Conditions: Solid Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
This extension study will provide continued onartuzumab and/or parent trial (P-trial) designated control treatments to participants with cancer who were previously enrolled in a company-sponsored onartuzumab P-trial and who derived benefit, as assessed by the responsible investigator, from the therapy administered in the P-trial. The study will also collect safety data with regard to administration of continued onartuzumab therapy.

Detailed description:

Arms:
arm 1: Participants will receive treatment with either the control treatment (erlotinib, bevacizumab) and/or onartuzumab-based study treatment (as during their P-trial) until progression of disease, unacceptable treatment related toxicity, withdrawal of consent, or death (whichever occurs first). All participants will continue on the same dose and schedule of control treatment as specified in their respective P-trial. The dose of onartuzumab will be calculated based on the participant's weight at the screening visit for the E-trial.

Interventions: intervention 1: Onartuzumab intervention 2: Bevacizumab intervention 3: Erlotinib
Intervention descriptions: intervention 1: Onartuzumab 10 mg/kg or 15 mg/kg will be administered intravenously on Day 1 of each 14- or 21-day cycle as specified in the P-trial and as per clinical judgment and discretion of the investigator. The actual dose of onartuzumab will be determined on the bases of participants weight at the time of enrollment in extension trial (E-trial). intervention 2: All participants will continue on the same dose and schedule of control treatment (bevacizumab) as specified in their respective P-trial. intervention 3: All participants will continue on the same dose and schedule of control treatment (erlotinib) as specified in their respective P-trial.

Protocol document:
Prot_000.pdf: 
Official Title: AN OPEN-LABEL, MULTICENTER EXTENSION 
STUDY OF ONARTUZUMAB IN PATIENTS WITH 
SOLID TUMORS ON STUDY TREATMENT 
PREVIOUSLY ENROLLED IN AN F. HOFFMANN-LA 
ROCHE- AND/OR GENENTECH-SPONSORED 
STUDY 
NCT Number: NCT02488330 
Document Date: Protocol Version 5: 17-August-2017 


PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Onartuzumab—F. Hoffmann-La Roche Ltd 
Protocol GO29646, Version 5 
PROTOCOL 
TITLE: 
AN OPEN-LABEL, MULTICENTER EXTENSION 
STUDY OF ONARTUZUMAB IN PATIENTS WITH 
SOLID TUMORS ON STUDY TREATMENT 
PREVIOUSLY ENROLLED IN AN F. HOFFMANN-LA 
ROCHE- AND/OR GENENTECH-SPONSORED 
STUDY 
PROTOCOL NUMBER: GO29646 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-005438-69 
IND NUMBER: 
100537 
TEST PRODUCT: 
Onartuzumab (RO5490258) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  16 January 2015 
DATES AMENDED: 
17-Aug-2017 14:38:04
Title
Approver's Name
Company Signatory
Date and Time (UTC)
Version 2:  1 September 2015 
Version 3:  30 June 2016 
Version 4:  22 July 2016 
Version 5:  See electronic date stamp below 


Onartuzumab—F.Hoffmann-La Roche Ltd
2/Protocol GO29646, Version 5
PROTOCOL AMENDMENT, VERSION5:
RATIONALE
Changes to the protocol, along with arationalefor each change,aresummarized below:

The protocol has been amended to update that all serious adverse events,whether
related or unrelated to onartuzumab, erlotinib,or bevacizumab thatoccurred while 
enrolled on study and also within the protocol-specified reporting period after the 
last dose of study drug,needto be reported to the Sponsor(Sections 3.3, 3.4.2, 
4.4.1, 5.2, 5.3, 5.4, 5.5, 5.7, and 6.5).  

Clarification has been added that bevacizumab and/or erlotinib are considered 
control treatment for this study(Sections 3.1 and5.1.7).

The reporting of the term “sudden death” has been updated to also require the 
presumedcause of death (Section5.3.5.3).

Event reporting for hospitalization has been clarified (Section 5.3.5.4).

The process for reviewing and handling protocol deviations hasbeen updated per 
internal standard operating procedures (Section 9.2).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Onartuzumab—F.Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT, VERSION5:
SUMMARY OF CHANGES
PROTOCOL SYNOPSIS
The protocol synopsis has been updated to reflect the changes to the protocol.
SECTION 1.5:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT

The Sponsor will collect safety data related toforthe investigationalagent, 
onartuzumab, as well as any drugs manufactured by the Sponsor and given as the 
control treatment in accordance with all local regulations.
SECTION 3.1:  DESCRIPTION OF STUDY
All patients will continue on the same dose and schedule of control treatment 
(bevacizumab and/or erlotinib) as specified in their respective P-trial.  
SECTION 3.3:  RATIONALE FOR STUDY DESIGN
OnlyAllserious adverse events assessed as related to onartuzumab, erlotinib, or 
bevacizumab will be reported.
SECTION 3.4.2:  Safety Outcome Measure
The safety outcome measure for this study isas follows:

Serious adverse events considered related or unrelated to onartuzumab
SECTION 4.4.1:  Informed Consent Forms and Screening Log
After informed consent signature but prior to the first dose of study therapy in the E-trial 
(onartuzumab and/or, if applicable, other P-trial IMP), serious adverse events,assessed 
aswhetherrelated or unrelated to onartuzumab, erlotinib, or bevacizumab,shouldbe 
reported.
SECTION 5.1.7:  Adverse Events Related to Control Treatment
Any adverse events known to be related to the control treatment(bevacizumab and/or 
erlotinib),whether given alone or in conjunction with onartuzumab, should be managed 
as per local standard of care.
SECTION 5.2:  SAFETY PARAMETERS AND DEFINITIONS
Only adverse events that fall into the category below should be reported to the Sponsor.

Serious adverse events, assessed aswhetherrelated or unrelated to onartuzumab, 
Avastin (bevacizumab), or Tarceva (erlotinib)
SECTION 5.2.2:  Serious Adverse Events (Immediately Reportable to the 
Sponsor)
Serious adverse events, whether related or unrelated, are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than24 hours after learning of the 
event; see Section5.4.2for reporting instructions).


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SECTION 5.3:  METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all serious adverse events (see 
Section5.2.1 for definition) assessed as related to onartuzumab, bevacizumab, or 
erlotinibarerecorded on the Adverse Event eCRF and reported tothe Sponsor in 
accordance with instructions provided in this section and in Sections5.45.6.
SECTION 5.3.1:  Adverse Event Reporting Period
Investigators will seek information on serious adverse events related to onartuzumab, 
bevacizumab, or erlotinib at each patient contact.  
After informed consent has been obtained, all serious adverse events considered related 
to onartuzumab, erlotinib, or bevacizumab should be reported (seeSectionfor 
instructions for reporting serious adverse events).  Afterwill be recorded during the 
study and for up to 30 days after the last dose of onartuzumabstudy treatment. After 
this period, the investigator should only report any serious adverse events that are 
assessedbelievedto be related to prior onartuzumab treatment.  For patients receiving 
only controlstudy drugtreatment, only serious adverse events related to treatment will 
be reported for bevacizumab and/or erlotinib if applicable to that patient(see Section 
5.6).
SECTION 5.3.5:  Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording all 
serious adverse events, assessed as whetherrelated or unrelated to onartuzumab, 
erlotinib, or bevacizumab, on the Adverse Event eCRF.  Avoid colloquialisms and 
abbreviations.
SECTION 5.3.5.3:  Deaths
The term "sudden death"should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24hours after the patient was last seen alive and stable.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death"should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be 
replaced by the established cause of death.  The term "sudden death"should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
SECTION 5.3.5.4:  Hospitalization or Prolonged Hospitalization
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event The following hospitalization 
scenarios are notconsidered to be adverse events:
[]


Onartuzumab—F.Hoffmann-La Roche Ltd
5/Protocol GO29646, Version 5
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
insteadThe following hospitalization scenarios are not considered to be serious adverse 
events, but should be considered as adverse events instead:
[]
SECTION 5.4:  IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
The following is a listof events that the investigator must report to the Sponsor within 24 
hours after learning of the event:

Serious adverse events, assessed aswhetherrelatedor unrelatedto onartuzumab

Serious adverse events, assessed aswhetherrelated or unrelated to Avastin 
(bevacizumab)

Serious adverse events, assessed aswhetherrelated or unrelated to Tarceva 
(erlotinib)

Pregnancies
SECTION 5.4.2.1:  Events That Are Ongoing from the Previous Protocol
Events that are ongoing from the P-trial should not be reported again under this protocol, 
unless the severity increases, andwhetherthe event is assessed asrelated or unrelated 
to onartuzumab, erlotinib,or bevacizumab.
SECTION 5.4.2.2:  Events That Occur after Study Drug Initiation
After initiation of study drug, seriousadverse events, assessed aswhetherrelated or 
unrelated to onartuzumab, bevacizumab, or erlotinib, will be reported until 30 days after 
the last dose of study drug.  
SECTION 5.5.1:  Investigator Follow-Up
Every effort should be made to follow allserious adverse events, considered to be
whetherrelated or unrelated to onartuzumab, erlotinib, or bevacizumab, until a final 
outcome can be reported.
SECTION 5.7:  EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND ETHICS 
COMMITTEES
The Sponsor will promptly evaluate all serious adverse events that are assessed as 
related to onartuzumabagainst cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.


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SECTION 6.5:  SAFETY ANALYSES
A summary of administration of study treatment (onartuzumab) and serious adverse 
events, consideredwhetherrelated or unrelated to onartuzumab, will be generated for 
these patients.
SECTION 9.2:  PROTOCOL DEVIATIONS
The Sponsor will review all protocol deviations and assess whether any represent a 
serious breach of Good Clinical Practice guidelines and require reporting to health 
authorities.As per the Sponsor's standard operating procedures, prospective requests 
to deviate from the protocol, including requests to waive protocol eligibility criteria, are 
not allowed.
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following Web site:
ww.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf


Onartuzumab—F.Hoffmann-La Roche Ltd
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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM..........................................11
PROTOCOL SYNOPSIS....................................................................................12
1.
BACKGROUND..........................................................................................16
1.1
Background on MET Signaling Pathway................................16
1.2
Background on Onartuzumab................................................17
1.2.1
Safety of Onartuzumab..........................................................17
1.3
Background on Erlotinib.........................................................17
1.4
Background on Bevacizumab................................................18
1.5
Study Rationale and Benefit-Risk Assessment......................18
2.
OBJECTIVES..............................................................................................20
3.
STUDY DESIGN.........................................................................................20
3.1
Description of Study..............................................................20
3.2
End of Study..........................................................................20
3.3
Rationale for Study Design....................................................21
3.3.1
Rationale for Onartuzumab Dose and Schedule...................21
3.4
Outcome Measures...............................................................21
3.4.1
Efficacy Outcome Measures..................................................21
3.4.2
Safety Outcome Measure......................................................21
4.
MATERIALS AND METHODS....................................................................21
4.1
Patients..................................................................................21
4.1.1
Inclusion Criteria....................................................................21
4.1.2
Exclusion Criteria...................................................................22
4.2
Study Treatment....................................................................22
4.2.1
Formulation, Packaging, and Handling..................................23
4.2.1.1
Onartuzumab.........................................................................23
4.2.1.2
Erlotinib..................................................................................23
4.2.1.3
Bevacizumab.........................................................................23
4.2.1.4
Non-Investigational Medicinal Product..................................23
4.2.2
Dosage, Administration, and Compliance..............................24
4.2.2.1
Onartuzumab.........................................................................24


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4.2.3 
Investigational Medicinal Product Accountability 
................... 25 
4.3 
Concomitant Therapy ............................................................ 25 
4.3.1 
Permitted Therapy 
................................................................. 25 
4.3.1.1 
Therapy for Febrile Neutropenia 
............................................ 26 
4.3.2 
Prohibited Therapy ................................................................ 26 
4.4 
Study Assessments 
............................................................... 26 
4.4.1 
Informed Consent Forms and Screening Log 
........................ 26 
4.4.2 
Medical History and Demographic Data ................................ 27 
4.4.3  
Physical Examinations 
........................................................... 27 
4.4.4 
Vital Signs 
.............................................................................. 27 
4.4.5 
Tumor and Response Evaluations 
......................................... 27 
4.4.6 
Laboratory Samples .............................................................. 28 
4.5 
Patient, Treatment, Study, and Site 
Discontinuation 
...................................................................... 28 
4.5.1 
Patient Discontinuation 
.......................................................... 28 
4.5.2 
Study Treatment Discontinuation 
........................................... 28 
4.5.3 
Study and Site Discontinuation 
.............................................. 28 
5. ASSESSMENT OF SAFETY 
....................................................................... 29 
5.1 
Safety Plan 
............................................................................ 29 
5.1.1 
Peripheral Edema and Generalized Edema 
(Anasarca) 
............................................................................. 29 
5.1.2 
Gastrointestinal Perforation 
................................................... 29 
5.1.3 
Venous Thromboembolic Events 
........................................... 30 
5.1.4 
Hypoalbuminemia 
.................................................................. 30 
5.1.5 
Arterial Thromboembolic Events 
............................................ 31 
5.1.6 
Neutropenia 
........................................................................... 31 
5.1.7 
Adverse Events Related to Control Treatment ...................... 32 
5.2 
Safety Parameters and Definitions 
........................................ 32 
5.2.1 
Adverse Events ..................................................................... 32 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) 
...................................................................... 33 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters 
................................................ 33 
5.3.1 
Adverse Event Reporting Period ........................................... 34 


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5.3.2 
Eliciting Adverse Event Information 
....................................... 34 
5.3.3 
Assessment of Severity of Adverse Events 
........................... 34 
5.3.4 
Assessment of Causality of Adverse Events ......................... 35 
5.3.5 
Procedures for Recording Adverse Events 
............................ 36 
5.3.5.1 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 36 
5.3.5.2 
Persistent or Recurrent Adverse Events 
................................ 37 
5.3.5.3 
Deaths 
................................................................................... 37 
5.3.5.4 
Hospitalization or Prolonged Hospitalization 
.......................... 37 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor 
.......................................................... 38 
5.4.1 
Emergency Medical Contacts 
................................................ 39 
5.4.2 
Reporting Requirements for Serious Adverse 
Events.................................................................................... 39 
5.4.2.1 
Events That Are Ongoing from the Previous 
Protocol ................................................................................. 39 
5.4.2.2 
Events That Occur after Study Drug Initiation 
........................ 39 
5.4.3 
Reporting Requirements for Pregnancies 
.............................. 40 
5.4.3.1 
Pregnancies in Female Patients 
............................................ 40 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
................. 40 
5.4.3.3 
Abortions ............................................................................... 41 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 41 
5.5 
Follow-Up of Patients after Adverse Events .......................... 41 
5.5.1 
Investigator Follow-Up 
........................................................... 41 
5.5.2 
Sponsor Follow-Up 
................................................................ 41 
5.6 
Post-Study Adverse Events 
................................................... 41 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees 
................................................................. 42 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
....................... 42 
6.1 
Determination of Sample Size 
............................................... 42 
6.2 
Summaries of Conduct of Study 
............................................ 42 
6.3 
Summaries of Treatment Group Comparability ..................... 42 
6.4 
Efficacy Analyses .................................................................. 43 


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6.5 
Safety Analyses 
..................................................................... 43 
7. DATA COLLECTION AND MANAGEMENT ............................................... 43 
7.1 
Data Quality Assurance 
......................................................... 43 
7.2 
Electronic Case Report Forms 
............................................... 43 
7.3 
Source Data Documentation 
.................................................. 44 
7.4 
Use of Computerized Systems 
.............................................. 44 
7.5 
Retention of Records 
............................................................. 45 
8. ETHICAL CONSIDERATIONS 
.................................................................... 45 
8.1 
Compliance with Laws and Regulations 
................................ 45 
8.2 
Informed Consent 
.................................................................. 45 
8.3 
Institutional Review Board or Ethics Committee 
.................... 46 
8.4 
Confidentiality 
........................................................................ 46 
8.5 
Financial Disclosure .............................................................. 47 
9. STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 47 
9.1 
Study Documentation ............................................................ 47 
9.2 
Protocol Deviations 
................................................................ 47 
9.3 
Site Inspections 
..................................................................... 47 
9.4 
Administrative Structure......................................................... 48 
9.5 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 48 
9.6 
Protocol Amendments ........................................................... 49 
10. REFERENCES ........................................................................................... 50 
 
 
LIST OF TABLES 
Table 1 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 35 
Table 2 
Causal Attribution Guidance ....................................................... 36 
 
 
LIST OF APPENDICES 
Appendix 1  Schedule of Assessments 
.......................................................... 53 


Onartuzumab—F.Hoffmann-La Roche Ltd
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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, MULTICENTER EXTENSION 
STUDY OF ONARTUZUMABIN PATIENTS WITH 
SOLID TUMORS ON STUDY TREATMENT 
PREVIOUSLY ENROLLED INANF. HOFFMANN-LA 
ROCHE-AND/OR GENENTECH-SPONSORED 
STUDY
PROTOCOL NUMBER: GO29646
VERSIONNUMBER:
5
EUDRACT NUMBER:
2014-005438-69
IND NUMBER:
100537
TEST PRODUCT:
Onartuzumab (RO5490258)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copyto 
your local study monitor.


Onartuzumab—F.Hoffmann-La Roche Ltd
12/Protocol GO29646, Version 5
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL, MULTICENTER EXTENSION 
STUDYOFONARTUZUMAB IN PATIENTS WITH SOLID 
TUMORSON STUDY TREATMENT PREVIOUSLY ENROLLED IN
ANF.HOFFMANN-LAROCHE-AND/OR 
GENENTECH-SPONSORED STUDY
PROTOCOL NUMBER:
GO29646
VERSION NUMBER:
5
EUDRACT NUMBER:
2014-005438-69
IND NUMBER:
100537
TEST PRODUCT:
Onartuzumab (RO5490258)
PHASE:
Phase IIIb/IV
INDICATION:
Solid tumors
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
The objectivesfor this study areas follows:
To provide continued onartuzumab and/or parent trial (P-trial)designated control 
treatments to patients with cancer who were previously enrolled in a Roche/Genentech-
sponsored onartuzumab P-trial and who derived benefit, as assessed by the responsible 
investigator, from the therapy administered in the P
-trial.
To collect safety data with regard to administration of continued onartuzumab therapy.
Study Design
Description of Study
This is a multicenter, open-labelPhase IIIb/IV study.  Patients on treatmentat the completionof 
the P-trial, defined as when relevant efficacy
 and safety analyses for the trial are completed by 
the Sponsor, should be enrolledinto this extension trial (E-trial).  Patients will receive treatment 
with either the control treatment(bevacizumab and/or erlotinib)and/or onartuzumab-based 
study treatment (as during their P-trial) until progression of disease, unacceptable treatment
relatedtoxicity, withdrawal of consent, or death (whichever occurs first).
Only patients previously enrolled and currently receiving treatment in the P-trialsare eligible for 
this trial.  Patients may be enrolled into the E-trial upon notification from the Sponsor to the 
investigator that the P-trial is completed.
All patients will continue on the same dose and schedule of control treatment as specified in 
their respective P-trial.  The dose of onartuzumab will be calculated based on the patient’s 
weight at the screening visit for the E-trial.  Data will be collected for administration of 
onartuzumab and any serious adverse event deemed related to onartuzumab, erlotinib, and/or 
bevacizumab treatment.
This trial will remain open for enrollment until all patients from eligible P-trials have completed 
their protocol-specified therapies.  The trial will close upon discontinuation of treatment of the 
last enrolled patient.


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Number of Patients
Up to 14 study centers will participate in this study in Europe, Africa, and Asia, enrolling a total 
of up to 17 patients.  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
Signed E-trial Informed Consent Form
Enrolled and receiving either control treatment and/or onartuzumab-based study treatment 
in an eligible P-trial
Has not met the treatment discontinuation criteria specified in their P-trial protocol at the 
time of enrollment into the E-trial
Ability to begin treatment in the extension (rollover) protocol within 42 days following the last 
day of the study in the antecedent protocol
For women who are not postmenopausal (12months of nontherapy-induced amenorrhea) 
or surgicallysterile (absence of ovaries and/or uterus):  agreement to remain abstinent or 
use single or combined non-hormonal contraceptive methods that result in a failure rate of 
1% per year during the treatment period and for at least180 days after the last dose of 
study drug
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of non-hormonal contraceptive methods with a failure rate of 1% per 
year include tubal ligation, male sterilization, hormonal implants, established, proper 
use of combined oral or injected hormonal contraceptives, and certain intrauterine 
devices.  Alternatively, two methods (e.g., two barrier methods such as a condom 
and a cervical cap) may be combined to achieve a failure rate of1% per year.  
Barrier methods must always be supplemented with the use of a spermicide.
For men:  agreement to remain abstinent or use a condom plus an additional contraceptive 
method that together result in a failure rate of 1% per year during the treatment period 
and for at least 180 days after the last dose of study drug and agreement torefrain from 
donating sperm during this same period
Men with a pregnant partner must agree to remain abstinent or use a condom for the 
duration of the pregnancy.
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Pregnancy orlactationor intentionto become pregnant during the study(serum pregnancy 
test required before enrollment)
Any non-protocol anti-cancer therapy started between discontinuation from treatment in P-
trial and start of enrollment in E-trial.
All patients will continue the therapy that they last received on their respective P-trials.  Dose or 
schedule modifications made during a patient’s treatment in the P-trial should be carried over 
into the E-trial (i.e., if a component of a combinationchemotherapy had been discontinued for 
toxicity, that component should not be resumed).
Length of Study
It is estimated that this study will last approximately 2 years.


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End of Study
The end of this study is defined as the date of the last patient, last visit (LPLV).  This 
corresponds to 30 days after the last patient discontinues all treatment (either onartuzumab, 
control treatment,or both) for any reason.  Once patients have discontinued either control 
treatment and/or onartuzumab-based study treatment and completed a 30-day follow-up visit, 
their participation in the trial is considered complete.
Outcome Measures
Efficacy Outcome Measures
This study includes no efficacy outcome measures.
Safety Outcome Measures
The safety outcome measure for this study isas follows:
Serious adverse events, whetherrelated orunrelated to onartuzumab
Investigational Medicinal Products
Onartuzumab (RO5490258)
Onartuzumab will be supplied as a sterile liquid in a single-use 15-cc vial.  Each 15-cc vial 
contains 600 mg of onartuzumab in 10 mL at a concentration of 60mg/mL in   mM histidine 
acetate,   mM sucrose,  
% polysorbate 20, pH 5.4.
Upon receipt, vials containing onartuzumab must be refrigerated at 2C8C (36F46F) and 
should remain refrigerated until just prior to use; do not freeze.  Vials should be protected from 
light.
Onartuzumab will be administered intravenously at either a dose of 10 mg/kg every 2 weeks or 
15 mg/kg every 3 weeks.
Erlotinib
Erlotinib oral tablets are conventional, immediate-release tablets containing erlotinib as the 
hydrochloride salt.  In addition to the active ingredient (erlotinib), tablets contain lactose 
(hydrous), microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, and 
magnesium stearate.
Erlotinib immediate-release tablets are available in 25-, 100-, and 150-mg strengths.
Bevacizumab
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate 
for solution for IV infusion.  Bevacizumab will be supplied in 20-mL (400-mg) glass vials 
containing 16 mL bevacizumab (25 mg/mL).  Vials contain bevacizumab with phosphate, 
trehalose, polysorbate 20, and Sterile Water for Injection, USP.  Vials contain no preservative 
and are suitable for single use only.
Non-Investigational Medicinal Products
Comparator
Non-investigational medicinal products for each subject in the E-trial will be the same as that in 
their P-trial.
Statistical Methods
Primary Analysis
The safety analyses will include only patients who received at least one dose of onartuzumab.  
A summary of administration of study treatment (onartuzumab) and serious adverse events 
considered related to onartuzumab will be generated for these patients.
Determination of Sample Size
The sample size of this E-trial will depend upon the number of patients eligible from P-trials who 
elect to transfer to this trial for continued treatment of their underlying cancer.  


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LIST OF ABBREVIATIONS AND DEFINITIONS OFTERMS
Abbreviation
Definition
ASCO
American Society of Clinical Oncology
CRO
contract research organization
CSF
colony-stimulating factors
CT
computed tomography (scan)
CVAD
central venous access devices
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EGF
epidermal growth factor
EGFR
epidermal growth factor receptor
E-trial
extension trial
FDA
U.S. Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IND
Investigational NewDrug
IRB
Institutional Review Board
IWRS
interactive web/voice response system
IV
intravenous
LPLV
last patient, last visit
MET
mesenchymalepithelial transition factor
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NSCLC
non–small cell lung cancer
P-trial
parent trial
PE/PP
polyethylene/polypropylene
PRO
patient-reported outcome
PVC
polyvinyl chloride
SPC
Summary of Product Characteristics
VTE
venous thromboembolic events
WOCP
women of childbearing potential


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1.
BACKGROUND
1.1
BACKGROUND ON METSIGNALING PATHWAY
Hepatocyte growth factor (HGF; also known as scatter factor) and its receptor 
mesenchymalepithelial transition factor (MET)promote cell proliferation, motility, 
invasion, survival, and morphogenic changes that can stimulate tissue repair and 
regeneration in normal tissue but can stimulate growth, invasion, and survival in tumor 
cells (Stoker et al. 1987; Miyazawa et al. 1989; Nakamura et al. 1989; Zarnegar and 
Michalopoulos 1989; Gherardi and Stoker 1990; Bottaro et al. 1991; Weidner et al. 1991; 
Ma et al. 2003).  The HGF/MET pathway is frequently dysregulated in many human 
malignancies via multiple mechanisms, including receptor mutation, aberrant autocrine 
production ofHGF and MET in the same tumor cell, and MET overexpression.  
Evidence of activating mutations in the MET kinase domain was characterized in cases 
of spontaneous and hereditary papillary renal cell carcinoma (Schmidt et al. 1997; 
Oliveroet al. 1999).  These activating mutations are transforming inNIH-3T3 cells and 
normal epithelial cells, in which the mutant receptors make cells hyperresponsive to 
HGF (Jeffers et al. 1997, 1998; Schmidt et al.1997, 1998; Michieli et al. 1999; Olivero et 
al. 1999; Lorenzatoetal.2002; Graveel et al. 2004).  Similarly, mutations in or loss of 
the juxtamembrane region of MET have been found in 2% of nonsmall cell lung cancer 
(NSCLC)(Kong-Beltranetal.2006).  Loss of function of the juxtamembrane domain, 
which encodes for a binding site for the Cbl E3 ubiquitin ligase, resultsin prolonged MET 
signaling following ligand stimulation, making tumor cells hyperresponsive to HGF.  
Other mutations and polymorphisms have been characterized in the MET extracellular 
domain; however, their role in driving tumorigenesis is not clear (Ma et al. 2005).  Most 
commonly, the level of MET expression is increased. 
Aberrant expression of HGF in epithelial-based tumor cellsor MET in mesenchymally
derived tumor cells results in the co-expression of both MET and HGF in an autocrine 
manner.  Because both MET and HGF need proteolytic activation outside of the cells, 
localized HGF production likely acts in both an autocrine and paracrine fashion with 
neighboring cells.  Co-expression of MET and HGF in tumors is fairly infrequent, 
occurring in 1% in most tumor indications.  However, someindications have 
demonstrated higher rates of autocrine co-expression, including glioblastoma (GBM) and 
some sarcomas such as osteosarcoma (Koochekpour et al. 1997; Fukudaetal. 1998; 
Moriyamaet al. 1999).  Nonclinical HGF/MET autocrine tumor models have 
demonstrated exquisite sensitivity to MET inhibitors in vitro and in vivo 
(Martensetal2006; Jin et al. 2008).
By far, the most common mechanism of dysregulation of the MET pathway is 
overexpression.  Levels of MET can be increased via METgene amplification or through 
amplification-independent means (Kuniyasu et al. 1992; Seruca et al. 1995).  Although
rates of METamplification are typically low in most tumor indications (~1%), rates can be 


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as high as 2%–4% in NSCLC (Toschi and Cappuzzo 2010).  METamplification and MET
overexpression have also been reported to occur as a mechanism of acquired 
resistance to other therapeutics such as epidermal growth factor receptor (EGFR)
inhibitors (Bean et al. 2007; Engelmanetal. 2007; Cappuzzo et al. 2009).  HGF is also 
increased in patients with cancer,although it is not commonly found to be dysregulated 
at the gene copy level, nor is it as dynamically changed as the receptor.  High levels of 
HGF and/or METhave been correlated with poor prognosis in several tumor types, 
including NSCLC (Ichimuraetal1996; Masuya et al. 2004). 
METis also known to be expressed on endothelial and lymphendothelial cells and,
therefore,has been implicated in the initiation, modulation, and/or maintenanceof 
angiogenesis and/or lymphangiogenesis (Zhao et al. 2011).  Therefore, the mechanism 
of action of METinhibitors,such as onartuzumab (MetMAb),may include both anti-tumor 
effects as well as anti-angiogenic and/or anti-lymphangiogenic effects.
1.2
BACKGROUND ON ONARTUZUMAB
Onartuzumab (MetMAb)is a recombinant, fully humanized, monovalent monoclonal 
antiMETantibody based on the human IgG1κ(kappa) framework sequence.  It binds 
in the Sema domain of METwithin the extracellular domain, where it acts to inhibit HGF 
binding and initiation of receptor activation.  This monovalent (or “one-armed”) antibody 
is composed of a full-length heavy chain, a light chain, and a truncated heavy chain th
at 
consists of only the C
H2 and CH3 domains.  The molecule is not glycosylated and has a 
molecular mass of approximately 99 kDa.  
The unique monovalent design of onartuzumab eliminates the potential for MET
activation via antibody-driven receptor dimerization, which can occur with a bivalent 
antibody against MET(Prat et al. 1998).  Onartuzumab is currently the only monovalent 
antibody in the clinic that targets the METreceptor.
See the Onartuzumab Investigator’sBrochure for details on nonclinical and clinical 
studies.
1.2.1
Safety of Onartuzumab
To date,more than 1300 patients have been exposed to onartuzumab as part of the 
clinical development program. Adverse events assessed as causally related to 
onartuzumab are peripheral edema (including anasarca), gastrointestinal(GI)perforation, 
venous thromboembolic events(VTEs), arterial thromboembolic events,and neutropenia.
Refer to the Onartuzumab Investigator’s Brochure for further information.
1.3
BACKGROUNDONERLOTINIB
Erlotinib (Tarceva, OSI-774) is an orally active antitumor agent developed for the 
treatment of NSCLC, pancreatic cancer,and other solid tumors.  Astellas Pharma US, 
Inc.(on behalf of OSI Pharmaceuticals, LLC), Genentech, Inc.,and F. Hoffmann-La 


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Roche Ltd are co-developing erlotinib globally.  Tarceva is currently approved for 
marketing in approximately 110countries worldwide.
Erlotinib acts through direct and reversible inhibition of the human epidermal growth 
factor receptor 1/epidermal growth factor receptor (HER1/EGFR, hereafter referred to as 
EGFR) tyrosine kinase.  Erlotinib inhibits human EGFR tyrosine kinase with a 50% 
inhibitory concentration (IC50) of 2nM (0.79ng/mL) in an in vitro enzyme assay and 
reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 20nM 
(7.9ng/mL).  EGFR is overexpressed in a significant proportion of epithelium-derived 
carcinomas.  Erlotinib inhibits the epidermal growth factor (EGF)-dependent proliferation 
of cells at nanomolar concentrations and blocks cell cycle progression at the G1 phase.  
Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 L858R mutations is 
higher than its affinity for the wild type receptor.
See the ErlotinibSummary of Product Characteristics (SPC)for details on nonclinical 
and clinical studies.
1.4
BACKGROUND ON BEVACIZUMAB
Bevacizumab (Avastin) is a recombinant humanized anti-vascular endothelial growth 
factor monoclonal IgG1 antibody that has undergone clinical development in numerous 
oncology indications. The development program includes studies sponsored and 
conducted by Genentech,Inc., F. Hoffmann-La Roche Ltd, and the National Cancer 
Institute in the U.S. On the basis of these studies,bevacizumab received marketing 
authorization approval in over 100 countries (including the U.S.and E.U.) for the 
treatment of patients with metastatic carcinoma of the colon or rectum. Marketing 
authorization has also been receivedin some of these countries for thetreatment of 
patients with either unresectable, locally advanced, recurrent,or metastatic 
nonsquamous NSCLC;metastaticbreast cancer;advanced and/or metastatic renal cell 
cancer;or malignant glioma (WHO Grade IV) glioblastoma. For specific details of 
approved indications, please refer to the approved local prescribing information.
See the BevacizumabSPCfor details onnonclinical and clinical studies.
1.5
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Onartuzumab has been investigated in several tumor types for which MET signaling has 
been implicated, generally through randomized Phase IIand Phase IIIclinical trials. In 
most of these investigative trials,henceforth referred to as“P-trials”(or parent trials),the 
addition of onartuzumab to a standard therapy (with which MET inhibition may be 
additive or synergistic)was evaluated. Patients were randomized in blindedfashion to 
either the control arm consisting of standard therapy or to the study arm consisting of 
standard therapy combined with onartuzumab.


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Per protocol, patients received control or study treatment until the earliest event of 
disease progression, an adverse event leading to discontinuation,or discontinuation per 
physician or patient decision.Afterthe completionof the final analysis ordiscontinuation
of these trials,study patients couldremain on their protocol-specified treatment if none 
of these events have occurred. Roche/Genentech have committed to provide continued 
protocol-defined treatment for patientsenrolled on a P-trialif medically appropriate and 
desired by the treating physician and the patient until one of the listed events has 
occurred.
This trial, henceforth referred to as the“E-trial”(or extension trial), allowscontinued 
treatment of patients on their P-trial protocol specified treatment after termination of their 
P-trial. This E-trial is designed to ensure an optimal benefit-riskratio. The study 
protocol includes the following measures to manage the risk:

The Sponsor will assess each trial carefully before declaring it a “qualifying” P-trial 
and enrolling its eligible patients into this E-trial.For example, a trialthat is 
prematurely stopped for safety issues related to onartuzumabwould not become a 
P-trial.

The dose of onartuzumab for each patient will becalculated based on the weight of 
the patient obtained during the screening visit for the E-trial.

The control treatment for each patient will remain as specified in the P
-trial, 
including protocol-mandated dose modifications, from which the patient had been 
enrolled. Doses for all drugs in the control treatment regimen will remain the same 
as the last dose received on the P-trial.

Clear guidance is provided on interruption and discontinuation for onartuzumab in 
case a patient develops severe side effects; this also takes into account side effects 
experienced during treatment in the P-trial.

The Sponsor will collect safety data fortheinvestigational agent, onartuzumab, as 
well as any drugs manufactured by the Sponsor and given as the control treatment 
in accordance with all local regulations.

Doses of study therapy have been chosen in accordance with Summary of Product 
Characteristics (SPC)and taking into account the available data on clinical studies 
as well as usual practices.

Becausethis is an E-trial, all centersalready have experience with the study 
treatment and have qualified and experienced specialists involved who are 
motivated to continue caring for the patients.


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2.
OBJECTIVES
The objectives for this study are as follows:

To provide continued onartuzumab and/or P-trialdesignated control treatments to 
patients with cancer who were previously enrolled in a Roche/Genentech-sponsored 
onartuzumab P-trial and who derived benefit, as assessed by the responsible 
investigator, from the therapy administered in the 
P-trial.

To collect safety data with regard to administration of continued onartuzumab
therapy.
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a multicenter, open-labelPhase IIIb/IV study.  Patients on treatment at the
completion of the P-trial, defined as when relevant efficacy and safety analyses for the 
trial are completed by the Sponsor,should be enrolled into this E-trial. Patients will 
receive treatment with either the control treatment and/or onartuzumab-based study 
treatment(as during their P-trial)until progression of disease, unacceptable treatment
relatedtoxicity, withdrawal of consent,or death (whichever occurs first).
Only patients previously enrolled and currently receiving treatment in the P-trialsare 
eligible for this trial. Patients maybe enrolled intothe E-trial upon notification from the 
Sponsor to the investigator that the P-trial is completed.
All patients will continue on the same doseand schedule of control treatment
(bevacizumab and/or erlotinib)as specified in their respective P-trial.The dose of 
onartuzumab will be calculated based on the patient’s weight at the screening visit for 
the E-trial. Data will be collected for administration of onartuzumab and any serious 
adverse eventdeemed related to onartuzumab, erlotinib,and/orbevacizumabtreatment.
This trial will remain open for enrollment until all patients from eligible P-trials have 
completed their protocol-specified therapies.The trial will close upon discontinuation of 
treatmentof the last enrolled patient.
3.2
ENDOF STUDY
The end of this study is defined as the date of the last patient, last visit (LPLV).  This 
corresponds to 30 days after the last patient discontinues all treatment (either 
onartuzumab, control treatment, or both) for any reason.  Once patients have 
discontinued either control treatment and/or onartuzumab-based study treatment and 
completed a 30-day follow-up visit, their participation in the trial is considered complete.


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3.3
RATIONALE FOR STUDY DESIGN
The primary aim is to provide continued protocol-specified control therapy and/or 
onartuzumab-based study therapy to patients with cancer who are benefiting from the 
therapy administered in the P-trial at time of termination of the P-trial. Therefore,this is 
an open-label, non-comparative study.  No efficacy analyses are planned.Allserious
adverse events will be reported.
3.3.1
Rationale for OnartuzumabDose and Schedule
The dosingschedule of administration in the E-trial will followthe corresponding P-trial
dosing administration schedule. Upon enrollment, patients in this E-trial will continue at 
the same dose of control treatmentthat they were receiving inthe P-trial. The dose of 
onartuzumab will be calculated based onthe patient’s weight obtained at the screening 
visit for the E-trial. Any dose modifications will mirror dose modification criteria 
described in the corresponding P-trial.
3.4
OUTCOME MEASURES 
3.4.1
Efficacy Outcome Measures
This study includes no efficacy outcome measures.
3.4.2
Safety Outcome Measure
The safety outcome measure for this study isas follows:

Seriousadverse eventsconsidered related or unrelated to onartuzumab
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients enrolled in an eligible onartuzumab P-trialthatis being terminated and who 
remain on either protocol-mandated control treatment or onartuzumab-based study 
treatment are eligiblefor enrollment.
4.1.1 
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed E-trial Informed Consent Form

Enrolled and receiving either control treatment and/or onartuzumab-based study 
treatment in an eligible P-trial

Has not met the treatment discontinuation criteria specified in their P-trial protocol at 
the time of enrollment into the E-trial

Ability to begin treatment in the extension (rollover) protocol within 42days following 
the last day of the study in the antecedent protocol

For women who are not postmenopausal (12months of nontherapy-induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  agreement to 


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remain abstinent or use single or combined non-hormonal contraceptive methods 
that result in a failure rate of 1% per year during the treatment period and for at 
least180daysafter the last dose of study drug
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.
Examples of non-hormonal contraceptive methods with a failure rate of 1% 
per year include tubal ligation, male sterilization, hormonal implants, 
established, proper use of combined oral or injected hormonal contraceptives, 
and certain intrauterine devices.  Alternatively, two methods (e.g., two barrier 
methods such as a condom and a cervical cap) may be combined to achieve a 
failure rate of1% per year.  Barrier methods must always be supplemented 
with the use of a spermicide.

For men:  agreement to remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for at least 180daysafter the last dose of study drug and
agreement torefrain from donating sperm during this same period
Men with a pregnant partner must agree to remain abstinent or use a condom 
for the duration of the pregnancy.
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle 
of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnancyorlactationor intentionto become pregnant during the study(serum 
pregnancy test required before enrollment)

Any non-protocol anti-cancer therapy started between discontinuation from 
treatment in P-trial and start of enrollment in E-trial.
All patients will continue the therapy that they last received on their respective P-trials. 
Dose or schedule modifications made during a patient’s treatment in the P-trial should 
be carried over into the E-trial (i.e.,if a component of a combination chemotherapy had 
been discontinued for toxicity, that component should not be resumed).
4.2
STUDY TREATMENT 
If not specified by this E-trial protocol, the default is to follow the guidance from the 
respective P-trial protocol per clinical judgment or discretion of the investigator.


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4.2.1
Formulation, Packaging, and Handling
4.2.1.1
Onartuzumab
Onartuzumab will be supplied as a sterile liquid in a single-use 15-cc vial.  Each 15-cc 
vial contains 600 mg of onartuzumab in 10mL at a concentration of 60 mg/mL in   mM 
histidine acetate,   mM sucrose,  
%polysorbate 20, pH 5.4.
Upon receipt, vials containing onartuzumab must be refrigerated at 2C8C (36F46F) 
and should remain refrigerated until just prior to use; do not freeze.  Vials should be 
protected from light.
For further details, see the Onartuzumab Investigator’s Brochure.
4.2.1.2
Erlotinib
Erlotinib oral tablets are conventional, immediate-release tablets containing erlotinib as 
the hydrochloride salt.  In addition to the active ingredient (erlotinib), tablets contain 
lactose (hydrous), microcrystalline cellulose, sodium starch glycolate, sodium lauryl 
sulfate, and magnesium stearate.
Erlotinib immediate-release tabletsare available in 25-, 100-, and 150-mg strengths.
For further details, see the manufacturer’s prescribing information for Tarceva(erlotinib).
4.2.1.3
Bevacizumab
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid 
concentrate for solution for IV infusion.Bevacizumab will be supplied in20-mL (400-mg) 
glass vials containing 16 mLbevacizumab (25 mg/mL). Vials contain bevacizumabwith 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection,USP. Vials 
contain no preservative and are suitable for single use only.
Upon receipt of the study drug, vials are to be refrigerated at 2°C–8°C (36°F–46°F) and 
should remain refrigerated until just prior to use. DO NOT FREEZE. DO NOTSHAKE. 
Vials should be kept in the outer carton due tolight sensitivity.
For further details, see the manufacturer’s prescribing information for Avastin 
(bevacizumab).
4.2.1.4
Non-Investigational Medicinal Product
Anti-cancer therapy, not manufactured by the Sponsor,given withor without
onartuzumabin the P-trial will be administered as per instructions in the P-trial and
classified as Non-IMPin this E-trial. The Sponsor will continue to provide those anti-
cancer therapies until treatment is permanently discontinued. 


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If onartuzumab is permanentlystopped for reasons other than disease progression, 
other P-trial IMP treatment may be continued under the E-trial until progression if the 
patient has no other form of access to treatment with those anti-cancer therapies.
Management (i.e.,handling, storage, administration, accountability,and disposal) of 
those anti-cancer drugs will be in accordance with instructionsdefined in the P-trial.
Investigators can prescribe non-IMP in accordance with their local label and standard of 
care. Their use will be in accordance with the relevant local guidelines and SPC. 
Management (i.e.,handling, storage, administration and disposal) will be in accordance 
with Good Clinical Practice (GCP)and local guidelines.
Please use commercial stock in keeping with the usual practice of the institution.
There are no special accountability arrangements.
4.2.2
Dosage, Administration, and Compliance
4.2.2.1
Onartuzumab
Onartuzumabwill be dosed in the clinic on Day 1 of each 14-or 21-day cycle as 
specified in the P-trialand as per clinical judgment and discretion of the investigator.  
The individual dose of onartuzumab for each patient will be 10mg/kg for 14-day cycles 
or 15 mg/kg for 21-day cycles. The patient’s weight at enrollment of the E-trial will be 
used to determine the actual dose of study drug.  This dose will be administered 
throughout the study and will not change according to weight.
Liquid onartuzumab should be diluted with sterile 0.9 NSS into a total volume of 250mL.  
Mix the IV bag by gently inverting after injecting the study drug; do not shake.  Once 
onartuzumab has been diluted into sterile saline, the solution should be used within 
8hours.  Dextrose should not be used for dilution of onartuzumab.  Anyremaining 
solution should be discarded.
Onartuzumab is administered as an IV infusion.  Doses of onartuzumab may be 
administered over 3010 minutes, with at least a 60-minute observation periodafter the 
infusion.
Vials are for single use only;vials used for one patient may not be used for any other 
patient.
The infusion solution must be administered using an infusion set with an in-line, sterile, 
non-pyrogenic, low-protein-binding filter (pore size of 0.2 micrometer or less).  
If diluted onartuzumab needs to be transported to another facility, it should be 
transported at 5°C and preferably diluted in polyvinyl chloride (PVC) bags (no need to 
remove the headspace).  Onartuzumab is stable in PVC (preferred) or 


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polyethylene/polypropylene (PE/PP) bags.  Up to 1 hour oftransportation at 2°–8°C in 
PE/PP bags or up to 3 hours of transportation at 2°–8°C in PVC bags is acceptable.
Guidelines for dose modification and treatment interruption or discontinuation of study 
treatment are provided in the respective P-trial protocol.
Serious adverse events related toan overdose or incorrect administration of 
onartuzumab, erlotinib,or bevacizumabshould be recorded on the AdverseEvent 
electronic Case Report Form (eCRF).
4.2.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (onartuzumab, erlotinib,and bevacizumab) 
will be provided by the Sponsor where required by local health authority regulations.  
The study site will acknowledge receipt of IMPs, using the interactive web/voice 
response system (IWRS)to confirm the shipment condition andcontent.  Any damaged 
shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsorwith the appropriate 
documentation.  The site
's method of IMP destruction must be agreed toby the Sponsor.  
The site must obtain written authorization from the Sponsorbefore any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3
CONCOMITANT THERAPY
4.3.1
Permitted Therapy 
Concomitant therapyincludes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbalor homeopathic remedies, nutritional supplements) used by a patient from 
the end of his or herparticipation in the P-trial to start of his or herparticipation in the 
E-trial.
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenancetherapy should continue their use.
Bisphosphonates or denosumab are acceptable for bone metastases if clinically 
indicated. 
Anticoagulation for maintenance of patency of permanent indwelling IV catheters is 
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4.3.1.1
Therapy for Febrile Neutropenia
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation 
of IV antibiotic therapy and colony-stimulating factors (CSFs) if clinically indicated.  Use 
of CSFs for subsequent cycles or dose reduction should be considered.
Routine use of CSFs is not permitted.  American Society of Clinical Oncology(ASCO)
guidelines for use of CSFs should be followed (Smith et al. 2006).
4.3.2
ProhibitedTherapy
Therapies prohibited in a P-trial remain prohibited when patients continue with their 
study treatment in the E-trial.
No other experimental or systemic anti-cancer therapy is permitted during study 
treatment except for localized radiotherapy for pain control.
4.4
STUDY ASSESSMENTS 
Please see Appendix1for the schedule of assessments performed during the study.
4.4.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing anystudy-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
A screening examination (“baseline”) should be performed between 42daysand 1day 
before the first dose of treatment in this E-trial (for specific timelines,see Appendix1), 
which will include the following procedures (unless the procedures have already been 
conducted during this time period as part of the patient’s routine clinicalcare):

Eligibility (inclusion and exclusion criteria, as listed in Section4.1.1and 
Section4.1.2, respectively)

Minimal patient characteristics will be collected(i.e.,date of birth, sex,P-trial 
protocol,and patient number).

Blood sampling for serum pregnancy testfor women of childbearing potential 
(WOCP)should be obtained within 7 days of the E-trial treatment.
The following procedures are recommendedand will usually be part of the patient’s 
routine care:

Complete physical examination and measurement of vital signs (including blood 
pressure)

Assessment of laboratory parameters

Tumorassessment (see Section4.4.5)


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Serious adverse events: After informed consent signature but prior to the first dose of 
study therapy in the E-trial (onartuzumaband/or,if applicable,other P-trial IMP), serious 
adverse events,whetherrelated or unrelated to onartuzumab, erlotinib, or bevacizumab,
should be reported.
Patients who meet all of the inclusion and exclusion criteria will be enrolled in the E-trial.
The investigator’s assessment of each screened patient with regard to the E-trial’s 
inclusion and exclusion criteria is to be documented in the patient’s medical record. 
4.4.2
Medical History and Demographic Data
Medical history and demographic data will be taken from a patient’s respective P-trial.
4.4.3
Physical Examinations
Physical examinations willbeperformedas per the institutions standard of care.
4.4.4
Vital Signs
Vital signs will be measured as per the institutions standard of care.
4.4.5
Tumor and Response Evaluations
The baseline for the tumorevaluation (i.e.,determination of progressive disease) is as 
per the P-trial.
Tumorassessments in this E-trial will be performed according to localstandards.It is 
recommendedto continue using the same imagingtechnique (computed tomography 
(CT) scans, X-rays,or magnetic resonance imaging [MRIs]) and the same tumor
evaluation criteria (e.g.,RECIST v1.0 or V1.1) as in the P-trial throughout this E-trial. 
Whenever possible, the same investigator or radiologist should make measurements for 
all assessments for each patientas per the P-trial.

Patients known to have bone metastases at baseline or with signs or symptoms 
suggestive of bone metastasis should undergo an isotope bone scan (this 
procedure is not mandatory if an 18-FDG PET scan has already been performed). 

CT/MRI scan of the brain is not mandatory but should be performed as soon as 
possible if there is a clinical suspicion of CNS metastasis (also see Section4.4.6).

If a patient inadvertently misses a prescribed tumorevaluation or a technical error 
prevents the evaluation, the patient may continue treatment until the next prescribed 
assessment, unless signs of clinicalprogression are present.If there is suspicion of 
disease progressionbased on clinical or laboratory findings before the next
prescribed assessment, an earlier assessment should be performed.

Symptomatic deterioration may occur in some patients.  In this situation, 
progression is evident in the patient’s clinical symptoms, but is not supported by the 
tumormeasurements. Additionally, the pharmacodynamicsmay be so evident in 


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some cases that the investigator may elect not to perform further disease 
assessments.  In such cases, the determination of clinical progression will be based 
on symptomatic deterioration.These determinations should be a rare exception as 
every effort should be made to document the objective progression of underlying 
malignancy with appropriate imaging.
4.4.6
LaboratorySamples
Laboratory tests, including those done for safety assessments, should be performed as 
per local standard of careand as indicated in Appendix1. In order to determine a 
patient’s eligibility for the E-trial, a serum pregnancy test for WOCP must be performed 
within 7 days of the E-trial treatment and recorded in the Screening section of the eCRF. 
Local laboratories will be used for all laboratory testing.
4.5
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.5.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include but are not limited to the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
4.5.2
Study Treatment Discontinuation
Patients must discontinue study treatment if they become pregnant.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.5.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severityof seriousadverse events in this studyindicates a 
potential health hazard to patients.

Inadequate supply of onartuzumab for patient administration.


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The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for GCP

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Onartuzumabis not planned to be developed towards registration.  Thus, the entire 
safety profile is not known at this time.  There is no antidotefor the adverse events 
related to onartuzumab administration.  Patients should discontinue onartuzumab if any 
adverse event, thought to be related or not, compromises the physical condition of the
patient.  Onartuzumab should not be restarted without agreement from the E-trial’s 
medical monitor.
5.1.1
Peripheral Edema and Generalized Edema (Anasarca)
The most frequently reported adverse events include peripheral edema and anasarca.  
In Study OAM4558g (2L/3L non–small cell lung cancer[NSCLC]), the incidence of 
edema (group term) irrespective of severitywas 30.4% in the onartuzumaberlotinib
arm compared with 10.5% in the placeboerlotinibarm.  In Study OAM4861g (TNBC), 
the incidence of edema (group term) was 62.9% in the onartuzumabbevacizumab
paclitaxelarm, 63.8% in the onartuzumabplacebopaclitaxel arm,and 21.0%in the 
placebobevacizumabpaclitaxelarm. 
The incidence of generalized edema (anasarca) in Study OAM4861g was 3.2% in the 
onartuzumabbevacizumabpaclitaxel arm, 5.2% in the 
onartuzumabplacebopaclitaxel arm, and 0% in placebobevacizumabpaclitaxel 
arm.
There is no specific treatment guidance for edema. Investigators have administered 
antidiuretics, albumin and/or mechanical pressure with bandaging of the affected limb 
withlimitedsuccess.  
5.1.2 
Gastrointestinal Perforation
A program-wide review of all ongoing and completed trials revealed a disproportionate 
incidence of GI perforation (by SMQ) in patients who received onartuzumab compared 


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with those who received the respective control treatment.  Seventeen events were 
reported in 1013 patients (1.6%) receiving onartuzumab-containing regimens, with 
5events reported in 891 patients (0.5%) receiving control regimens.  The imbalance was 
also observed when the analysis was limited only to reports of actual GI perforation 
events: 12events (1.1%) in patients receiving onartuzumab-containing regimens and 
2events (0.2%) in patients receiving control regimens. 
Patients may be at increased risk for the development of GI perforation when treated 
with onartuzumab.  In patients who develop GI perforation,treatment with onartuzumab 
must be permanently discontinued.
5.1.3
Venous Thromboembolic Events
An analysis of all Phase II clinical trials revealed a disproportionate incidence of VTEsin 
patients who received onartuzumab compared with those who received the control 
treatment.  A total of 79VTEs of any grade were reported in 529 patients (14.9%) 
receiving onartuzumab-containing regimens, whereas 38 VTEs of any grade were 
observed in 454patients (8.4%) receiving control regimens.
The analysis of serious events took into consideration a variety of potential interacting 
factors (central venous access devices [CVADs], edema, history of VTE, risk factors for 
VTE, and anatomical site of thrombus).  No imbalance of numbers was noted between 
onartuzumab and control arms that may suggest any one factor contributing to the 
increased risk observed with onartuzumab.  However, limitations of this analysis were 
the inclusion of only serious events,no weighting of risk factors for thrombosis,no 
inclusion ofCVAD presence on case report forms,and the lack of risk factor data on 
patients without VTE.
It is the Sponsor’s view, based on the currently available data from all trials, that patients 
may be at increased risk for the development of VTE when treated with onartuzumab.  
Patients and physicians are advised to be observant for the signs and symptoms of VTE 
and to instruct patients to seek medical care if they develop symptoms, such as 
shortness of breath, chest pain, or arm or leg swelling.  Thromboprophylaxis should be 
considered based on a careful assessment of an individual patient’s underlying risk 
factors.  Any thromboprophylaxis should follow current local institutional guidelines and 
best practice.
5.1.4
Hypoalbuminemia
In Study OAM4861g (TNBC), the incidence of low albumin laboratory value was 75.8% 
in the onartuzumabbevacizumabpaclitaxel arm, 87.9% in the 
onartuzumabplacebopaclitaxel arm, and 26.2% in the 
placebobevacizumabpaclitaxel arm.


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There was no increase in proteinuria reported in Study OAM4861g; the incidence was 
3.2% in the onartuzumabbevacizumabpaclitaxel arm, 3.4% in the 
onartuzumabplacebopaclitaxel arm, and 11.3% in the 
placebobevacizumabpaclitaxel arm.
There are no specific management guidelines for the eventof hypoalbuminemia that the 
Sponsor can recommend.  Any treatment should follow current local institutional 
guidelines and best practice. 
5.1.5
Arterial Thromboembolic Events
An imbalance in the incidence of ATEs was noted with 11 of 877 patients (1.3%) in 
onartuzumab-containing arms and 2of 794 patients (0.3%) in control arms experiencing 
such an event (as of 13 June 2014).  All the events were reported as serious.  One fatal
event each was reported in the onartuzumab-containing and control arms.  The most 
frequent event was acute myocardial infarction/myocardial infarction (8patients [0.9%]) 
in the onartuzumab-containing arms and 1 patient [0.1%] in the control arms).
It is the Sponsor’s view, based on the currently available data from all trials, that patients 
may be at increasedrisk for the development of ATEwhen treated with onartuzumab. 
Patients and physicians are advised to be observant for the signs and symptoms of ATE
and to instruct patients to seek medical care if they develop symptoms,such as 
shortness of breath, chest pain, or arm or leg swelling.Thromboprophylaxis should be 
considered based on a careful assessment of an individual patient’s underlying risk 
factors. Any thromboprophylaxis should follow current local institutional guidelines and 
best practice.
5.1.6
Neutropenia
Neutropenia was reported as an adverse event in studies where onartuzumab was 
evaluated in combination with infusional chemotherapy or infusional chemotherapy in 
combination with bevacizumab.  In several of these studies, adverse event rates of 
neutropenia were higher in the onartuzumab-containing arms than the 
placebo-containing control arms.  Instudies with an infusional chemotherapy backbone, 
neutropenia adverse events (of any grade) in onartuzumab-containing arms were 
reported at a rate up to 63.3% (Study YO28252; onartuzumabmFOLFOX6 [n60]vs. 
50% for placebomFOLFOX6 [n60]) and as low as 17.2% (Study OAM4861g; 
onartuzumabplacebopaclitaxel [n58] vs. 16.1% for 
placebobevacizumabpaclitaxel [n62]).  Grade 3 neutropenia adverse events in 
onartuzumab-containing arms were reported at a rate up to 58.3% (Study YO28252; 
onartuzumabmFOLFOX6 [n60] vs. 45% for placebomFOLFOX6 [n60]) and as 
low as 12.1% (Study GO27821; onartuzumabpemetrexedplatinum [n58] vs. 17.5% 
for placebopemetrexedplatinum[n57]).


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There has been no observed imbalance in severe infection events between control and 
onartuzumab arms.  Patients receiving onartuzumab in combination with infusional 
chemotherapy (with or without concomitant bevacizumab) may be at risk of developing 
neutropenia.  Patients should be monitored closely for this, and dosing of concomitant 
infusional chemotherapies should be modified or interrupted according to study protocol.
Any treatment for neutropenia should follow currentlocalinstitutional guidelines and best 
practice.
5.1.7
Adverse Events Related to Control Treatment
Any adverse events known to be related to the control treatment(bevacizumab and/or 
erlotinib),whether given alone or in conjunction with onartuzumab, should be managed 
as per local standard of care.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring serious adverse events,performing 
protocol-specified safety laboratory assessments,and conductingother protocol-
specified tests that are deemed critical to the safety evaluation of the patient on study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section5.4.
Only adverse events that fall into the categorybelow should be reported to the Sponsor.

Serious adverse events,whetherrelatedor unrelatedto onartuzumab, Avastin 
(bevacizumab), or Tarceva (erlotinib)
5.2.1
Adverse Events
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) other than the cancer for 
which the patient is receiving treatment on the P-trial and E-trial

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug


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
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g.,screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e.,the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section5.3.5.4)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to amother exposed to 
study drug

Is a significant medical event in the investigator
's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe"and "serious"are notsynonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]criteria; 
see Section5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events,whether related or unrelated, are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section5.4.2for reporting instructions).
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETYPARAMETERS
The investigator is responsible for ensuring that all serious adverse events (see 
Section5.2.1for definition) arerecorded on the Adverse Event eCRF and reported 
tothe Sponsor in accordance with instructions provided in this section and in 
Sections5.45.6.


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For each serious adverse event recorded on the Adverse Event eCRF, the investigator 
will make an assessment of seriousness (see Section5.2.2for seriousness criteria), 
severity (see Section5.3.3), and causality (see Section5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on serious adverse events at each patient contact.  
After informed consent has been obtained, all serious adverse events will be recorded 
during the study and for up to 30 days after the last dose of study treatment. After 
this period, the investigator should report any serious adverse events that are believedto 
be related to prior study drugtreatment(see Section5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
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.  Table1will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table1
Adverse Event Severity Grading Scalefor Events Not Specifically 
Listed in NCI CTCAE
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 livinga
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limitingself-care activities of daily livingb,c
4
Life-threatening consequences or urgent intervention indicated
d
5
Death related to adverse eventd
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which 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 who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2for reporting instructions), per the definition of serious 
adverse event inSection5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes"or"no"
accordingly.  The following guidance should be taken into consideration(see also 
Table2):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (asapplicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table2
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient
'sclinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, ifapplicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g.,preexisting medical condition, underlying disease, intercurrent illness, 
orconcomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
firstdose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording AdverseEvents
Investigators should use correct medical terminology/concepts when recording all 
serious adverse events,whetherrelated or unrelated to onartuzumab,erlotinib, or 
bevacizumab,on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Adverse Events That AreSecondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be consideredas an 
independent event.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be consideredthe adverse event.

If vomiting results in severe dehydration, both events should be considered
separately.

If a severe GIhemorrhage leads to renal failure, both events should be considered
separately.

If dizziness leads to a fall and consequent fracture, all three events should be 
consideredseparately.


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
If neutropenia is accompanied by aninfection, both events should be considered
separately.
Only seriousadverse events relatedtoonartuzumab, bevacizumab, or erlotinibwill be 
reported for this E-trial.
5.3.5.2
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported. If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded.  If the event becomes 
serious, it should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning that the event became serious; see Section5.4.2for reporting instructions).  
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  
5.3.5.3
Deaths
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section5.3.1) that are attributed by the investigator solely to progression of solid tumors
should be recorded only on the Study Completion/Early Discontinuation eCRF.  All other 
on-study deaths, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death"should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death"should 
be replaced by the established cause of death.  The term "sudden death"should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death").
5.3.5.4
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization(i.e., in-patient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section5.2.2), except as outlined 
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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experiencedan adverse event

Hospitalization due solely to progression of the underlying cancer
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event:

Serious adverse events,whetherrelatedor unrelatedto onartuzumab

Serious adverse events,whetherrelated or unrelated toAvastin (bevacizumab)

Serious adverse events,whetherrelated or unrelated toTarceva(erlotinib)

Pregnancies
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery


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
Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/ethics 
committee (EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Medical Monitor:
, M.D.
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D., Ph.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a RocheMedical 
Monitor, and track all calls.  TheEmergency Medical Call Center Help Desk will be 
available 24 hours per day, 7days per week.  Toll-free numbers for the Help Desk,as 
well as Medical Monitor contact information,will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events
5.4.2.1
Events That Are Ongoing from the Previous Protocol
Events that are ongoing from the P-trialshould not be reported again under this protocol, 
unless the severity increases,whetherthe event is related or unrelated to onartuzumab,
erlotinib,or bevacizumab.
5.4.2.2
Events That Occur afterStudy DrugInitiation
After initiation of study drug, seriousadverse events,whetherrelated or unrelated to 
onartuzumab, bevacizumab, or erlotinib,willbe reported until 30 daysafter the last dose 
of study drug.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the AdverseEvent eCRF 
and submit the report via the electronic data capture (EDC) system.  Areport will be 
generated and sent to Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, theSerious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to Roche or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  


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Instructions for reporting post-studyadverseevents are provided in Section5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the last 
dose of onartuzumab.  A Pregnancy Report eCRF should be completed by the 
investigator immediately (i.e., no more than 24hours after learning of the pregnancy) 
and submitted via the EDC system.  A pregnancy report will automatically be generated 
and sent to Roche Safety Risk Management.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.
In the event that the EDC system is unavailable, theClinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to Roche or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
180days after the last dose of study drug.  APregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the investigator will update the 
Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetusto support an informed decision in cooperation with the treating physician and/or 
obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section5.4.3.1.


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5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (asthe Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section5.4.2).  
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug orthefemale partner of a malepatient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTERADVERSEEVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events,whetherrelated or unrelated to onartuzumab, erlotinib,
or bevacizumab,until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructionsprovided in Section5.4.3.1.
5.5.2
Sponsor Follow-Up
For serious adverse events and pregnancies, the Sponsor or a designee may followup 
by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
details and outcome information (e.g.,from hospital discharge summaries, consultant 
reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
30 daysafter the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  


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The investigator should report these events directly to Roche or its designee, either by 
faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of Special 
Interest Reporting Formusing the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events against cumulative 
product experience to identify and expeditiously communicate possible new safety 
findings to investigators, IRBs, ECs, and applicable health authorities based on 
applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using theOnartuzumab,Erlotinib,and 
BevacizumabInvestigator’s Brochures.
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator
's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.  These anticipated events include but are not limited to the following:

Events related to infusional chemotherapy,such as alopecia and myelosuppression
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
No formal statisticalhypothesis testing isplanned for this study.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size of this E-trial will depend upon the number of patients eligible from 
P-trials who elect to transfer to this trial for continued treatment of their underlying 
cancer.  
6.2
SUMMARIES OF CONDUCTOF STUDY
Enrollment of patients and discontinuation from the study will be summarized.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
No formal comparisons of treatment groups are planned.


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6.4
EFFICACY ANALYSES
No formal efficacy analyses are planned.
6.5
SAFETY ANALYSES
The safety analyses will include only patients who received at least one dose of 
onartuzumab.A summary of administration of study treatment (onartuzumab)and
serious adverse events,whetherrelated or unrelated to onartuzumab,will be generated 
for these patients.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsorwill supply eCRF specifications for this study.  A contract research 
organization (CRO) will beresponsible for data management of this study, including 
quality checking of the data.  Data entered manually will be collected via EDC using 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system.
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Other electronic data will be sent directly totheSponsor, using
theSponsor’s standard procedures to handle and process the electronic transfer of 
these data.
The Sponsorwill perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data.  
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent withthe CRO’s standard procedures. 
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a CRO-designated EDC system.  Sites will 
receive training and have access to a manual for appropriate eCRF completion.  eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patientdata for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from sourcedocuments. 
Source documents (paper or electronic) are those in which patient data are recorded
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes
(PROs), evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copiesof transcriptions that are certified after verification as 
being accurate and complete, microfiche, photographic negatives, microfilm or magnetic 
media, X-rays, patient files, and records kept at pharmacies, laboratories, and 
medico-technical departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The studysite must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into astudysite’s computerized medical 
record system (i.e., in lieu oforiginal hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.


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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, includingeCRFs, electric PRO data (ifapplicable), Informed Consent Forms, 
laboratory test results, and medicationinventory records, must be retained by the 
Principal Investigator for at least 15years after completion or discontinuation of the 
study, or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After thatperiod of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsorprior to transferring any records to 
anotherparty or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for GCPand 
the principlesof the Declaration of Helsinkior the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. Food and Drug Administration (FDA)regulations and 
applicable local, state, and federal laws.  Studies conducted inthe European Union (E.U.) 
or European Economic Areawill comply with the E.U.Clinical Trial Directive 
(2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver
's Informed Consent Form, ifapplicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsoror its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission. The final IRB/ECapproved Consent Forms must be provided to the 
Sponsorfor health authority submission purposes according to local requirements.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.


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The Consent Forms should berevised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsorfor health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participationin the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available forverification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEWBOARD OR ETHICSCOMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
Inaddition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsormaintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsorlocation.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (orseparate 


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authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted orrequired by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfarefor treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor
monitors, representatives, and collaborators, andthe IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, includingan audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report anydeviations that might have an impact on patient safety and 
data integrity to the Sponsor or designee and to the IRB/EC in accordance with 
established IRB/EC policies and procedures.  The Sponsor will review all protocol 
deviations and assess whether any represent a serious breach of Good Clinical Practice 
guidelines and require reporting to health authorities.As per the Sponsor's standard 
operating procedures, prospective requests to deviate from the protocol, including 
requests to waive protocol eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits may be conducted by the Sponsoror an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 


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permit national and local health authorities, Sponsormonitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study is sponsored by F. Hoffmann-La Roche Ltd.  Up to 14study centers will 
participate in this study in Europe, Africa,and Asia, enrolling a total of up to 17patients.  
The Sponsor will provide clinical operations oversight, data management support, and 
medical monitoring.  An IWRS will be used to manage site drug supply.  The analysis of 
any laboratory samples (taken for safety assessments as per Appendix1) will be 
performed by the local laboratories.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
ww.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within sixmonths after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any
country, the Sponsoraims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsorprior 
to submissionfor publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsorwill generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsorpersonnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsorpersonnel.


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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g.,change in Medical Monitor or contact information).


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10.
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Onartuzumab—F.Hoffmann-La Roche Ltd
53/Protocol GO29646, Version 5
Appendix1
Schedule of Assessments
Screening
(Rollover from P-trial 
into E-Trial; 
Day 42 to Day 1)
Treatment 
Period
Per Patient 
Visit
Treatment 
Period
Per 6 Patient 
Visits or 90120 
days (10 
days)
Safety FU
30 (3 days) 
after Last Dose 
of Study 
Therapy
Informed Consent
x
Confirmation of eligibility
x
Patient characteristics 
(Sex, date of birth, tumor 
type)
x
Serum pregnancy test for 
WOCPa
x
Urine pregnancy test for 
WOCP
xf
Weight
x
Onartuzumab 
OtherP-trialanti-cancer 
IMP(s) if applicable
b
x
Hematology and chemistry 
laboratory testinge
x
xc
Progression assessment
Per local 
standardd
SAE
x (see Section5.1) 
x
x
Note:  Additional assessments (as per local standard and clinical judgment of the investigator) will only be 
documented in the patients’ source documents.
FUfollow-up; IMPinvestigational medicinal product; SAEserious adverse event; WOCPwomen of 
childbearing potential.
a Pregnancy test: WOCP will have a serum pregnancy test no more than 7 days prior to the first trial 
treatment.
b Classified as non-IMP in the E-trial;see also Section4.2.1.
c Hematology and chemistry laboratory testing at screening visit and then every six visits or 90–120 days 
(10 days) of treatment to include:
-Hematology:  including hemoglobin, hematocrit, platelets count, WBC count, WBC differential count 
(neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells).  WBC differential count 
in absolute value is preferred, however percentages are also acceptable. 
-Chemistry:  including sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, 
total bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, phosphorus,and magnesium.
d The same methods as per P-trial are recommended.
e The chemistry and hematology laboratory tests are not collected on the eCRF.
f Urine pregnancy test to be performed before each patient visit.  If the urine pregnancy test is positive, 
study drug will not be administered and a serum pregnancy test must be performed.