. For diarrhea, after alternative etiologies are ruled out, anti- 
diarrheal medications should be utilized. 
 
QTC prolongation: For patients with >CTCAE grade 3 QTC prolongation should have study drug 
interrupted and monitoring of ECGs performed until resolution to baseline. If the toxicity resolves or 
reverts to ≤CTCAE grade 1 within 2 weeks of onset, study drug may be restarted at the same dose 
or reduced dose using the dose reduction levels in the table above. If the toxicity does not resolve to 
≤CTCAE grade 1 within 2 weeks, the patient will be permanently withdrawn from study drug. 
 
Interstitial  lung disease/pneumonitis: 
If a new or worsening of pulmonary symptoms (e.g., dyspnea) or occurrence of a radiological 
abnormality suggestive of ILD is observed, an interruption in study drug dosing is recommended. 
In the presence of confirmatory CT scans where other causes of respiratory symptoms have been 
excluded, a diagnosis of ILD should be considered and study drug permanently discontinued. In the 
absence of a diagnosis of ILD, study drug may be restarted following consultation with the Principal 
investigator and sponsor. 
 
Please refer to the package insert for further details. 
 
Bevacizumab 
Bevacizumab dose will not be reduced for reasons other than a >10% change in weight from 
baseline. Bevacizumab treatment may be either temporarily or permanently suspended in the case  
of bevacizumab-related events such as fistulae, GI perforation, hypertension, proteinuria, 
thrombosis/embolism, hemorrhage, CHF, wound healing complications, PRES (or RPLS) and 
hypersensitivity/allergic  reactions in addition to any other serious bevacizumab-related toxicity (grade 
3 or 4). 


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In addition, bevacizumab should be temporarily withheld in the event of febrile grade 4 neutropenia 
and/or grade 4 thrombocytopenia (regardless of the relationship to treatment), since these conditions 
are predisposing factors for an increased bleeding tendency.  To summarize, bevacizumab s hould 
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 treatment temporarily) 
• 
Grade ≥ 2 fistula (hold temporarily or permanently discontinue) 
 
• 
GI perforation (permanently discontinue) 
 
• 
Major surgery or wound healing complications (hold temporarily or permanently discontinue) 
 
• 
Medically  significant hypertension  not  controlled with antihypertensive  therapy,  hypertensive 
crisis or hypertensive encephalopathy (permanently discontinue) 
• 
Grade ≥ 3 left ventricular dysfunction (CHF) (permanently discontinue) 
 
• 
Nephrotic syndrome (permanently discontinue) 
 
• 
Arterial thrombosis/embolism (any grade) (permanently discontinue) 
 
• 
Grade ≥ 3 venous thrombosis/embolism (hold temporarily or permanently discontinue for grade 
4) 
• 
CNS bleeding (any grade) or  ≥ grade 3 bleeding of any kind (permanently discontinue) 
 
• 
Grade ≥ 2 hemoptysis (hold temporarily or permanently discontinue) 
 
• 
Hypersensitivity/allergic  reactions related to bevacizumab (permanently discontinue) 
 
• 
PRES (or RPLS) (permanently discontinue) 
 
If bevacizumab is permanently suspended, patients  will no longer need to have Urinalysis, Dipstick 
done every 2 cycles to measure proteinuria. 
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 


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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 with PRES. 
Gastrointestinal Perforation and Fistula 
Bevacizumab has been associated with serious cases of GI perforation in patients with mCRC and a 
few reports of gallbladder  perforation have been reported from the post-marketing experience. The 
presentation of these events has varied in type and severity, ranging from free air seen only on the 
plain abdominal X-ray, which resolved without treatment, to a colonic perforation with abdominal 
abscess and fatal outcome. The common feature among these cases was intra abdominal 
inflammation, either from gastric ulcer disease, tumor necrosis, diverticulitis or chemotherapy- 
associated colitis.  Nevertheless, a causal association of an intra-abdominal inflammatory process 
and GI perforation to treatment with bevacizumab has not been established. However, caution 
should be exercised when treating patients with intra-abdominal inflammatory process with 
bevacizumab. Bevacizumab should be permanently discontinued in patients who develop GI 
perforation. 
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-marketing reports. Temporarily discontinue 
bevacizumab in patients with grade 2 or 3 non- tracheoesophageal fistula until resolution to ≤ grade 
1. Permanently discontinue bevacizumab in patients with tracheoesophageal fistula or any grade 4 
fistula. 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. 
 
 
Wound Healing Complications 
Increased incidences of post-operative bleeding or wound healing complications have been  
observed in clinical trials of bevacizumab in relapsed glioma and mCRC and BC. Bevacizumab 
therapy should not be initiated for at least 28 days following major surgery or until the surgical wound 
is fully healed as bevacizumab may adversely impact wound healing. 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 
permanently  discontinued. 
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. 
Hypertension 
An increased incidence of hypertension has been observed in patients treated with bevacizumab. 
Clinical safety data suggest the incidence of hypertension is likely to be dose-dependent. Pre- 
existing hypertension should be adequately controlled before starting bevacizumab treatment. There 
is no information on the effect of bevacizumab in patients with uncontrolled hypertension at the time 
of initiating therapy. Blood pressure must be assessed before each bevacizumab administration. In 
most cases hypertension is controlled adequately  using standard antihypertensive  treatment 


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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. 
Congestive Heart Failure (CHF) 
Events consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic 
declines in left ventricular ejection fraction (LVEF) to symptomatic CHF, requiring treatment or 
hospitalization. Most of the patients who experienced CHF had metastatic breast cancer and had 
received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk 
factors for CHF were present. Caution should be exercised when treating patients with clinically 
significant cardiovascular disease such as pre-existing coronary artery disease, concomitant 
cardiotoxic therapy or CHF with bevacizumab. Bevacizumab should be permanently discontinued in 
patients with ≥ grade 3 CHF. 
 
Proteinuria 
In clinical studies, the incidence of proteinuria was higher in patients receiving bevacizumab in 
combination with chemotherapy compared to those who received chemotherapy alone. Proteinuria 
reported as an AE with bevacizumab treatment has ranged in severity from clinically asymptomatic, 
transient, trace proteinuria to nephrotic syndrome with the great majority as grade 1 proteinuria. The 
proteinuria seen in bevacizumab clinical trials was not associated with renal dysfunction and rarely 
required permanent discontinuation of bevacizumab therapy. Patients with a history of hypertension 
may be at increased risk for the development of proteinuria when treated with bevacizumab. 
Proteinuria must be assessed by dipstick before each bevacizumab administration unless proteinuria 
has been determined by 24-hour urine collection. Patients who have permanently discontinued 
bevacizumab will not be tested for proteinuria with dipstick. 


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Table 11.1 
Bevacizumab Treatment Management  for Proteinuria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ntinue bevacizumab 
 
 
 
Arterial  thrombosis/embolism 
Bevacizumab should be discontinued in patients who develop arterial thromboembolic events. A 
history of arterial thromboembolic events or age greater than 65 years has been associated with an 
increased risk of arterial thromboembolic events during bevacizumab therapy. Patients receiving 
bevacizumab plus chemotherapy with a history of arterial thromboembolism and age greater than 65 
years have a higher risk. Caution should be taken when treating these patients with bevacizumab. 
 
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 coumarin derivatives should 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. 
NCI CTCAE 
v. 4.0 
Urinalysis 
Treatment Action 
Grade 1 
1+ proteinuria 
No bevacizumab dose modification 
urinary protein < 
1.0 g/24 hrs 
Grade 2 
2+ proteinuria 
For 2+ dipstick: may administer bevacizumab 
urinary protein 
without dose modification and collect 24-hour urine 
1.0-3.4 g/24 hrs 
prior to subsequent  bevacizumab administration. 
For 3+ dipstick: must obtain 24-hour urine prior to 
administering bevacizumab 
Suspend bevacizumab for urinary protein ≥2 g/24 
hrs. Resume bevacizumab when proteinuria is < 2 
g/24 hrs. 
Grade 3 
urinary protein 
Suspend bevacizumab. 
≥3.5 g/24 hrs 
Resume bevacizumab when proteinuria is < 2 g/24 
hrs. 
Nephrotic syndrome 
Permanently disco 


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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 tumor-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: 
o grade 3 or 4 bleeding of any kind 
o any grade of CNS bleeding.  Patients should be monitored for signs and symptoms of CNS 
bleeding. 
Bevacizumab should be temporarily held or permanently discontinued for grade ≥ haemoptysis 
(defined as ≥ 2.5 mL bright red blood per episode). The safety of re-initiating bevacizumab in 
patient’s previously experiencing grade ≥ 2 haemoptysis has not been evaluated.  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. 
Hypersensitivity/Allergic Reactions and Infusion-Associated Reactions 
Bevacizumab should be permanently discontinued in patients exhibiting  hypersensitivity/allergic 
reactions. The NCI CTCAE distinguish between hypersensitivity reactions and acute infusion 
reactions induced by cytokine release. Despite the different possible mechanisms underlying 
hypersensitivity and infusion reactions, the clinical signs and symptoms associated with these 
reactions overlap.  Patients may be at risk of developing infusion reactions to bevacizumab. Close 
observation of the patient during and following the administration of bevacizumab is recommended 
as expected for any infusion of a therapeutic humanised monoclonal antibody. If an infusion reaction 
occurs, the infusion should be discontinued and appropriate medical therapies should be 
administered. A systematic premedication is not warranted. 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw was reported in patients receiving bevacizumab mainly in combination with 
bisphosphonates in the post-marketing setting.  The pathogenesis of the osteonecrosis is unclear. 
For further information, please refer to the Avastin® Investigator’ Brochure. 
Ovarian Failure 
Ovarian failure has been reported more frequently in patients receiving bevacizumab. Ovarian 
function recovered in the majority of women after bevacizumab discontinuation. For further 
information, please refer to the Avastin® Investigator’ Brochure. 
 
Bevacizumab experience in lung cancer trials: 
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 


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risk-benefit. 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 + bevacizumab arm (Sandler et al. 2006).  GI hemorrhages, including rectal 
bleeding and melena have been reported in patients with CRC, and have been assessed as tumor-
associated hemorrhages. Tumor-associated hemorrhages were also seen rarely in other  tumor 
types and locations and included cases of CNS bleeding in patients with CNS metastases and in 
patients with glioblastoma. 
 
The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab 
has not been prospectively evaluated in randomised clinical studies. In an exploratory retrospective 
analysis of data from 13 completed randomised 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 haemorrhage was reported. Intracranial 
haemorrhage can occur in patients with relapsed glioblastoma. In study AVF3708g,  CNS 
haemorrhage was reported in 2.4% (2/84) of patients in the Avastin alone arm (Grade 1); and in 
3.8% (3/79) of patients treated with Avastin and irinotecan (Grades 1, 2 and 4). Patients with 
untreated CNS metastases were routinely excluded from clinical trials with Avastin, based on 
imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patient 
has not been prospectively evaluated in randomised clinical studies. Patients should be monitored  
for signs and symptoms of CNS bleeding,  and Avastin treatment discontinued in cases of intracranial 
bleeding. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
The same method of assessment and the sametechnique (i.e. with or without contrast) should be 
used to characterize each identified and reported lesion at baseline, and every nine weeks (+/- 1 
weeks).  Designated radiologists at MSKCC (named on the study face sheet) will interpret the study 
CTs according to RECIST 1.1 criteria. 
Tumor response will be assessed using RECIST 1.1. A CT chest/abdomen/pelvis will be performed  
to demonstrate all known areas of measurable disease. The baseline study will occur no more than 4 
weeks prior to first study drug administration. A CT scan with contrast will be the preferred method 
and modality of imaging. A CT scan without contrast can be used in patients with contraindications to 
radiographic contrast media used in CT scans. All patients must have at least one measurable 
disease lesion by CT. MRI brains (+/- spine) will be required as well to assess CNS involvement. 
All measurable lesions, up to a maximum of 5 lesions total, representative of all involved organs 
should be identified as target lesions and recorded and measured at baseline. Target lesions should 
be selected on the basis of their size, should be representative of all involved organs, and should 
lend themselves to reproducible repeat measurements. All other lesions (or sites of disease) should 
be identified as non-target lesions and should also be recorded at baseline as well. Definitions of 
response in target and non-target lesions are described in Table 12.1 and 12.3 below. Table 12.3 
provides overall responses for all possible combinations of tumor responses in target and nontarget 
lesions. 


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Table 12.1: Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters 
of the target lesions 
Progressive disease (PD): 
At least a 20% increase in the sum of the diameter of 
the target lesions or the appearance of one or more 
new lesions 
Stable disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD 
 
 
Table 12.2: Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions 
Incomplete response/Stable disease (SD): 
Persistence of one or more non-target lesions 
Progressive disease (PD): 
Appearance of one or more new lesion and/or 
unequivocal progression of existing non-target lesion 
 
 
Table 12.3: Combinations of responses 
Target lesions 
Nontarget lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Discontinuation of treatment 
Early death is defined as having no repeat tumor assessments following initiation of study therapy 
resulting from death of the patient due to disease or treatment. Patients with global deterioration of 
health status requiring discontinuation of treatment without objective evidence of disease 
progression will be recorded as ‘symptomatic deterioration’. Every effort will be made to document 
objective progression even after discontinuation of treatment. 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of treatment until disease 
progression, as defined in Table 12.3. 
 
Other definitions 
Evaluable for toxicity: All patients who receive ≥ 80% of all  treatment doses with osimertinib and 
bevacizumab during cycle 1 of phase I will be evaluable for toxicity during the DLT period. However, 
patients who are replaced during the first cycle of treatment in the dose de-escalation phase for any 
reason other than DLT will not be included in the assessment of MTD. 
Evaluable for efficacy: All patients at MTD will be included in the analysis of efficacy. Patients 


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treated at the MTD with a DLT who do not continue treatment on study will not be included in the 
phase 2 portion of the study. If patients at the MTD with a DLT continue on study, they will be 
included in the efficacy analyses. 
Progression-free survival (PFS) is defined as the duration of time from first treatment to time of 
progression (in the CNS or systemically) or death, whichever occurs first. 
Intracranial progression-free survival (PFS) is defined as the duration of time from first treatment to 
time of progression (in the CNS) or death, whichever occurs first. 
Overall survival (OS) is defined as the duration of time from first treatment to time of death. 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. Other reasons for study discontinuation include 
but are not limited to: 
• Change in patient eligibility 
• Non-compliance with the defined treatment plan 
• Protocol violation 
• Investigator’s decision based on patient’s best interest 
• W ithdrawal of consent 
• Severe, unexpected toxicities/side effects 
• Lost to follow up 
• Death 
• Progression of disease (defined by RECIST 1.1) 
 
For the Phase 1 portion of the study, patients who withdraw from the study for reasons other than 
DLT without completing a full treatment cycle will be replaced. 


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14.0 
BIOSTATISTICS 
Phase 1: 
Primary Objective: To determine the safety and tolerability of the combination of osimertinib and 
bevacizumab in patients with EGFR mutant lung cancers. 
Endpoints: Identify any doselimiting toxicities of the combination and establish the MTD. A dose limiting 
toxicity is a binary outcome where a patient either experiences a DLT or not. DLT is defined as any of 
the toxicities described in Section 9.4 that occurs within one cycle after initiation of treatment with 
osimertinib and bevacizumab. The MTD is defined as the highest dose at which not more than 1/6 of the 
patients experience a DLT. 
Method: A standard 3+3 design will be used to find the maxim um tolerated dose (MTD). Wewill begin 
with dose level 1 and de-escalate to dose level -1 if significant toxicity is seen with the combination. 
Table 14: Dose levels 
 
Dose level 
Osimertinib 
Bevacizumab 
-1 
40mg daily 
15mg/kg every 3 weeks 
1 
80mg daily 
15mg/kg every 3 weeks 
 
Three patients will be enrolled at dose level 1 (Osimertinib 80mg once daily and bevacizumab 
15mg/kg intravenously once every three weeks and assessedfor dose limiting toxicities (DLTs) for 1 
full cycle (21 days). Toxicity will be graded according to NCI CTCAE version 4.0. 
If 0-1 DLTs occur at dose level 1 during cycle 1, an additional 3 patients will be treated at dose level 
1. If 0-1 DLTs occur during cycle 1 in the 6 patients treated, dose level 1 will be determined to be 
the MTD. If 2 or greater DLTs occur at dose level 1, we will de-escalate to dose level -1. 
 
The dose escalation scheme is as follows: 
 
1. If zero to one of the initial three patients at a given dose level experiences DLT, three additional 
patients will be treated at the same dose level. 
2. If two or more patients experience DLT at dose level 1, 3 patients will be treated at dose level 
-1. 
3. Should two or more patients experience the DLT at dose level -1, the study will be halted, and 
alternative combination dosing will be considered. 
4. If only three patients were treated at a dose under consideration as the MTD, an additional 
three patients will be treated at that level to confirm previous results. 
 
Thus, the maximum number of patients that will be enrolled in the phase I portion is 12 (6 at each 
dose level). The probability of escalation given different true rates of dose-limiting toxicity is given 
below 


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Toxicity rate 
0.10 
0.20 0.30 
0.40 
0.50 
Probability of escalation 
91% 71% 49% 
31% 
17% 
 
The MTD will be the recommended dose for the phase 2 portion.  At the completion of the phase 1 
portion, 6 patients will have been treated at the MTD. These patients will be followed for response 
assessment and included in the phase 2 portion of the study. Patients treated at the MTD with a DLT 
who do not continue treatment on study will not be included in the phase 2 portion of the study. If 
patients at the MTD with a DLT continue on study, they will be included in the efficacy analyses. 
Given an expected accrual rate of 2 patients per month, the phase 1 portion of the study will be 
completed within 6 months or less. 
 
 
Phase 2: 
 
Primary Objective: Assess the progression-free survival at 12 months of combination Osimertinib 
and bevacizumab in patients with untreated EGFR-mutant lung cancers. 
Secondary Objective: 1) Measure overall response rate (CR+PR), 2) measure progression-free 
survival 3)measure intracranial progression-free survival 4) measure overall survival 5) further define 
the toxicity profile of the combination 
Methods: 
A thirty patient subgroup of the AURA study received Osimertinib 80mg daily as first-line treatment 
for EGFR-mutant lung cancer (Ram lingam PASCO 2015). After 12 months of follow up, the  
median PFS was not yet reached. The percent of progression-free surviving patients is 73% at 
12 months with a 95% CI of 51% to 87%. W e decided to use the lower bound  of the 95% CI of 1- 
year PFS from the AURA study with 51% as the historical control. 
Hoping to see an improvement in 1-year PFS from 51% to 70%, we will need 43 patients to 
provide 80% power while controlling the Type I error at 5% in a single-stage design. W e will need 
to see at least 28 patients alive and free from progression at 12 months in order to consider this 
treatment strategy promising. Overall survival (OS), progression-free survival at 12 months and 
progression-free survival (PFS) will be estimated using the Kaplan-Meier  method, with the follow- 
up starting at the initiation of therapy. Patients will be censored at the time of the last on-study 
evaluation if they do not experience the event of interest. Intracranial progression will be 
calculated by looking specifically for growth or new lesions or leptomeningeal disease in the 
central nervous system. Overall response rate (CR + PR) will be calculated, utilizing best overall 
response, including exact 95% confidence intervals. 
Patients who undergo intra-patient dose escalation from dose -1 to dose 1 if dose 1 is established 
as the MTD, will not be included in the response rates, PFS, or OS. Safety and tolerability  will be 
summarized using descriptive statistics. The toxicities and the adverse events will be assessed for 
each patient according to the NCI CTCAE version 4.0 criteria. Given an expected accrual rate of 
2 patients per month, the accrual for the expansion portion of the study will be completed in about 
19 months. If an efficacy signal is seen when assessing the PFS at one year, a larger, multicenter, 
randomized study will be considered to more accurately compare the efficacy of Osimertinib 
monotherapy to Osimertinib plus bevacizumab. 


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Patients will remain on study until progression or they come off study treatment for other reasons. 
Patients will have an end of treatment visits that concludes study follow up. They will not be contact 
directly once off study treatment, but every effort with be made to document their disease 
progression and survival status for the progression-free survival rate at 12 months and overall 
survival information. If patients’ disease progression status is unobserved at 12 months despite the 
effort, they will be counted as progression so that the PF survival rate at 12 months will be a 
conservative estimate. 
 
Correlative Studies: 
 
Primary Objective: 1) to identify EGFR T790M in pre and post treatment samples 2) perform next- 
generation sequencing based mutation testing on tumors before treatment and at progression. 
 
 
Correlatives: For the correlative studies, the analysis is primarily exploratory and hypothesis generating. 
Correlative studies will be performed on all patients, (from the phase 1 and 2 portions of the study) 
including descriptive summaries of mutation testing. The only exception is the IMPACT analyses which 
will be limited to patients with samples available. There is an  optional tumor biopsy at best 
response.Tissue will only be available after protocol treatment from subjects who agree to a standard 
of care post-progression biopsy. W hile all the genes in the IMPACT panel will be assessed, only those 
with at least 10% prevalence in this trial will be statistically analyzed. 
Method: 
EGFR T90M status will be determined pre-treatment for all patients and post treatment in those 
patients who progress using direct sequencing. The proportion of patients with T790M mutation in both 
tumor tissue will be calculated along with the exact 95% confidence interval. The pre- treatment EGFR 
T790M mutations along with the gene mutations identified by the IMPACT panel will be 
univariately correlated with response using Chi-squared test and with PFS and OS using logrank test. 
Since the expected number of genes to be analyzed is in the order of hundreds, the Benjamini- 
Hochberg procedure (15) will be considered to control the false discovery rate at 0.05 level. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND  RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 


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All participants must be registered in the Clinical Trial Management Systems (CTMS) program 
at Memorial Sloan Kettering Cancer Center. 
 
15.3 
Randomization 
 
No randomization will occur in this study. 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A Clinical Research Coordinator (CRC)) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol study 
team. The data collected for this study will be entered into a secure database (Clinical Research 
Database (CRDB). Source documentation will be available to support the computerized patient 
record. The principal investigator will maintain ultimate responsibility for the clinical trial. 
 
16.2 
Quality Assurance 
 
W eekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action.  Random -sample data quality 
and protocol compliance audits will be conducted by the study team, at a minimum of two 
times per year, more frequently if indicated. 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring  (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/patientsafety/dsm  -guidelines/page1 
 
The DSM Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC 
Intranet at: 
http://smskps ps9/dept/ocr/OCR%20W   ebs ite%20Doc uments/Clinical%20Research%20Qualit  
y%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.p   df 


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There are several different  mechanisms by which clinical trials are monitored for data safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The Data and Safety Monitoring  Committee (DSMC) reports to the 
Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessedfor its 
level or risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industry sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be reviewed 
with the participant, including a discussion of the possible toxicities and side effects. Alternative, 
non-protocol, treatment options will be discussed with the patient. It will be reviewed that 
participation in this clinical trial is voluntary and that the patient may withdraw consent at any time. 
The study is designed with careful safety monitoring for toxicity including physician visits and serial 
cardiac monitoring. Specific guidelines for symptom management are in place to protect the study 
participant. 
 
Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the inclusion 
criteria will be eligible. Up to 12 patients will be enrolled unto the phase 1 portion, and an additional 
43 patients will be enrolled onto the Phase 2 portion. Patients eligible will be 18 years of age or older 
with a KPS of 70% or greater. Both men and women and members of all ethnic groups are eligible 
for this trial. Pregnant and breast-feeding women are excluded from this study. This protocol does 
not include children because the number of children is expected to be limited for the patient 
population expected to be accrued onto this study. Also, the majority of children are already 
accessed by a nationwide pediatric cancer research network. This statement is based on exclusion 
4b of the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research 
Involving  Human Subjects. 
 
Consent process: All patients at MSKCC who meet the inclusion criteria will be eligible. Participation 
in the trial is voluntary. All patients will be required to sign a statement of informed consent, which 
must conform to IRB guidelines. The informed consent procedure is described in Section 18.0. 
 
Possible Toxicities/Side-Effects: There are risks associated with treatment as described in Section 
11.0; however, patients screened for enrollment will be deemed appropriate for treatment 
independent of this study. 


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Benef its: This alternative regimen of Osimertinib and bevacizumab has the potential to prolong 
progression-free survival, improve the response rate and/or overall survival compared to standard 
dosing erlotinib in the first-line treatment setting. Patients who progress on combination Osimertinib 
and bevacizumab can still receive standard, second-line chemotherapy and/or can participate in an 
alternative clinical trial. 
 
Cos ts:  Patients will be not be charged for bevacizumab. Patients will be charged forphysician 
visits, routine laboratory tests and radiologic studies required for monitoring their condition. 
The patients will not be billed for the Osimertinib. 
 
Alternatives: The alternative to this trial would be treatment with erlotinib or afatinib monotherapy or 
standard cytotoxic chemotherapy. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and hospital 
records are confidential. Patients’ names and any other identifying information will not be used in 
reports or publications resulting from this study. Other authorized agencies and appropriate internal 
personnel (e.g. qualified monitors from MSKCC) and external personnel, the FDA, and/or other 
governmental agencies) may review patient records as required. 
 
The consent indicates  that individualized  de identified  information collected for the purposes of this 
study may be shared with other qualified  researchers. Only researchers who have received approval 
from MSK will be allowed to access this information which will not include  protected health 
information,  such as the participant’s  name, except for dates. It is also stated in the Research 
Authorization that their research data may be shared with other qualified  researchers. 
 
 
 
Patient safety: Patients are monitored by physicians and oncology nurses who are very familiar with 
clinical trials. In the case of an adverse reaction, immediate medical attention is available. In the 
evenings and weekends, we have a 24-hour urgent carefacility for outpatients. The PI or co-PI will 
also be available at all times to organize any necessary intervention. 
Monitoring of data to ensure safety: This study is to be monitored by the institutional IRB. This 
incorporates an independent data and safety monitoring committee established by arrangement with 
the National Cancer Institute. The analysis of safety will include all patients. Adverse events, 
including all toxic effects of treatment, will be tabulated individually, and summarized by severity and 
causality. 
 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 


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protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
The consent indicates that individualized  de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified  researchers. 
17.3 
Adverse Event and Serious Adverse Event (SAE) Reporting 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational medicinal product (IMP) or other protocol-imposed 
intervention, regardless of attribution. 
This includes the following: 
 
• 
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with non-small cell lung 
cancer that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
• 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. 
 
Adverse Event Reporting Period 
 
The study period during which AEs and SAEs must be reported begins after informed consent 
is obtained and initiation of study treatment and ends 30 days following the last administration 
of study treatment or study discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to prior study treatment. 
 
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 
osimertinib and/or 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 
There is a plausible temporal relationship between the onset of the AE and administration of 
the osimertinib or 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 osimertinib and/or bevacizumab; and/or the AE abates or resolves upon 
discontinuation of the study drug or dose reduction and, if applicable, reappears upon re- 
challenge. 
No 
Evidence exists that the AE has an etiology other than the osimertinib or bevacizumab (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to osimertinib and/or 
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. 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
 
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. 
b. 
Deaths: All deaths that occur during the protocol-specified AE reporting period (see 
Section I), regardless of attribution, will be reported to the appropriate parties. When recording 
a death, the event or condition that caused or contributed to the fatal outcome should be 


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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” 
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”). 
d. Hospitalizations for Medical or Surgical Procedures 
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 or prolonged hospitalization required to allow efficacy measurement for 
the study or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease 
of the study 
 
Assessment of Severity of Adverse Events 
 
The adverse event severity grading scale for the NCI CTCAE v4.0 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. 
 
 
 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 


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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 version of NCI CTCAE v4.0, w hich can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
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 w ho 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 4 and 5 events must be reported as serious adverse events 
 
 
Pregnancy: If a female subject becomes pregnant while receiving the study drug or within 6 
months after the last dose of study drug, or if the female partner of a male study subject 
becomes pregnant while the study subject is 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. 
AEs of Special Interest (AESIs) 
 
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. 
 
Adverse events of special interest for this study include the following: 
 
• 
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: 
o Treatment-emergent ALT or AST > 3 x ULN in combination with total bilirubin > 


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2 x ULN 
 
o Treatment-emergent ALT or AST > 3 x ULN in combination with clinical 
jaundice 
 
• 
Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP),  as defined below: 
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 the study drug is suspected 
 
 
The Avastin Events of Special Interest are: 
 
o Hypertension ≥ grade 3 
o Proteinuria ≥ grade 3 
 
o GI perforation, abscesses and fistulae (any grade) 
 
o Wound healing complications ≥ grade 3 
 
o Haemorrhage ≥ grade 3 (any grade CNS bleeding; ≥ grade 2 haemoptysis) 
o Arterial thromboembolic events (any grade) 
 
o Venous thromboembolic events ≥ grade 3 
 
o PRES (or RPLS; any grade) 
 
o CHF ≥ grade 3 
o Non-GI fistula or abscess ≥ grade 2 
Other Special Situations Reports 
 
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech: 
Data related to the Product usage during breastfeeding 
Data related to overdose, abuse, misuse or medication error  (including potentially 
exposed or intercepted medication errors) 
 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 
 
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. 
Post-Study Adverse Events 
 
For studies involving collection of survival data the investigator after the end of the adverse 
event reporting period (defined as 30 days after the last dose of study drug) should report all 
deaths, (regardless of cause), and any serious adverse event including development of cancer 
or a congenital anomaly in a subsequently conceived offspring of a female subject who 
participated in the study that is believed to be related to prior exposure to study drug. 
Case Transmission Verification will be performed by both parties during this period (half- 
yearly) to ensure successful transmission of Single case reports. 
Serious Adverse Events 
 
An AE should be classified as an SAE if any of the following criteria are met: 
 
▪ 
It results in death (i.e., the AE actually causes or leads to death). 
▪ 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
▪ 
It requires or prolongs inpatient hospitalization. 
▪ 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
▪ 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to the IMP. 
▪ 
It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent 
one of the outcomes listed above). 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 


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and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar days 
of the event. 
 
 
The report should contain the following information: 
 
• The date the adverse event occurred 
 
• The adverse event 
 
• The grade of the event 
 
• Relationship of the adverse event to the treatment(s) 
 
• If the AE was expected 
 
• Detailed text that includes the following 
 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
 
• If an amendment will need to be made to the protocol and/or consent form 
 
• If the SAE is an Unanticipated Problem 
 
 
 
17.2.1  SAE Reporting to AstraZeneca and Genentech 
 
Any AE from the time the first dose of study treatment is administered through 30 days after 
the last dose should be reported. AstraZeneca and Genentech are required to evaluate and 
expedite reporting of serious adverse events to worldwide regulatory authorities; therefore,  
the appropriate parties, as specified in this section, must be notified immediately (within 24 
hours of awareness) regarding the occurrence of any serious adverse event.  All investigators 
participating in ongoing clinical studies with the study medication will receive copies of these 
reports for prompt submission to their Institutional Review Board (IRB) or Independent  Ethics 
Committee (IEC). 
 
Exchange OF SINGLE CASE REPORTS 


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Memorial Sloan Kettering Cancer will be responsible for collecting all protocol-defined 
Adverse Events (AEs)/Serious Adverse Events (SAEs), other Special Situation 
reports, AESIs and Product Complaints with an AE where the patient has been 
exposed to the Product via the MSKCC PIMS report form. The completed MSKCC 
SAE report should be sent to the Genentech contact specified below. Transmission of 
these reports (initial and follow-up) will be either electronically via email or by fax and 
within the timelines specified below: 
 
 
Fax: 650-238-6067 
Email:  usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
Transmission of these reports (initial and follow-up) will be either electronically or by fax and 
within the timelines specified below: 
 
Serious Adverse Drug 
Reactions (SADRs) 
15 calendar days of the 
awareness date 
Other SAEs 
30 calendar days of the 
awareness date. 
Special Situation Reports 
(Pregnancy) 
 
Special Situation Reports 
(Other) 
30 calendar days of the 
awareness date. 
30 calendar days of the 
awareness date. 
Product Complaints 
15 calendar days of the 
awareness date. 
AESIs 
15 calendar days of the 
awareness date. 
 
 
 
• Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen 
(15) calendar days of the awareness date. 
 
• 
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. 
• 
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. 
 
Other Special Situation Reports, as defined above, shall be transmitted to Genentech within thirty 
(30) calendar days of the awareness date. 
 
• 
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. 
 
• 
AESIs 
 
AESIs requiring expedited reporting (related or possibly related to Genentech product or where the 
causality is assessed as unknown or not provided) shall be forwarded to Genentech within fifteen (15) 
calendar days of the awareness date. Others (non-related to Genentech product) shall be sent within 
thirty (30) calendar days. 
 
Case Transmission Verification of Single Case Reports 
 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech via Memorial Sloan Kettering Cancer Center 
emailing Genentech a Quarterly line-listing documenting single case reports sent by Memorial Sloan 
Kettering Cancer Center 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’. 


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Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Memorial Sloan Kettering Cancer Center 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. 
 
 
GENENTE CH REPORTING GUIDELINES 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within form: 
 
• 
Protocol number and title description 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-Up Information 
• 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original report and submitting it as follow-up 
• 
Adding supplemental summaryinformation and submitting it as follow-up with the original form 
• 
Summarizing new information and faxing it with a cover letter including patient identifiers (i.e. 
D.O.B. initial, patient number), protocol description and number, if assigned, brief adverse 
event description, and notation that additional or follow-up information is being submitted (The 
patient identifiers are important so that the new information is added to the correct initial 
report) 
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual 
case safety reports from the study to the regulatory authority in compliance with applicable 
regulations. 
 
Memorial Sloan Kettering Cancer Center will be responsible for the expedited 
reporting of safety reports originating from the Study to the Ethics Committees 
and Institutional  Review Boards (IRB), where applicable. 
 
Memorial Sloan Kettering Cancer Center will be responsible for the 
distribution of safety information to its own investigators, where relevant, in 
accordance with local regulations. 
 
Memorial Sloan Kettering Cancer Center will be responsible for the 
distribution of safety information to Site IRB: 
MSK  Institutional  Review  Board (IRB) - 212-639-7592. 
MSK  Patient  Representative  Department  - 212-639-7202. 


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For questions related to safety reporting, please contact Genentech Drug Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
 
Other Reports 
 
Memorial Sloan Kettering Cancer Center will forward a copy of the Final Study 
Report to Genentech upon completion of the Study. 
STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
Fiona Yeh – yehf@mskcc.org 
 
 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
QUERIES 
 
Queries related to the Study will be answered by Memorial Sloan Kettering Cancer 
Center. However, responses to all safety queries from regulatory authorities or for 
publications will be discussed and coordinated between the Parties. The Parties agree 
that Genentech shall have the final say and control over safety queries relating to the 
Product. Memorial Sloan Kettering Cancer Center agrees that it shall not answer such 
queries from regulatory authorities and other sources relating to the Product 
independently but shall redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met. The Parties will clearly indicate on the request 
the reason for urgency and the date by which a response is required. 
 
SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the 
indication(s), on the conduct of the Study, may lead to labeling changes or regulatory 
actions that limit or restrict the way in which the Product is used, or where there is 
media involvement, the Party where the crisis originates will contact the other Party 
as soon as possible. 
 
The Parties agree that Genentech shall have the final say and control over safety crisis 
management issues relating to the Product. Memorial Sloan Kettering Cancer Center 
agrees that it shall not answer such queries from media and other sources relating to the 
Product but shall redirect such queries to Genentech. 


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COMPLIANCE WITH PHARMACOVIGILANCE  AGREEMENT / AUDIT 
 
The Parties shall follow their own procedures for adherence to AE reporting timelines. 
Each Party shall monitor and, as applicable, request feedback from the other Party 
regarding AE report timeliness in accordance with its own procedures. The Parties agree 
to provide written responses in a timely manner to inquiries from the other Party 
regarding AE reports received outside the agreed upon Agreement timelines. If there is 
any detection of trends of increasing or persistent non-compliance to transmission 
timelines stipulated in this Agreement, both Parties agree to conduct ad hoc or institute a 
regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange 
timelines, with this Agreement, the Parties will jointly discuss and collaborate on 
clarifying and resolving the issues causing non-compliance. Every effort will be made by 
the non-compliant Party to solve the non-compliance issues and inform the other Party 
of the corrective and preventative actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an 
audit under the provisions of this Agreement can be requested by either Party. The 
Parties will then discuss and agree in good faith upon the audit scope, agenda and 
execution of the audit. The requesting Party will bear the cost of the audit. 
 
 
18.1 INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 


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receive a copy of the signed informed consent form. 
 
 
 
19.0 
REFERENCES 
 
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Janne PA, W ang X, Socinski MA, et al. Randomized Phase II Trial of Erlotinib Alone or W ith 
Carboplatin and Paclitaxel in Patients W ho W ere Never or Light Former Smokers W ith Advanced Lung 
Adenocarcinoma: CALGB 30406 Trial. Journal of clinical oncology 2012; 30(17):2063-9. 
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Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired 
resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clinical cancer 
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Janne PA, Yang J, Kim DW , et al. AZD9291 in EGFR inhibitor-resistant non-small cell lung 
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Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin 
alone or with bevacizumab for non-small-cell lung cancer. NEJM 2006;355(24):2542-50. 
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Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus 
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Herbst RS, O'Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, et al. Phase II study 
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Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, et al. Efficacy of bevacizumab 
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Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with 
bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung 
cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 
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Ichihara E, Hotta K, Nogami N, Kuyama S, Kishino D, Fujii M, et al. Phase II trial of gefitinib 
in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with 
activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. Journal of 
thoracic oncology. 2015;10(3):486-91. 
11. 
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus 
cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the 
epidermal growth factor receptor (W JTOG3405): an open label, randomised phase 3 trial. The lancet 
oncology.  2010;11(2):121-8. 
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Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus 
standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation- 
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Zhou C, W u YL, Chen G, Feng J, Liu XQ, W ang C, et al. Erlotinib versus chemotherapy as 
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(OPTIMAL,  CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The lancet 
oncology.  2011;12(8):735-42. 
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Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or 
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Benjamini, Y., & Hochberg, Y.. (1995). Controlling the False Discovery Rate: A Practical 
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20.0 
APPENDICES 
 
None