A Randomized Phase II Induction Discontinuation Trial of Emactuzumab Following Paclitaxel and Bevacizumab in Patients With Platinum-Resistant, Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Phase: PHASE2
Conditions: Fallopian Tube Adenocarcinoma, Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Mucinous Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Fallopian Tube Transitional Cell Carcinoma, Fallopian Tube Undifferentiated Carcinoma, Malignant Ovarian Brenner Tumor, Ovarian Adenocarcinoma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Mucinous Adenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Adenocarcinoma, Ovarian Transitional Cell Carcinoma, Ovarian Undifferentiated Carcinoma, Primary Peritoneal Serous Adenocarcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2015-0647_MOD001 
Protocol Title 
A RANDOMIZED PHASE II INDUCTION DISCONTINUATION TRIAL OF 
EMACTUZUMAB FOLLOWING PACLITAXEL AND BEVACIZUMAB IN 
PATIENTS WITH PLATINUM-RESISTANT, EPITHELIAL OVARIAN, 
FALLOPIAN TUBE OR PRIMARY PERITONEAL CANCER. 
Protocol Phase 
2 
Protocol Version 
9.0 (Institutional Version 11) 
Version Date 
07/18/2020 
Investigational 
Products 
Emactuzumab 
Protocol PI 
Anil Sood, MD 
Department 
Gynecologic Oncology and Reproductive Medicine 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
132167 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 1 of 108 
REDIRECT 
(RANDOMIZED INDUCTION DISCONTINUATION TRIAL OF EMACTUZUMAB) 
A RANDOMIZED PHASE II INDUCTION DISCONTINUATION TRIAL OF EMACTUZUMAB 
FOLLOWING PACLITAXEL AND BEVACIZUMAB IN PATIENTS WITH PLATINUM-
RESISTANT, EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL 
CANCER.  
NCT 02923739  
IND 132167 
M.D. ANDERSON 2015-0647 
Protocol Number / Version: 
Date:   
REDIRECT v9  
18 July 2020 
Sponsor : 
 
 
 
PrinicipaI Investigator:  
 
 
 
 
 
 
 
 
Co-Principal Investigator: 
The University of Texas M.D. Anderson Cancer 
Center 
1155 Herman Pressler Drive 
Houston TX 77030 
 
 
Anil Sood, MD 
Department of Gynecologic Oncology & Reproductive 
Medicine, Unit 1362 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-745-5266 
Pager: 713-404-8831 
asood@mdanderson.org 
 
Shannon N. Westin, MD 
Department of Gynecologic Oncology & Reproductive 
Medicine, Unit 1362 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-794-4314 
Pager: 713-404-6547 
swestin@mdanderson.org 
 
 
 
 
 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 2 of 108 
 
COLLABORATORS: 
 
Amir A. Jazaeri, MD 
Department of Gynecologic Oncology & Reproductive Medicine, Unit 1362 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-745-1613 
Pager: 713-404-0934 
aajazaeri@mdanderson.org 
 
Michael Frumovitz, MD, MPH 
Department of Gynecologic Oncology & Reproductive Medicine, Unit 1362 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-792-9599 
Pager: 713-606-1714 
mfrumovitz@mdanderson.org 
 
Pamela T. Soliman, MD 
Department of Gynecologic Oncology & Reproductive Medicine, Unit 1362 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-745-2352 
Pager: 713-404-3269 
psoliman@mdanderson.org 
 
Ying Yuan, PhD 
Department of Biostatistics, Unit 1411 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-563-4271 
yyuan@mdanderson.org 
 
 
Priya R. Bhosale, MD 
Department of Diagnostic Radiology, Unit 1473 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-792-0221 
Pager: 713-606-3650 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 3 of 108 
priya.bhosale@mdanderson.org 
Bruno C. Odisio, MD 
Department of Interventional Radiology, Unit 1471 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-563-1066 
Pager: 713-404-0930 
bcodisio@mdanderson.org 
Preetha Ramalingam, MD 
Department of Pathology Admin., Unit 0085 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
Phone: 713-794-5698 
Pager: 713-404-9316 
PRAMALINGAM@MDANDERSON.ORG 
Nicole Fleming, MD 
Assistant Professor 
Phone: 281-566-1900 
Email: nfleming@mdanderson.org 
MD Anderson in Sugar Land 
1327 Lake Pointe Parkway 
Sugar Land, TX 77478 
MD Anderson in Katy 
19770 Kingsland Blvd. 
Houston, TX 77094 
MD Anderson in The Woodlands 
Medical Arts Center I & III 
17198/17450 St. Luke’s Way 
The Woodlands, TX 77384 
MD Anderson in the Bay Area 
18100 St. John Dr. 
Nassau Bay, TX 77058 
David Warshal, MD, FACOG 
Associate Professor 
MD Anderson Cancer Center at Cooper 
Two Cooper Plaza 
Camden, NJ 08103 
Phone: 855.632.2667 
Email: Warshal-David@CooperHealth.edu 
Jayanthi S. Lea, MD 
Assistant Professor 
University of Texas Southwestern Medical Center 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 4 of 108 
2201 Inwood Rd. 
Dallas, TX 75390-9125 
Phone: 214-648-3026 
Fax: 214-648-8404 
Email: Jayanthi.Lea@utsouthwestern.edu 
Kathleen Moore, MD 
Associate Professor 
The University of Oklahoma Health Sciences Center 
1100 N. Lindsay, SOCC 5050 
Oklahoma city, OK 73104 
Phone: 405-271-8707 
Email: Kathleen-moore@ouhsc.edu 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 5 of 108 
TABLE OF CONTENTS 
COLLABORATORS: .................................................................................................................................................. 2 
TABLE OF CONTENTS .......................................................................................................................................... 5 
SYNOPSIS OF PROTOCOL ................................................................................................................................. 14 
TABLE 1 
 SCHEDULE OF ASSESSMENTS: PART 1 SAFETY LEAD-IN ............................................... 15 
TABLE 2 
 SCHEDULE OF ASSESSMENTS PART 2A: INDUCTION TREATMENT ........................... 18 
TABLE 3 
SCHEDULE OF ASSESSMENTS PART 2B: RANDOMIZED TREATMENT ........................ 21 
TABLE 4. PK/PD SCHEDULE OF ASSESSMENTS (PART 1 AND PART 2) ............................................. 24 
BACKGROUND AND RATIONALE .......................................................................................................... 24 
1.1 
BACKGROUND – OVARIAN CANCER ........................................................................................................................ 24 
1.2 
CHEMOTHERAPIES FOR PLATINUM-RESISTANT OVARIAN CANCER .................................................................... 25 
1.2.1 
Taxanes ..................................................................................................................................................................... 25 
1.2.2 
Bevacizumab .......................................................................................................................................................... 26 
Figure 1: Summary of Phase III Trials Using Bevacizumab in Women with Ovarian Cancer. ...................... 26 
1.2.2.1 
AURELIA: bevacizumab in platinum-resistant ovarian cancer62 ...................................................... 27 
1.2.2.2 
The Immune contribution to angiogenesis escape ................................................................................. 28 
1.2.3 
Emactuzumab ........................................................................................................................................................ 29 
1.2.3.1 
Safety .......................................................................................................................................................................... 29 
1.2.3.2 
Efficacy ...................................................................................................................................................................... 31 
1.3 
STUDY RATIONALE ..................................................................................................................................................... 31 
OBJECTIVES ................................................................................................................................................ 32 
2.1 
PRIMARY ..................................................................................................................................................................... 32 
2.2 
SECONDARY OBJECTIVES ........................................................................................................................................... 32 
2.3 
EXPLORATORY OBJECTIVES ...................................................................................................................................... 33 
STUDY DESIGN ........................................................................................................................................... 33 
3.1 
OVERVIEW OF STUDY DESIGN .................................................................................................................................. 33 
3.1.1 
Part 1 (Safety Lead-in): ..................................................................................................................................... 33 
3.1.2 
Part 2 (Induction/Randomization): ............................................................................................................ 34 
3.1.2.1 
Part 2A (see Schema): ......................................................................................................................................... 34 
3.1.2.2 
Part 2B (see Schema): ......................................................................................................................................... 34 
3.1.3 
Rationale for study design: .............................................................................................................................. 34 
3.1.3.1 
Part 1 (safety lead-in): ........................................................................................................................................ 34 
3.1.3.2 
Parts 2A and 2B (induction/discontinuation randomized phase II): ............................................. 35 
3.1.4 
Rationale for dose selection ............................................................................................................................. 35 
3.1.5 
Rationale for Tumor biopsy ............................................................................................................................. 35 
3.2 
END OF STUDY ............................................................................................................................................................ 36 
3.3 
NUMBER OF PATIENTS .............................................................................................................................................. 36 
3.4 
PARTICIPATING SITES ............................................................................................................................................... 36 
3.5 
RANDOMIZATION AND STRATIFICATION ................................................................................................................ 36 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 6 of 108 
STUDY POPULATION ............................................................................................................................... 36 
4.1 
OVERVIEW .................................................................................................................................................................. 36 
4.2 
INCLUSION CRITERIA ................................................................................................................................................. 37 
4.3 
EXCLUSION CRITERIA ................................................................................................................................................ 37 
4.4 
CONCOMITANT MEDICATION AND TREATMENT .................................................................................................... 40 
4.4.1 
Permitted Therapy ............................................................................................................................................... 40 
4.4.2 
Prohibited Therapy .............................................................................................................................................. 41 
4.5 
CRITERIA FOR PREMATURE WITHDRAWAL ............................................................................................................ 41 
4.6 
REPLACEMENT POLICY .............................................................................................................................................. 41 
SCHEDULE OF ASSESSMENTS AND PROCEDURES........................................................................... 42 
5.1 
SCREENING EXAMINATION AND ELIGIBILITY SCREENING FORM ......................................................................... 42 
5.2 
PROCEDURES FOR ENROLLMENT OF ELIGIBLE PATIENTS .................................................................................... 42 
5.3 
CLINICAL ASSESSMENTS AND PROCEDURES ........................................................................................................... 42 
5.3.1 
Tumor response criteria .................................................................................................................................... 42 
5.3.2 
Tumor imaging ...................................................................................................................................................... 42 
5.3.3 
CA-125 ....................................................................................................................................................................... 42 
5.3.4 
Scheduling of tumor assessments .................................................................................................................. 43 
5.3.5 
Physical examination and measurement of vital signs ....................................................................... 43 
5.3.6 
Performance status ............................................................................................................................................. 43 
5.3.7 
Clinical safety assessments ............................................................................................................................... 43 
5.4 
LABORATORY ASSESSMENTS .................................................................................................................................... 43 
5.4.1 
Efficacy laboratory assessments .................................................................................................................... 43 
5.4.2 
Safety laboratory assessments ....................................................................................................................... 43 
5.5 
PHARMACODYNAMIC AND BIOMARKER ASSESSMENTS ....................................................................................... 44 
5.5.1 
Handling of Specimens ....................................................................................................................................... 44 
5.5.2 
Storage of Specimens .......................................................................................................................................... 45 
5.5.3 
Labeling of Specimens ........................................................................................................................................ 45 
5.6 
END OF TREATMENT VISIT ...................................................................................................................................... 45 
5.7 
SAFETY FOLLOW-UP .................................................................................................................................................. 45 
5.7.1 
30-Days Safety Follow-Up ................................................................................................................................. 45
5.8 
SURVIVAL FOLLOW-UP .............................................................................................................................................. 45 
5.9 
STUDY EXIT ................................................................................................................................................................. 46 
INVESTIGATIONAL MEDICINAL PRODUCTS ..................................................................................... 46 
6.1 
DOSE AND SCHEDULE OF STUDY TREATMENTS ..................................................................................................... 46 
6.2 
DOSE MODIFICATIONS AND DELAYS ........................................................................................................................ 47 
6.3 
EMACTUZUMAB: PREPARATION AND ADMINISTRATION OF ............................................................................... 47 
6.3.1 
Formulation, Packaging and Labeling of Emactuzumab................................................................... 47 
6.3.2 
Preparation of Emactuzumab ........................................................................................................................ 47 
6.3.3 
Premedication ........................................................................................................................................................ 48 
6.3.4 
Administration of Emactuzumab (Parts 1 and 2B) .............................................................................. 48 
6.3.5 
Rate of Infusion of Emactuzumab ................................................................................................................. 48 
6.3.6 
Assessment of Compliance ................................................................................................................................ 48 
6.3.7 
Destruction of Emactuzumab ......................................................................................................................... 49 
6.3.8 
Reconciliation ........................................................................................................................................................ 49 
6.3.9 
Dose Modifications and Delays (Emactuzumab) ................................................................................... 49 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 7 of 108 
6.3.9.1 
During the Infusion .............................................................................................................................................. 50 
6.3.9.1.1 
Infusion-Related Reactions ......................................................................................................................... 50 
TABLE 5: MANAGEMENT OF INFUSION RELATED REACTIONS ............................................................ 51 
6.3.9.2 
After Infusion .......................................................................................................................................................... 53 
6.3.9.2.1 
Management of Diarrhea ............................................................................................................................. 53 
TABLE 6: DOSE-DELAY CRITERIA FOR DIARRHEA .................................................................................. 54 
6.3.9.2.2 
Management Guidelines for Hepatic Events ........................................................................................ 55 
TABLE 7: GUIDELINES ON THE MANAGEMENT AND REPORTING OF ELEVATED LIVER 
ENZYMES ............................................................................................................................................................... 56 
6.3.9.2.3 
Neutrophil Count ............................................................................................................................................. 60 
6.3.10 
Management of EmactuzumabToxicities ...............................Error! Bookmark not defined. 
6.3.10.1 
Periorbital Edema ................................................................................................................................................. 60 
6.3.10.2 
Dermatologic Toxicity ......................................................................................................................................... 60 
TABLE 8: MANAGEMENT GUIDELINES FOR POTENTIAL DERMATOLOGICAL TOXICITY/ RASH 
DURING TREATMENT WITH EMACTUZUMAB .......................................................................................... 60 
6.4 
BEVACIZUMAB ............................................................................................................................................................ 61 
6.4.1 
Bevacizumab Administration ......................................................................................................................... 62 
6.4.2 
Bevacizumab Storage ......................................................................................................................................... 62 
6.4.3 
Management of Bevacizumab Toxicities ................................................................................................... 63 
TABLE 9 MANAGEMENT OF GRADE 3 OR 4 BEVACIZUMAB-RELATED AES ..................................... 63 
6.4.3.1 
Reversible Posterior Leucoencephalopathy Syndrome ........................................................................ 63 
6.4.3.2 
CNS Bleeding ........................................................................................................................................................... 64 
6.4.3.3 
Hypertension .......................................................................................................................................................... 64 
TABLE 10. BEVACIZUMAB TREATMENT MANAGEMENT FOR HYPERTENSION .............................. 64 
6.4.3.4 
Proteinuria ............................................................................................................................................................... 65 
TABLE 11. BEVACIZUMAB TREATMENT MANAGEMENT FOR PROTEINURIA ................................. 65 
6.4.3.5 
Dose interruption due to infusion-associated reactions ...................................................................... 65 
6.4.3.6 
Surgical procedures and wound healing complications ....................................................................... 66 
6.4.3.7 
Thrombosis/embolism ....................................................................................................................................... 66 
6.4.3.8 
Hemorrhage ............................................................................................................................................................ 67 
6.4.3.9 
Gastrointestinal Perforation and Fistula ..................................................................................................... 67 
6.4.3.10 
Congestive Heart Failure ................................................................................................................................... 67 
6.4.3.11 
Hypersensitivity/Allergic Reactions and Infusion-Associated Reactions ..................................... 68 
6.4.3.12 
Osteonecrosis of the Jaw .................................................................................................................................... 68 
6.5 
PACLITAXEL ................................................................................................................................................................ 68 
6.5.1 
Dose Modifications ............................................................................................................................................... 68 
6.5.2 
Management of Paclitaxel Toxicities ........................................................................................................... 68 
6.5.2.1 
Hematological toxicity ........................................................................................................................................ 68 
TABLE 12. SUMMARY OF PACLITAXEL DOSE REDUCTIONS ................................................................. 68 
6.5.2.2 
Non-hematological toxicity ............................................................................................................................... 69 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 8 of 108 
6.5.2.2.1 
Mucositis and cutaneous toxicity ............................................................................................................. 69 
6.5.2.2.2 
Neurological toxicity ...................................................................................................................................... 69 
6.5.2.2.3 
Hypersensitivity premedication ............................................................................................................... 69 
6.5.2.2.4 
Other Major Organ Toxicity (not evaluated as disease related).................................................. 69 
SAFETY INSTRUCTIONS AND GUIDANCE ........................................................................................... 70 
7.1 
AES AND LABORATORY ABNORMALITIES ............................................................................................................... 70 
7.1.1 
Clinical AEs .............................................................................................................................................................. 70 
7.1.1.1 
Intensity .................................................................................................................................................................... 70 
TABLE 13. GRADING OF AES ACCORDING TO NCI CTCAE V 4.03 ......................................................... 70 
7.1.1.2 
Drug – AE relationship ........................................................................................................................................ 70 
7.1.1.3 
SAEs (immediately reportable to Genentech/Genentech) .................................................................. 71 
7.1.1.4 
Progression of underlying malignancy ........................................................................................................ 71 
7.1.2 
Treatment and follow-up of AEs .................................................................................................................... 72 
7.1.3 
Laboratory test abnormalities ....................................................................................................................... 72 
7.1.3.1 
Follow-up of abnormal laboratory test values ......................................................................................... 73 
7.2 
HANDLING OF SAFETY PARAMETERS ...................................................................................................................... 73 
7.2.1 
Reporting of AEs ................................................................................................................................................... 73 
7.2.1.1 
AEs of Special Interest (AESIs) ........................................................................................................................ 74 
7.2.1.1.1 
Special Situation Reports ............................................................................................................................. 74 
7.2.2 
Reporting of SAEs (immediately reportable)........................................................................................... 75 
TABLE 14 SAE COLLECTION BEFORE, DURING AND AFTER-STUDY DRUG DOSING ...................... 75 
7.2.3 
Reporting to Regulatory Authorities, Ethics Committees, and Investigators ........................... 76 
7.2.4 
Pregnancy ................................................................................................................................................................ 77 
7.2.5 
Warnings and precautions ............................................................................................................................... 77 
7.2.6 
Safety Crisis Management ................................................................................................................................ 78 
7.2.7 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-sponsored Multicenter IND 
Protocols ................................................................................................................................................................................... 78 
7.2.8 
Study Monitoring .................................................................................................................................................. 80 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .......................................................... 80 
8.1 
SAFETY DECISION RULE FOR LEAD IN: PART 1 .................................................................................................... 80 
8.1.1 
Patient Enrollment to Safety Lead in: Part 1 ........................................................................................... 82 
8.2 
STATISTICAL CONSIDERATIONS FOR PART 2 ........................................................................................................ 82 
8.2.1 
Induction Therapy: Part 2A ............................................................................................................................. 82 
8.2.1.1 
Estimation of Sample size: Part 2A ................................................................................................................ 83 
8.2.2 
Randomization Cohort: Part 2B .................................................................................................................... 83 
8.2.2.1 
Estimation of Treatment Effect: Part 2B ..................................................................................................... 83 
8.2.2.2 
Statistical Analyses: Part 2B ............................................................................................................................. 83 
8.2.2.2.1 
Interim Analysis: Part 2B ............................................................................................................................. 83 
TABLE 15: OPERATING CHARACTERISTICS OF SAFETY STOPPING RULE ........................................ 84 
8.2.3 
Secondary efficacy variables ........................................................................................................................... 84 
8.2.3.1 
Analyses of Biomarkers: Part 2B .................................................................................................................... 85 
8.2.4 
Safety variables ..................................................................................................................................................... 86 
8.2.5 
Analysis populations ........................................................................................................................................... 86 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 9 of 108 
8.2.5.1 
Safety analysis population ................................................................................................................................ 86 
8.2.5.2 
Efficacy analysis population(s) ....................................................................................................................... 86 
8.2.6 
Safety data analysis ............................................................................................................................................. 86 
8.2.6.1 
Toxicity and Efficacy Reporting to MDACC IND Office .......................................................................... 87 
DATA QUALITY ASSURANCE ................................................................................................................. 87 
9.1 
DATA COLLECTION ..................................................................................................................................................... 87 
9.2 
DATA MANAGEMENT ................................................................................................................................................. 88 
9.3 
STUDY CLOSE OUT ..................................................................................................................................................... 88 
9.4 
ASSIGNMENT OF PREFERRED TERMS ...................................................................................................................... 88 
9.5 
STUDY COMMITTEES .................................................................................................................................................. 88 
ETHICAL ASPECTS ............................................................................................................................... 89 
10.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI ............................................................................................ 89 
10.2 
INFORMED CONSENT ................................................................................................................................................. 89 
10.3 
INDEPENDENT ETHICS COMMITTEES ..................................................................................................................... 89 
CONDITIONS FOR MODIFYING THE PROTOCOL ......................................................................... 90 
CONDITIONS FOR TERMINATING THE STUDY ............................................................................ 90 
STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING ..................................................... 90 
13.1 
INVESTIGATOR'S FILES / RETENTION OF DOCUMENTS ........................................................................................ 90 
13.2 
SOURCE DOCUMENTS AND BACKGROUND DATA .................................................................................................... 91 
13.3 
AUDITS AND INSPECTIONS ........................................................................................................................................ 91 
13.4 
CASE REPORT FORMS ............................................................................................................................................... 91 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS ................................. 91 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ......................................... 91 
APPENDICES .......................................................................................................................................... 92 
16.1 
APPENDIX 1 EVALUATION OF RESIDUAL DISEASE, EVALUATION OF AND DEFINITIONS OF RESPONSE AND 
PROGRESSION ............................................................................................................................................................................. 92 
16.1.1 
Tumor Imaging and Assessment of Disease (RECIST v1.1) .......................................................... 92 
16.1.2 
Measurability of Tumor Lesions ............................................................................................................... 92 
16.1.3 
Response Criteria ............................................................................................................................................ 93 
16.1.3.1 
Evaluation of Target Lesions ............................................................................................................................ 93 
16.1.3.2 
Evaluation of Non-target Lesions ................................................................................................................... 93 
16.1.3.3 
Appearance of New Lesions ............................................................................................................................. 93 
16.1.3.4 
Evaluation of Overall Response with Modifications ............................................................................... 93 
TABLE 16. EVALUATION OF OVERALL RESPONSE ................................................................................... 94 
TABLE 17. EVALUATION OF OVERALL RESPONSE ................................................................................... 94 
16.1.3.5 
MRI Scans ................................................................................................................................................................. 94 
16.1.4 
CA-125 responses ............................................................................................................................................ 95 
16.1.4.1 
PROGRESSION OR RECURRENCE BASED ON SERUM CA-125 LEVELS .......................................... 95 
16.2 
APPENDIX 2 - ECOG PERFORMANCE STATUS SCALE .......................................................................................... 96 
16.3 
APPENDIX 3 – ICH GUIDELINES FOR CLINICAL SAFETY DATA MANAGEMENT, DEFINITIONS AND 
STANDARDS FOR EXPEDITED REPORTING, TOPIC E2 .......................................................................................................... 97 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 10 of 108 
16.3.1 
MD Anderson Cancer Center SAE Reporting Guidelines ................................................................ 99 
16.4 
APPENDIX 4: NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES ........................................ 100 
16.5 
APPENDIX 5: PROCEDURE FOR OBTAINING A URINE PROTEIN: .................................................... 101 
16.6 
APPENDIX 6- GENENTECH CONTACTS ................................................................................................................ 102 
16.7 
APPENDIX 7- SAFETY REPORTING FAX COVER SHEET ..................................................................................... 104 
REFERENCES ....................................................................................................................................... 105 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 11 of 108 
Glossary Of Abbreviations 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BP 
Blood pressure 
CHF 
Congestive heart failure 
Cl 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CrCl 
Creatinine clearance 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
CTCAE 
Common toxicity criteria adverse events 
CVA 
Cerebrovascular accident 
CVAD 
Central venous access device 
CXR 
Chest X-ray 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EPO 
Erythropoietin 
ESF 
Eligibility screening form 
FBC 
Full blood count 
GCP 
Good clinical practice 
G-CSF
Granulocyte colony-stimulating factor 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
HT 
Hypertension 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 12 of 108 
Glossary Of Abbreviations 
 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
INR 
International normalised ratio 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
Intent–to-treat 
i.v. 
Intravenous 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
MUGA 
Multi Gated Acquisition Scan 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFIBIO 
Biological progression-free interval 
PFS 
Progression-free survival 
PI 
Principal investigator 
PP 
Per protocol 
PR 
Partial response 
PS 
Performance status 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SCr 
Serum creatinine 
SD 
Stable disease 
SMPC 
Summary of product characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TFI 
Therapy free interval 
TNM 
Primary tumor/regional lymph nodes/distant metastasis 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 13 of 108 
Glossary Of Abbreviations 
 
TTP 
Time to tumor progression 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood count 
WOCP 
Women of child-bearing potential 
 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 14 of 108 
SYNOPSIS OF PROTOCOL 
Abbreviated Title 
A Randomized Phase II Induction Discontinuation Trial of 
Emactuzumab following Paclitaxel and Bevacizumab in 
Patients with platinum-resistant, epithelial ovarian, 
fallopian tube or primary peritoneal cancer 
Sponsor 
University of Texas MD Anderson Cancer Center 
Study Phase 
II 
Trial Design 
Prospective, open-label, randomized, 
induction/discontinuation, two-arm trial. 
Clinical Indication 
Patients with epithelial ovarian cancer (EOC), fallopian 
tube carcinoma (FTC) or primary peritoneal carcinomas 
(PPC) who have undergone an appropriate attempt at, or 
completed primary platinum-based therapy, as deemed by 
the investigator, for their initial disease.  
Primary Objective 
To compare the progression-free survival of patients 
randomized to paclitaxel plus bevacizumab or to 
paclitaxel, bevacizumab plus emactuzumab. 
Type of control 
NACT patient population 
Investigational 
Agent 
Emactuzumab 
Route of 
administration 
IV 
Treatment Groups 
Part 1: Safety Lead-in of Emactuzumab + Paclitaxel + 
Bevacizumab 
Part 2A: Paclitaxel + Bevacizumab 
Part 2B: 
Arm 1: Paclitaxel + Bevacizumab 
Arm 2: Paclitaxel + Bevacizumab + Emactuzumab 
Number of Study 
subjects 
121 
Part 1: Approximately 9 patients for safety assessment. 
Part 2A: Approximately 112 patients will be enrolled in the 
induction phase 
Part 2B: 80 patients, 40 per arm will be randomized. A 15% 
drop-out rate is assumed for this study.  
Estimated duration 
of Study 
36 months 
Duration of 
Participation 
14 months 
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Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 15 of 108 
TABLE 1 
SCHEDULE OF ASSESSMENTS: PART 1 SAFETY LEAD-IN 
SCREENING 
TREATMENT PERIOD 
(1 cycle = 4 weeks) 
Visits every 7  3 days 
End of 
Treatment 
[q] 
FOLLOW -UP AFTER STUDY 
TREATMENT TERMINATION 
DOES NOT PROCEED TO PART 2B) 
Cycle 
- 4
-1
Cycle 1 
Cycle 2 and subsequent 
cycles 
Safety follow-
up 30 days 
after end of 
treatment    
( 5 days) 
Survival follow-up 
Study Day 
-28 to
1
-7 to
1[r]
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 22 
Informed consent 
X 
Demographics 
X 
Medical history [a] 
X 
Physical 
examination [b] 
X 
X 
X 
X 
X 
Vital signs [c] 
X 
X[d[
X 
X[d]
X 
X[d]
X 
X[d]
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
ECG [e] 
X 
Hematology [f] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry [g] 
X 
X 
X[t]
X[t] 
X 
X 
Coagulation tests [h] 
X 
X 
X[t] 
X 
Urinalysis [i] 
X 
X 
X 
X 
CA-125 
X 
X 
X 
X 
X 
Pregnancy test [j] 
X 
Tumor assessments 
[k] 
X[k] 
X[k]
X[k]
X 
Adverse events [l] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status [m] 
X 
Concomitant 
medication [n] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archival Tissue [s] 
X 
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Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 16 of 108 
PD Blood [o] 
X 
X 
Paclitaxel 80 mg/m2 
i.v. [p]
X 
X 
X 
X 
X 
X 
X 
X 
Bevacizumab 10 
mg/kg i.v. [p] 
X 
X 
X 
X 
Emactuzumab 
1000mg i.v. [p] 
X 
X 
X 
X 
[a] Relevant medical history only.  Includes confirmation of histological diagnosis.
[b] Full physical examination should be performed at screening.  Subsequent physical examinations should be symptom directed.
[c] Vital signs include blood pressure, respiration rate, pulse, temperature, and weight. Height is only measured at screening.
[d] Vital signs (including supine blood pressure, respiratory rate, pulse rate and temperature) to be measured as follows on days patients receive Emactuzaumab:
•
pre-infusion
•
every 15 minutes until the end of Emactuzumab infusion
•
every 30 minutes until the infusion line is removed.
[e] As clinically indicated. MUGA may be obtained for clinical suspicion of decrease cardiac function
[f] Hematology: perform tests as per local standard of care and clinical indication.  However as a guide, this could include hemoglobin, RBC, platelet count, WBC
with differential count (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
[g] Biochemistry: perform tests as per local standard of care and clinical indication.  However as a guide, this could include sodium, potassium, calcium, blood
urea nitrogen (BUN), uric acid, total protein (or albumin only), alkaline phosphatase, creatinine kinase, AST/SGOT, ALT/SGPT, GGT, LDH, total bilirubin,
blood glucose, creatinine.
[h] Coagulation tests: INR, aPTT. Patient receiving full dose of coumarin derivatives at baseline should have 2 consecutive screening INR measurements 1–4
days apart. INR/aPTT for the patient on (prophylactic or full) anticoagulation therapy will be checked at least before start of every chemotherapy cycle.
[i] Urinalysis: To calculate UPC ratio. 24-hour urine collection needed in the event of proteinuria  +2. Proteinuria testing can be performed according to local
standards.
[j] Pregnancy test (women of child-bearing potential only): Serum pregnancy test within 7 days prior to the first study treatment or within 14 days with a
confirmatory urine pregnancy test within 7 days prior to the first study treatment.
[k] Baseline assessments of the pelvis and abdomen (preferably CT, or MRI in case of contrast allergy) and (by X-ray or preferably by CT-scan) of the chest.
These must be performed no more than 4 weeks before the first study treatment. Patients will be assessed for disease response or progression throughout the
study according to RECIST after every 8* weeks using the same imaging method as used during screening (CT or MRI or plain X-ray).  Pre-cycle clearance
assessments must be performed within days 23-28 of the previous cycle.  Method of tumor assessment should be consistent throughout all visits and
performed until disease progression. Tumor assessment will only be performed post-study treatment in the absence of confirmation of disease progression, at
8*-week intervals.  If the screening assessment is completed within 30 days of Cycle 1 Day 1, the assessment does not need to be repeated.
Notes*   If there is suspicion of disease progression based on clinical or laboratory findings before the next scheduled assessment, an unscheduled assessment 
should be made. 
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Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 17 of 108 
[l] Follow-up on serious or study drug-related AEs. All grade 2–5 events need to be recorded in the eCRF. Only SAEs caused by protocol-mandated
interventions to be collected prior to initiation of study medication.
[m]
Patients will be followed for overall survival until death; immediate and subsequent treatment regimens will be recorded if it is available.  Patients with
complete response will be followed every 3 months for 2 years, every 4 months in the third year, then every 6 months for 2 additional years.
[n] All concomitant medication needs to be recorded in the eCRF. Only concomitant medication as per Section 4.4 must be recorded.
[o] See Table 4.  .  PD: Please refer to Section 5.6.
[p] Emactuzumab should be administered before bevacizumab and then paclitaxel at the first cycle and throughout subsequent cycles. See Section 3.1 for
additional instructions of infusion. Treatment will continue until progressive disease (PD), unacceptable toxicity or patient request for discontinuation. If
paclitaxel is discontinued due to toxicity prior to PD, bevacizumab or bevacizumab/emactuzumab should be continued until PD, toxicity or patient request for
discontinuation, whichever occurs first.
[q] Should patients be taken off study at any time during treatment, scheduled cycle day assessments may replace applicable End of Treatment visit
assessments.
[r] If Day 1 assessments are completed within 7 days of treatment start date, Day 1 assessments do not have to be repeated.  This applies to applicable
screening assessments.
[s] If archival tissue is not available, a biopsy to obtain tissue will not be necessary nor will it deter patient from eligibility. A minimum of ten (10) unstained slides
are ideal.
[t] Biochemistry and coagulation tests to include Total Bilirubin, Creatinine Kinase, LDH, AST, ALT, Alkaline Phosphatase, Albumin, GGT, aPTT/INR will be
performed on Day 15 of cycle 1 ONLY for management of elevated liver enzymes. Weekly monitoring for grade 2 AST/ALT and monitoring daily for grade 3
AST/ALT until the event is assessed as stable by the investigator and toxic or viral etiologies are excluded is required per protocol and as clinically indicated.
Refer to Table 7 in section 6.3.9.2.2.
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Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 18 of 108 
TABLE 2 
SCHEDULE OF ASSESSMENTS PART 2A: INDUCTION TREATMENT 
SCREENING 
TREATMENT PERIOD 
Initial Treatment Phase 
Paclitaxel/Bevacizumab 
(1 Cycle = 4 Weeks)  
Visits Every 7  3 Days 
FOLLOW -UP AFTER 
STUDY TREATMENT 
TERMINATION  
Cycle 
- 4
-1
Cycle 1 
Cycle 2 
End of 
Treatme
nt [p] 
Safety follow-up 30 days 
after end of treatment    
( 5 days) 
Study Day 
-28 to
1
-7 to
1 [q]
Day 1 
Day 8 
Day 
15 
Day 22 
Day 
1 
Day 
8 
Day 15 
Day 22 
Informed consent 
X 
Demographics 
X 
Medical history [a] 
X 
Physical examination 
[b] 
X 
X 
X 
X 
X 
Vital signs [c] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
ECG [d] 
X 
Hematology [e] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry [f] 
X 
X 
X[s]
X 
X 
X 
Coagulation tests [g] 
X 
X 
X[s]
X 
X 
Urinalysis [h] 
X 
X 
X 
X 
CA-125 
X 
X 
X 
X 
X 
Pregnancy test [i] 
X 
Tumor assessments 
[j] 
X 
X[j]
X[j] 
X 
Adverse events [k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication [l] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archival Tissue [r] 
X 
Proprietary of MD Anderson Cancer Center

Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 19 of 108 
PD Blood [m] 
X 
PD Tissue [n] 
X 
X 
Paclitaxel 80 mg/m2 
i.v. [o]
X 
X 
X 
X 
X 
X 
X 
X 
Bevacizumab 10 
mg/kg i.v. [o] 
X 
X 
X 
X 
[a] Relevant medical history only.  Includes confirmation of histological diagnosis.
[b] Full physical examination should be performed at screening.  Subsequent physical examinations should be symptom directed.
[c] Vital signs include blood pressure, respiration rate, pulse, temperature, and weight.  Height is only measured at screening.
[d] As clinically indicated. MUGA may be obtained for clinical suspicion of decrease cardiac function
[e] Hematology: perform tests as per local standard of care and clinical indication.  However as a guide, this could include hemoglobin, RBC, platelet count,
WBC with differential count (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
[f]
Biochemistry: perform tests as per local standard of care and clinical indication.  However as a guide, this could include sodium, potassium, calcium,
blood urea nitrogen (BUN), uric acid, total protein (or albumin only), alkaline phosphatase, creatinine kinase, AST/SGOT, ALT/SGPT, GGT, LDH, total
bilirubin, blood glucose, creatinine.
[g] Coagulation tests: INR, aPTT. Patient receiving full dose of coumarin derivatives at baseline should have 2 consecutive screening INR measurements
1–4 days apart. INR/aPTT for the patient on (prophylactic or full) anticoagulation therapy will be checked at least before start of every chemotherapy
cycle.
[h] Urinalysis: To calculate UPC ratio. 24-hour urine collection needed in the event of proteinuria  +2. Proteinuria testing can be performed according to
local standards.
[i]
Pregnancy test (women of child-bearing potential only): Serum pregnancy test within 7 days prior to the first study treatment or within 14 days with a
confirmatory urine pregnancy test within 7 days prior to the first study treatment.
[j]
Baseline assessments of the pelvis and abdomen (preferably CT, or MRI in case of contrast allergy) and (by X-ray or preferably by CT-scan) of the
chest. These must be performed no more than 4 weeks before the first study treatment. Patients will be assessed for disease response or progression
throughout the study according to RECIST after every 8* weeks using the same imaging method as used during screening (CT or MRI or plain X-ray).
Pre-cycle clearance assessments must be performed within days 23-28 of the previous cycle.  Method of tumor assessment should be consistent
throughout all visits and performed until disease progression. Tumor assessment will only be performed post-study treatment in the absence of
confirmation of disease progression, at 8*-week intervals. See Section 5.3.1.3.  If stable disease is confirmed at the end of Cycle 2, then patient may
proceed to Schedule of Assessments for Part 2B.  Patients with progression and objective response will be taken off study.  If the screening
assessment is completed within 30 days of Cycle 1 Day 1, the assessment does not need to be repeated.
Notes*   If there is suspicion of disease progression based on clinical or laboratory findings before the next scheduled assessment, an unscheduled
assessment should be made
[k] Follow-up on serious or study drug-related AEs. All grade 2–5 events need to be recorded in the eCRF. Only SAEs caused by protocol-mandated
interventions to be collected prior to initiation of study medication.
[l]
All concomitant medication needs to be recorded in the eCRF. Only concomitant medication as per Section 4.4 must be recorded.
[m] See Table 4.  PD: Please refer to Section 5.6.
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Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 20 of 108 
[n] Tumor biopsy (See Section 5.6) will be obtained no sooner than 7 days before infusion therapy. On treatment biopsy; post induction biopsy will be done
for patients undergoing randomization (after 2 cycles of therapy, see Table 3), or optionally if progression occurs (End of Treatment Visit).
[o] Treatment will continue until progressive disease (PD), unacceptable toxicity or patient request for discontinuation. If paclitaxel is discontinued due to
toxicity prior to PD, bevacizumab should be continued until PD, toxicity or patient request for discontinuation, whichever occurs first.
[p] Should patients be taken off study at any time during treatment, scheduled cycle day assessments may replace applicable End of Treatment visit
assessments.
[q] If Day 1 assessments are completed within 7 days of treatment start date, Day 1 assessments do not have to be repeated.
[r]
If archival tissue is not available, pre-treatment biopsy material does not need to be utilized for the purposes of archival tissue, nor will it deter patient
from eligibility. A minimum of twenty five (25) unstained slides are ideal.
[s] Biochemistry and coagulation tests to include bilirubin, creatinine kinase, LDH, AST, ALT, GGT, Alkaline Phosphatase, and aPTT/INR will be performed
on Day 15 of cycle 1 ONLY for management of elevated liver enzymes. Weekly monitoring for grade 2 AST/ALT and monitoring daily for grade 3
AST/ALT until the event is assessed as stable by the investigator and toxic or viral etiologies are excluded is required per protocol and as clinically
indicated. Refer to Table 7 in section 6.3.9.2.2.
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Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 21 of 108 
TABLE 3 
SCHEDULE OF ASSESSMENTS PART 2B: RANDOMIZED TREATMENT 
Treatment Period 
Randomized Cohorts  
Arm 1 (Paclitaxel/Bevacizumab) & Arm 2 
(Paclitaxel/Bevacizumab/Emactuzumab) 
(1 cycle = 4 weeks)  
Visits every 7  3 days 
End of 
Treatment 
[p] 
FOLLOW -UP AFTER STUDY 
TREATMENT TERMINATION  
Week or cycle 
Cycle 1 
Cycle 2 and subsequent cycles 
Safety follow-
up 30 ( 5 
days) days 
after end of 
treatment 
Survival  
follow-up 
Study day 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 Day 15 
Day 
22 
Physical examination [a] 
 X 
X 
X 
X 
Vital signs [b] 
Xc 
X 
Xc 
X 
Xc 
X 
Xc 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
ECG [d] 
Hematology [e] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry [f] 
X 
X[q]
X 
X 
X 
Coagulation tests [g] 
X 
X[q]
X 
X 
Urinalysis [h] 
X 
X 
X 
CA-125 
X 
X 
X 
X 
Tumor assessments [i] 
X 
X[i] 
X 
Adverse events [j] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status [k] 
X 
Concomitant medication 
[l] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD Blood [m] 
X[m] 
PD Tissue [n] 
X 
X 
Arm 1 Drug Administration [o] 
Paclitaxel 80 mg/m2 i.v. 
X 
X 
X 
X 
X 
X 
X 
X 
Bevacizumab 10 mg/kg 
i.v.
X 
X 
X 
X 
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Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 22 of 108 
Arm 2 Drug Administration [o] 
Paclitaxel 80 mg/m2 i.v. 
X 
X 
X 
X 
X 
X 
X 
X 
Bevacizumab 10 mg/kg 
i.v.
X 
X 
X 
X 
Emactuzumab 1000mg 
i.v.
X 
X 
X 
X 
[a] Subsequent physical examinations should be symptom directed.
[b] Vital signs include blood pressure, respiration rate, pulse, temperature, and weight.  Height is only measured at screening.
[c] Vital signs (including supine blood pressure, respiratory rate, pulse rate and temperature) to be measured as follows on days patients receive
Emactuzumab:
•
pre-infusion
•
every 15 minutes until the end of Emactuzumab infusion
•
every 30 minutes until the infusion line is removed.
[d] As clinically indicated. MUGA may be obtained for clinical suspicion of decrease cardiac function
[e] Hematology: perform tests as per local standard of care and clinical indication.  However as a guide, this could include hemoglobin, RBC, platelet
count, WBC with differential count (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
[f]
Biochemistry: perform tests as per local standard of care and clinical indication.  However as a guide, this could include sodium, potassium, calcium,
blood urea nitrogen (BUN), uric acid, total protein (or albumin only), alkaline phosphatase, creatinine kinase, AST/SGOT, ALT/SGPT, GGT, LDH,
total bilirubin, blood glucose, creatinine.
[g] Coagulation tests: INR, aPTT. Patient receiving full dose of coumarin derivatives at baseline should have 2 consecutive screening INR
measurements 1–4 days apart. INR/aPTT for the patient on (prophylactic or full) anticoagulation therapy will be checked at least before start of every
chemotherapy cycle.  As clinically indicated (every treatment visit if patient receiving anticoagulation treatment)
[h] Urinalysis: To calculate UPC ratio. 24-hour urine collection needed in the event of proteinuria  +2.  Proteinuria testing can be performed according
to local standards.
[i]
Patients will be assessed for disease response or progression throughout the study according to RECIST after every 8* weeks using the same
imaging method as used during screening (CT or MRI or plain X-ray).  Pre-cycle clearance assessments must be performed within days 23-28 of the
previous cycle.  Method of tumor assessment should be consistent throughout all visits and performed until disease progression. Tumor assessment
will only be performed post-study treatment in the absence of confirmation of disease progression, at 8*-week intervals.  See Section 5.3.1.3.
Patients with evidence of progression will be followed for overall survival then taken off study.
Notes*   If there is suspicion of disease progression based on clinical or laboratory findings before the next scheduled assessment, an unscheduled
assessment should be made
[j]
Follow-up on serious or study drug-related AEs. All grade 2–5 events need to be recorded in the eCRF. Only SAEs caused by protocol-mandated
interventions to be collected prior to initiation of study medication.
Proprietary of MD Anderson Cancer Center

Investigational Drug 
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 23 of 108 
[k]
Patients will be followed for overall survival; immediate and subsequent treatment regimens will be recorded if it is available.  Patients with complete
response will be followed every 3 months for 2 years, every 4 months in the third year, then every 6 months for 2 additional years.
[l]
All concomitant medication needs to be recorded in the eCRF. Only concomitant medication as per Section 4.4 must be recorded.
[m] See Table 4.  PD: Please refer to Section 5.6.
[n] Pre-randomization tumor biopsy (See Section 5.6) will be obtained no sooner than 7 days before infusion therapy. If progression occurs (End of
Treatment Visit), an optional biopsy may occur.
[o] Treatment will continue until progressive disease (PD), unacceptable toxicity or patient request for discontinuation. If paclitaxel is discontinued due to
toxicity prior to PD, bevacizumab should be continued until PD, toxicity or patient request for discontinuation, whichever occurs first.
[p] Should patients be taken off study at any time during treatment, scheduled cycle day assessments may replace applicable End of Treatment visit
assessments.
[q] Biochemistry and coagulation tests to include bilirubin, creatinine kinase, LDH, AST, ALT, GGT, Alkaline Phosphatase, and aPTT/INR will be
performed on Day 15 of cycle 1 ONLY for management of elevated liver enzymes. Weekly monitoring for grade 2 AST/ALT and monitoring daily for
grade 3 AST/ALT until the event is assessed as stable by the investigator and toxic or viral etiologies are excluded is required per protocol and as
clinically indicated. Refer to Table 7 in section 6.3.9.2.2.
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 24 of 108 
TABLE 4. PD SCHEDULE OF ASSESSMENTS (PART 1 AND
PART 2) 
Time point 
Sample Type 
PD Blood 
Part 1 
(Paclitaxel, Bevacizumab, Emactuzumab) 
Cycle 1 Day 1 
Pre-dose (w/in 4 hours pre-infusion) 
X 
Cycle 3 Day 1 
Pre-dose (w/in 4 hours pre-infusion) 
X 
Cycle 5 Day 1 
Pre-dose (w/in 4 hours pre-infusion) 
X 
End of Treatment 
X 
Part 2A 
(Paclitaxel, Bevacizumab) 
Cycle 2 Day 22 
Pre-dose (w/in 4 hours pre-infusion) 
X 
Part 2B Arms 1 & 2 
(Paclitaxel, Bevacizumab) or (Paclitaxel, Bevacizumab, Emactuzumab) 
Cycle 3 Day 1 
Pre-dose (w/in 4 hours pre-infusion) 
X 
Cycle 5 Day 1 
Pre-dose (w/in 4 hours pre-infusion) 
X 
End of Treatment 
X 
;; PD = pharmacodynamic 
BACKGROUND AND RATIONALE 
1.1 Background – Ovarian Cancer 
Epithelial ovarian cancer, along with primary peritoneal carcinoma and fallopian tube carcinoma, is the 
fifth most common cause of cancer-related death in women in many developed countries.1  It is also the 
gynecological malignancy with the highest mortality rate.1,2  Despite improvements in the treatment of 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 25 of 108 
ovarian cancer, increases in OS have been modest 3,4 and as such, mortality remains high. This is partly 
due to the fact that ovarian cancer is frequently not diagnosed until it has progressed to an advanced 
stage. Ovarian cancer is considered a chemo-responsive neoplasm, with initial response rates to 
systemic chemotherapy exceeding 80% when integrated with primary cytoreductive surgery.5 Despite 
this, over 50% of women diagnosed with epithelial ovarian cancer eventually go on to die from their 
disease.6 Major trials published over the past 15 years report that the median PFS for patients with 
advanced disease ranges between 16 and 23 months while the median OS lies between 31 and 65 
months.7-11 
 
The majority of patients who achieve a CR with first-line chemotherapy ultimately develop recurrent 
disease. These patients can be subdivided into platinum-sensitive or platinum-resistant groups.12 
Platinum-sensitive patients have been principally defined as those in whom disease has recurred more 
than 6 months after cessation of initial platinum-containing chemotherapy.12 Platinum-based therapies 
are typically used to retreat these patients, in light of clinically meaningful responses observed in these 
patients following a second platinum-based treatment. 13 Currently, there is no optimal treatment strategy 
for platinum-resistant patients whose disease recurs within 6 months of completing initial platinum-based 
chemotherapy.12,14 Despite a wide range of available treatments, prolonged survival has not been shown 
in this setting, and ORR is generally less than 20%.12,15 As resistant-disease is not curable, the goals of 
treatment for these patients include palliation of symptoms, prolonged survival and improvements in 
quality of life.13,15,16  
 
Platinum-resistance is therefore a significant clinical problem for which improved treatment regimens are 
needed. In this regard, molecular targeted therapeutic agents herald a new era for cancer treatment. In 
the setting of epithelial ovarian cancer, a growing body of evidence supports the use of anti-angiogenic 
agents in combination with chemotherapies.17 In particular, bevacizumab (Avastin®), a monoclonal 
antibody targeted against the pro-angiogenic vascular endothelial growth factor (VEGF), holds 
significant therapeutic potential. 
 
1.2 Chemotherapies for platinum-resistant ovarian cancer 
Platinum-resistant ovarian cancer is non-curable and so symptom management, delayed disease 
progression and improvement in both quality and length of life are the primary treatment 
objectives.13,15,16, 62 Patients are often treated with sequential lines of single-agent chemotherapy. 
Although taxanes are now routinely administered alongside the platinum-containing compound in initial 
therapy, this need not preclude taxane use following disease recurrence.18,19 Other commonly used 
agents include topotecan and pegylated liposomal doxorubicin (PLD). 
 
1.2.1 
Taxanes 
Taxanes such as docetaxel and paclitaxel are cytotoxic agents that induce cell cycle arrest by inhibiting 
tubulin depolymerization and therefore stabilising microtubules.20 Following the demonstration of 
superior survival with paclitaxel plus cisplatin over cyclophosphamide plus cisplatin in first-line therapy, 
taxane/platinum combinations have become a standard of care for initial treatment.9,29 For this reason, 
most platinum-resistant patients have also been exposed to taxanes.30 However, the mechanisms of 
platinum and taxane resistance are different: therefore patients resistant to platinum may respond to 
second-line taxanes, even if included in their initial regimen.18,21 Furthermore, cross-resistance to 
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Investigational Drug  
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Bevacizumab 
Study Number: 
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Version Number: 
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paclitaxel is incomplete.22,23 As such, paclitaxel is considered to be a potentially active agent for the 
treatment of platinum-resistant disease.2, 62 
 
In the setting of relapsed disease, paclitaxel is typically administered at 175 mg/m2 as a 3-hour infusion 
every 3 weeks.24,25 In a randomized trial of platinum-resistant patients, paclitaxel was associated with an 
ORR of 17%, median duration of response of 6 months and median OS of around 9 months.26 Major 
AEs include severe neutropenia (grade 4 rates up to 23%) and neurotoxicity (in up to 42% of 
patients).16,25,27  
 
In resistant disease, two Phase II studies have been conducted in which paclitaxel was administered on 
a weekly schedule. Markman et.al. reported the results of the first study where 53 patients received 
paclitaxel 80mg/m2 once every 7 days.18 Of the 36 patients with measurable disease, 25% experienced 
an objective response. The median time to progression was 24 weeks and the median overall survival 
was found to be 58 weeks. In terms of safety, the treatment regimen was found to be reasonably well 
tolerated with only 5 patients needed to be discontinued due to toxicity (4 because of peripheral 
neuropathy and 1 due to painful fingernail beds). 
 
Building upon the findings, another Phase II study was conducted by the same group.19 48 patients were 
enrolled into a study investigating the same 80mg/m2 weekly paclitaxel dose. By contrast to the first trial, 
this study allowed patients (following an initial 12 weeks of dosing) to be treated for 3-weeks, with a 1 
week break. In this chemo-resistant population, the objective response rate was 20.9%.  As anticipated, 
the most common toxicity was neuropathy (21%) and grade 2 and 3 neurotoxicity (4%).  
 
Most recently, there are emerging data indicating that weekly paclitaxel dosing schedule may be more 
effective and less toxic than standard paclitaxel dosing. An ongoing Phase III trial in Japan called 
NOVEL28 compares the PFS in patients with stage II–IV epithelial ovarian cancer treated with first-line 
carboplatin plus standard paclitaxel (3-week schedule) versus carboplatin plus a weekly paclitaxel (80 
mg/m2) regimen. An interim analysis revealed that while toxicities were similar in both groups, there was 
a markedly improved PFS for the weekly paclitaxel/carboplatin arm (27.9 months) compared with the 
standard schedule (17.1 months) (P=0.0014). The findings from the NOVEL trial are consistent with 
previous Phase II trials showing activity of weekly paclitaxel (80 mg/m2 i.v.) in patients with platinum- 
and paclitaxel-resistant ovarian cancer.18,19 In light of the findings from the NOVEL study, weekly 
paclitaxel may become more widely used in daily clinical practice.62  
1.2.2 
Bevacizumab 
 For detailed background information, please refer to the latest bevacizumab Investigators’ Brochure.  
  
The addition of bevacizumab to chemotherapy has been shown to improve PFS and/or OS in a series of 
large, randomized Phase III clinical trials in a wide range of tumor types, including metastatic colorectal 
cancer,44-47 non-small cell lung cancer,48 locally recurrent or metastatic breast cancer49-50 and metastatic 
renal cell carcinoma51,52, as well as, ovarian cancer. See Figure 1for a summary of the randomized 
phase III trials of bevacizumab in ovarian cancer. 
 
Figure 1: Summary of Phase III Trials Using Bevacizumab in Women with Ovarian Cancer. 
 
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Oncology  REDIRECT v.9 
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Study 
Setting 
N 
Treatment Arm 
PFS 
(median, 
months) 
PFS-HR 
(95% CI) 
OS 
(median,
months) 
OS-HR 
(95% CI) 
GOG-218 Front-line & 
Maintenanc
e 
18 
I: Paclitaxel + Carboplatin + 
Placebo; Placebo 
Maintenance 
II: Paclitaxel + Carboplatin 
+ Bevacizumab; Placebo
Maintenance
III: Paclitaxel + Carboplatin
+ Bevacizumab;
Bevacizumab Maintenance
10.3 
11.2 
14.1 
---------- 
0.91 (0.8-
1.04) 
0.72 (0.63-
0.82) 
39.3 
38.7 
39.7 
---------- 
1.036 
(0.83-1.3) 
0.92 (0.73-
1.15) 
ICON7 Front-line 
and 
Maintenanc
e 
15 
I: Paclitaxel + Carboplatin 
II: Paclitaxel + Carboplatin 
+ Bevacizumab;
Bevacizumab Maintenance
17.4 
19.8 
---------- 
0.87 (0.77-
0.99) 
58 
58.6 
---------- 
0.85 (0.69-
1.04) 
AURELIA Recurrent, 
Platinum-
Resistant 
36 
I: Chemotherapy 
(paclitaxel-weekly, 
topotecan-daily x 5 or 
weekly, PLD) 
II: Chemotherapy + 
bevacizumab 
3.4 
6.7 
---------- 
0.48 (0.36-
0.6) 
13.3 
16.6 
---------- 
0.85(0.66-
1.08) 
OCEANS Recurrent, 
Platinum-
Sensitive 
48 
I: Gemcitabine + 
Carboplatin + Placebo 
(combination and 
maintenance) 
II: Gemcitabine + 
Carboplatin + Bevacizumab 
(combination and 
maintenance) 
8.4 
12.4 
---------- 
0.48 (0.39-
0.61) 
32.9 
33.6 
---------- 
0.95 (0.77-
1.18) 
GOG-213 
Recurrent, 
Platinum-
Sensitive 
67 
I: Paclitaxel + Carboplatin 
II: Paclitaxel + Carboplatin 
+ Bevacizumab;
Bevacizumab maintenance
10.4 
13.8 
---------- 
0.61 (0.52-
0.72) 
37.3 
42.2 
---------- 
(0.83 (0.68-
1.005) 
PFS: Progression-Free Survival; OS: Overall Survival; HR: Hazard Ratios 
1.2.2.1 AURELIA: bevacizumab in platinum-resistant ovarian cancer62 
Patients presenting with platinum-resistant recurrent ovarian cancer are usually treated with single-agent 
chemotherapy; there are many acceptable options with previous phase III trials failing to demonstrate a clear 
“winner”. Bevacizumab, a monoclonal antibody targeting VEGF, has been extensively studied in ovarian 
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cancer, and has clinical activity as a single agent and in combination with platinum-based chemotherapy 
both in the front-line and in recurrent platinum-sensitive settings. AURELIA was the first randomized phase 
III trial combining bevacizumab with chemotherapy in platinum-resistant ovarian cancer.62  Eligible patients 
had measurable/assessable disease, progressing within 6 months of completing platinum-based therapy. 
Patients with refractory disease, history of bowel obstruction, or more than two prior anticancer regimens 
were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly 
paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with 
bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks, depending on the regimen) until 
progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was 
permitted after progression with chemotherapy alone. The primary end point was progression-free survival 
(PFS) by RECIST. Secondary end points included objective response rate (ORR), overall survival (OS), 
safety, and patient-reported outcomes. The PFS hazard ratio (HR) was 0.48 (95% CI, 0.38 to 0.60; 
unstratified log-rank P < 0.001) representing a median PFS of 3.4 months with chemotherapy alone to 6.7 
months with bevacizumab-containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P < 
0.001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P = .174; median OS, 13.3 versus 16.6 months, 
respectively). Grade 2 or higher hypertension and proteinuria were more common with bevacizumab. GI 
perforation occurred in 2.2% of bevacizumab-treated patients versus 0 in the chemotherapy treated patients. 
Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was 
not significant. No new safety signals were observed.  
 
1.2.2.2 
The Immune contribution to angiogenesis escape 
 
Numerous studies have highlighted the 
association between inflammation and 
tumor progression 21,22.  Tumor-
associated macrophages (TAMs) 
represent a major inflammatory 
component of the tumor stroma and are 
associated with cancer progression and 
resistance to antiangiogenic 
therapy23,24.(See Figure 2)  Cytokines in 
the 
tumor microenvironment polarize TAMs 
toward an M2 phenotype, marked by increased expression of IL-10, TGFβ, VEGF, MMPs and other 
cytokines that suppress adaptive immunity and stimulate metastasis and angiogenesis25,26.  In addition, 
TAMs accumulate in hypoxic regions of tumors and hypoxia resulting from antiangiogenic therapy has been 
associated with increased TAM infiltration27.  It has recently been shown that targeting tumor vasculature 
with lower vascular-normalizing doses of an anti-VEGFR2 antibody, as opposed to high 
antivascular/antiangiogenesis doses, can polarize TAMs from an immune inhibitory M2 phenotype to an 
immune stimulatory M1 phenotype that may be more effective with other anticancer therapies28.  In vivo 
studies have shown that depleting peritoneal macrophages/TAMs inhibits ascites and decreases tumor 
progression and angiogenesis29.  Zoledronic acid (ZA) is clinically used to prevent or treat osteoporosis and 
also impairs M2 polarization of macrophages.  Depletion of macrophages by ZA in combination with 
sorafenib significantly inhibited tumor progression, tumor angiogenesis and metastasis in a hepatocellular 
carcinoma murine model compared to treatment with sorafenib alone30.  CSF-1R tyrosine kinase inhibitors 
target TAMs and alter macrophage polarization31.  Targeting CSF-1R also inhibits tumor angiogenesis 
  
Fig 2. Hypothetical 
model of adaptive 
resistance to anti-
VEGF therapy. 
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associated with decreased expression of proangiogenic genes.  The combination of a CSF-1R inhibitor with 
an anti-VEGFR-2 antibody synergistically suppressed tumor growth and angiogenesis, suggesting that 
combination therapy may inhibit tumor growth better than either approach alone32.  
1.2.3 
Emactuzumab 
Emactuzumab is a recombinant, humanized monoclonal antibody (mAb) of the immunoglobulin (Ig) IgG1 
subclass directed against CSF-1R expressed on macrophages.  It binds to the membrane proximal 
extracellular domains D4 and D5, which constitute the receptor dimerization interface.  RO5509554 blocks 
CSF-1− and IL-34−mediated as well as ligand-independent activation of the receptor, which results in induction 
of apoptosis of M2-like macrophages differentiated in vitro in the presence of CSF-1 while sparing the M1-like 
GM-CSF−differentiated macrophages.  CSF-1−differentiated macrophages have been shown to suppress T 
cell activation in an in vitro co-culture assay (Ries et al. 2014).  In human breast cancer tissue, M2-like 
(CD68 +/CD163 +) macrophages and CSF-1R−expressing macrophages are co-localized.  In the cynomolgus 
monkey, 13 weeks of treatment with RO5509554 reduced CD163 positive macrophages in the liver and colon 
but not in the alveolar macrophages. 
 Emactuzumab is a first in class, novel, CSF-1R inhibitor with nanomolar affinity for CSR-1R and has 
demonstrated single agent phase I activity in solid tumors. (Investigator’s Brochure) Combination therapy with 
weekly paclitaxel did not produce new safety signals at the recommended phase II dose. 
A dose dependent decrease in dermal macrophages was observed in surrogate skin biopsies from 200 mg 
onwards reaching plateau at ≥ 900 mg doses for monotherapy and in combination with paclitaxel. A 
decrease in TAMs (Tumor Associated Macrophages) from paired tumor biopsies was also observed. Such a 
decrease did not show a clear dose dependent trend, most likely due to the higher variability observed in the 
tumor biopsies and the limited number of patients in each dose cohort. In summary, the PK/PD analysis 
from the Phase I dose escalation study indicated that a dose of 1000 mg given Q2W would achieve the 
required ≥90% target saturation resulting in depletion of macrophages, without altering the safety/tolerability 
profile. Based upon this information a dose of 1000 mg Q2W was recommended to be administered for Part 
II of the study in monotherapy for all indications and in combination with paclitaxel 80 mg/m2.  
Please see Investigator’s Brochure for more details on emactuzumab. 
1.2.3.1 Safety  
Preliminary safety data were available for a total of 205  at the clinical cutoff date of 01 November 2015. 
Emactuzumab doses of up to 3000 mg have been administered to patients as monotherapy and up to 2000 
mg in combination with fixed-dose paclitaxel.  Emactuzumab was generally well tolerated.  
The maximum tolerated dose (MTD) was not reached in either study arm based on the predefined incidence 
of dose-limiting toxicities (DLTs). In Arm A (emactuzumab monotherapy), 1300 AEs were reported in 147 
patients. The most common adverse events (AEs) were asthenia, pruritus, periorbital edema, and peripheral 
edema. The majority of AEs were Grade 1 or 2. One Grade 5 (fatal) AE of large intestinal obstruction due to 
progressive disease, one Grade 5 (fatal) AE of cerebrovascular ischemia, and one Grade 3 AE of 
confusional state due to progressive disease with a fatal outcome were reported; neither was considered as 
related to study treatment. There were 50 serious AEs (SAEs) reported, with 18 related SAEs. A total of 16 
patients were withdrawn from treatment in 
Arm A. 
In Arm B (emactuzumab in combination with paclitaxel), 793 AEs were reported in 54 patients. The most 
common AEs were asthenia, periorbital edema, anemia, and nausea. As in Arm A, the majority of AEs were 
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Version Number: 
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Grade 1 or 2. There were one Grade 5 (fatal) AE of large intestine perforation, considered as related to 
treatment and a DLT, and one Grade 5 (fatal) AE of malignant bowel obstruction, considered as not related 
to treatment, reported in Arm B. There were 46 SAEs reported, with 16 related SAEs. A total of 6 patients 
were withdrawn from treatment in Arm B. 
 
There were 19 deaths (11 in Arm A and 8 in Arm B) reported in the study, with progression of the underlying 
disease considered to be the cause of 17 deaths. One patient in Arm A died due to unrelated 
cerebrovascular ischemia. The cause of death for one patient in Arm B was metastatic progressive disease 
and the AE of large intestine perforation, considered as related to treatment and a DLT. However, it could 
not be ruled out that the perforation was due to the underlying disease in this patient with known and 
progressive peritoneal carcinomatosis. 
 
 
 
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Investigational Drug  
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Version Number: 
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See the emactuzumab Investigator’s Brochure for details on the clinical safety of emactuzumab. 
1.2.3.2  Efficacy 
 
A total of 205 patients had been assessed for tumor response at the time of the clinical cutoff date of 01 
November 2015. Of the 205 patients enrolled in the study at this date, 167 patients had been evaluated for 
tumor responses according to RECIST v1.1. 
Of the 167 evaluable patients, 2 of 47 patients with pigmented villonodular synovitis [PVNS] in Arm A 
(emactuzumab monotherapy) had a best timepoint response on study of CR, whereas 35 of 47 patients with 
PVNS in Arm A and 7 of 46 patients with locally advanced and/or metastatic ovarian or breast cancer in Arm 
B (in combination with paclitaxel) had a best timepoint response on study of PR; PVNS is a reactive 
inflammatory disorder and clonal neoplastic proliferation with a chromosomal translocation CSF-1 COL6A3 
that leads to overexpression of CSF-1 in malignant cells. A total of 53 patients had stable disease while on 
study (10 of 47 patients with PVNS in Arm A, 19 of 74 non-PVNS patients in Arm A, and 24 of 46 patients 
with locally advanced and/or metastatic ovarian or breast cancer in Arm B). 
1.3 Study rationale  
Relapsed ovarian cancer is not currently curable. Careful investigation of novel agents in this cohort has 
reliably extended PFS without a clear impact on OS. Indeed, many patients ultimately develop progressive 
disease on bevacizumab. The mechanisms for this clinical phenotype are not precisely known but likely 
involve a multifactorial process of endogenous and exogenous growth factors, stromal and endothelial 
alteration and immunosurveillance suppression. We have extensively studied this latter effect in preclinical 
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models by inducing a resistant state in in vivo orthotopic murine models under continuous anti-VEGF 
therapy and have identified multiple adaptive changes, including infiltration of CD11b+F4/80+macrophages 
(TAMs) and CD11b+Gr-1+ (MDSCs). These induced alterations were strongly associated with increasing 
vessel count and density suggesting that therapy targeted to these adaptive responses might induce more 
robust anti-tumor activity. We formally tested this hypothesis by treating anti-VEGF resistant murine 
orthotopic ovarian cancer xenografts with zoledronic acid and liposomal clodronate while continuing anti-
VEGF therapy and demonstrated restored clinical response. Clinically, elevated tumoral macrophages 
(CD68+, High >15/hpf) are associated with poor outcome in women with ovarian cancer.  (see Figure).  
 
We propose a clinical study in recurrent platinum-
resistant ovarian cancer patients that directly 
evaluates the ability of TAM-targeting by 
emactuzumab to overcome induced angiogenesis 
resistance following exposure to bevacizumab. This 
novel trial design will enable evaluation of clinical 
efficacy endpoints, as well as, microenvironment 
adaptive changes in response to combination 
paclitaxel/bevacizumab. We will also generate 
correlative dynamic imaging and develop a significant 
safety database to draw upon for future clinical 
investigation and drug development. In light of the 
recent approval of bevacizumab in combination with 
chemotherapy, the current trial design provides a 
unique opportunity to clearly understand one aspect of adaptive resistance in the tumor microenvironment 
and evaluate highly effective targeted adjuvants to overcome this response to therapy.  
 
The rationales for the study design and dose selection are described in detail in sections 3.1.1 and 3.1.2. 
 OBJECTIVES  
 
2.1 Primary   
• 
Part 1: To evaluate the safety of administration of paclitaxel, bevacizumab and emactuzumab over 4 
weeks.  
• 
Part 2B: To compare the progression-free survival (PFS) of patients with stable disease following Part 
2A randomized to paclitaxel plus bevacizumab or to paclitaxel, bevacizumab plus emactuzumab. 
 
2.2 Secondary objectives 
• 
To estimate the progression-free survival (PFS) of the treatment arms. 
• 
Objective response rate (ORR) 
▪ 
by RECIST and CA-125 response criteria (“responders”). 
▪ 
by RECIST only (“RECIST responders”). 
▪ 
by CA-125 response criteria only (“CA-125 responders”).  
• 
Biological progression-free interval (PFIbio) 
▪ 
by serum CA-125 assessed according to the GCIG criteria 
( http://www.gcig.igcs.org/CA-125.html ). 
• 
Overall survival (OS). 
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• 
Safety and tolerability. 
2.3 Exploratory objectives 
• 
To assess the utility of surrogate biomarkers and the anti-tumor response to therapy with the combination 
treatment of bevacizumab and emactuzumab, we will draw 20 ml blood for plasma markers (VEGF, 
VEGFR, IL6, IL8, FGF, PDGFAA, CSF1, and IL34) and other chemokines identified by secretome 
proteomics) and potential exosomal markers (M2-like markers VEGFR1-3, CD11b +CD68, 
CD11b+CD14/CD15/CD33,CD11b+CD11c,MHCII),priortoinitiationof 
paclitaxel/bevacizumab/emactuzumab and after pre-infusion every 4 weeks for the patient safety lead-in 
(Part 1), and randomized therapy (Part 2B).  In Part 2, we will seek to obtain 2 biopsies, one pre-treatment 
tissue biopsy prior to initiation of Part 2A and one pre-randomization tissue biopsy prior to initiation of Part 
2B. These biopsied tissues will be used for monitoring dynamic changes in adapted macrophages (with 
phenotype of M2-like: VEGFR1-3+, CD markers (e.g. +CD68, CD163+), CSF1/CSF1R+ and MHCIIlow), 
and hypoxia markers as well as CD4/CD8, NK, and T-reg. If a third biopsy is obtained (following 
progression) we will run a third set of tissue biomarkers; biopsy at progression is optional. In addition, we 
will also evaluate other molecular pathways (e.g., epigenetic modifications. 
• 
To assess tumor alterations by serial non-invasive imaging macrophage-specific imaging, ADC (Apparent 
Diffusion Coefficient) for cellularity, and DCE (Dynamic Contrast Enhanced) for vasculature. 
 STUDY DESIGN 
3.1 Overview of study design 
This trial consists of 2 Parts:  
3.1.1 
Part 1 (Safety Lead-in):  
Safety assessment in 9 patients of paclitaxel plus bevacizumab plus emactuzumab. To ensure patient 
safety, the first three patients will be enrolled staggered with one week between enrollments of each 
patient. All three patients must complete one cycle of triplet therapy prior to enrollment of any additional 
patients on Part 1 of the study. If no dose-limiting toxicities are observed, the remaining six patients may 
be enrolled simultaneously. If dose-limiting toxicities are observed at any time, refer to section 8.1.1 of 
the protocol for patient enrollment requirements. Doses to be used in this cohort will mimic the starting 
doses in Part 2B outlined in the next section. Specifically: 
o 
Paclitaxel 80 mg/m2 as a 1-hour i.v. infusion on days 1, 8, 15 and 22 q4w 
o 
Bevacizumab 10 mg/kg i.v. d1,15 
o 
Emactuzumab 1000 mg i.v. d1,15 
 
Emactuzumab dose was chosen from the phase I dose escalation and confirmed in the phase I combination 
trial with paclitaxel. Emactuzumab should be administered before bevacizumab and then paclitaxel at the 
first cycle and throughout subsequent cycles. 
 
For bevacizumab and paclitaxel, pre-medication should be implemented according to local practices.  For 
emactuzumab, premedication may be administered, if needed, starting at Cycle 2 and at the discretion of the 
investigator. 
 
Patients will be evaluated for tolerance of the triplet through 4 weeks of therapy. While a dose modification 
will be provided to account for toxicity, the non-overlapping adverse events seen in the paclitaxel plus 
emactuzumab phase I provide some confidence this triplet will be well tolerated as the doublet of paclitaxel 
plus bevacizumab 
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3.1.2 
Part 2 (Induction/Randomization): 
3.1.2.1 Part 2A (see Schema): 
Induction: all enrolees will receive paclitaxel plus bevacizumab for 2 cycles (8 weeks) and undergo 
evaluation for response 
3.1.2.2 Part 2B (see Schema): 
Randomized phase II. Patients with stable disease will be randomized 1:1 to continued paclitaxel plus 
bevacizumab (Arm 1) or paclitaxel plus bevacizumab plus emactuzumab (Arm 2). 
Arm 1 (Paclitaxel plus bevacizumab): 
Eligible patients will receive:  
•
Paclitaxel 80 mg/m2 as a 1-hour i.v. infusion on days 1, 8, 15 and 22 q4w.
•
Bevacizumab 10 mg/kg i.v. on days 1 and15
These doses were chosen from the AURELIA trial which shares identical eligibility to the current trial and is 
the FDA approved doses for this chemotherapy backbone.  
Pre-medication should be implemented according to local practices.  
Upon disease progression patients in Arm 1 will receive standard of care.     
Arm 2 (Paclitaxel plus bevacizumab plus emactuzumab): 
•
Arm 1 therapy and schedule will be used plus Emactuzumab 1000 mg i.v. on days 1 and 15 over 90
minutes
Emactuzumab should be administered before bevacizumab and then paclitaxel at the first cycle and 
throughout subsequent cycles. For bevacizumab and paclitaxel, pre-medication should be implemented 
according to local practices.  For emactuzumab, premedication may be administered starting at Cycle 2, and 
at the discretion of the investigator. 
In case paclitaxel is discontinued before diagnosis of progressive disease, patients should continue to 
receive emactuzumab at 1000 mg i.v. d1,15 and bevacizumab 10 mg/kg i.v. d1,15.  
After disease progression, study therapy should be discontinued permanently and patients will receive 
standard of care treatment.  
3.1.3 
Rationale for study design:   
The trial will take place in two sequential Parts. 
3.1.3.1 Part 1 (safety lead-in):  
Although paclitaxel and bevacizumab have been extensively studied in AURELIA and other clinical trials, 
and paclitaxel and emactuzumab has been studied in a phase I trial upon which the phase II dose of 
emactuzumab was established, the triplet of paclitaxel, bevacizumab and emactuzumab has not been 
studied. There appear to be no drug-drug interaction or overlapping adverse events. The Part 1 safety lead-
in will consist of 9 evaluable patients (receiving 1 cycle of triplet therapy). PD blood will be collected pre-
infusion for translational analysis.Once patient 9 clears the toxicity window (1 cycle of triplet therapy), the 
trial will move to Parts 2A & 2B. 
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3.1.3.2 Parts 2A and 2B (induction/discontinuation randomized phase II): 
The Figure 3 outlines the trial schema. The primary 
focus of the trial is to assess whether emactuzumab can 
overcome induced events in the tumor microenvironment 
limiting efficacy from paclitaxel plus bevacizumab. As 
outlined below, chemotherapy and bevacizumab can 
impact the profile of infiltrating mononuclear cells and 
macrophages to overcome anti-VEGF targeting. The trial 
design was chosen to optimize and identify that cohort of 
women neither primarily progressing on 
paclitaxel/bevacizumab (primary refractory) nor 
demonstrating rapid response. Part 2A patients will 
undergo tissue biopsy to establish primary and provide 
material for pharmacodynamic testing and then initiate 
treatment on paclitaxel plus bevacizumab therapy in the 
doses and schedule outlined in the package insert for 
this FDA-approved combination. Only one assessment 
cycle (8 weeks = 2 courses) will be used to evaluate 
those with rapid progression or response. Those with 
stable disease will enter Part 2B, and will undergo a 
follow-up biopsy and then randomization to either 
continued therapy (standard of care) or triplet therapy 
adding emactuzumab. The primary efficacy endpoint 
(progression-free survival) will compare the randomized 
cohort. Paired tissue sampling will be interrogated for tumor microenvironment cellular perturbations. 
3.1.4 
Rationale for dose selection 
In the AURELIA study, paclitaxel 80 mg/m2 as a 1-hour i.v. infusion was administered on days 1, 8, 15 and 
22 along with bevacizumab 10 mg/kg days 1 and 15 on a 28-day cycle. This schedule will be used in the 
current study for both the induction phase (Part 2A: all patients) and randomization phase (Part 2B: control 
population following randomization). 
Emactuzumab dosing was chosen from the phase I paclitaxel plus emactuzumab trial identifying 1000 mg 
flat dose administered every 2 weeks to be optimal with weekly paclitaxel at this schedule.  
The combination of weekly paclitaxel plus bevacizumab plus emactuzumab will be administered during Part 
1 (safety lead in) as well as in Part 2 (randomized experimental group) 
3.1.5 
Rationale for Tumor biopsy 
TAM infiltration and differentiation is dependent on the respective tumor micro-milieu in primary and 
metastatic lesions. Furthermore the respective immune status and pre-treatment of the patient might 
influence the patient’s tumor microenvironment. Therefore all patients entering Part 2A will undergo a 
mandatory pre-treatment biopsy to define the TAM infiltration and CSF-1R expression levels at baseline but 
will not be used to determine patient eligibility for the trial.  
Archival tumor tissue cannot substitute for the fresh biopsies as macrophage infiltration and differentiation is 
micro-milieu dependent. The tumor micro-milieu may be variable in the primary tumor due to pre-treatment 
of the patient and as well be altered in metastatic lesions. To better understand this potential heterogeneity, 
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collection of archival tissue will also be done. Patients enrolling onto Part 2B will undergo a second biopsy to 
evaluate induced microenvironment alterations in cellular populations that represent incomplete clinical 
response to induction paclitaxel plus bevacizumab. Patients demonstrating primary progression after Part 
2A will be approached for an off-treatment biopsy to understand alterations representing this poor clinical 
response.  
3.2 End of study 
End of study is defined as the date of the last visit of the last patient. The primary analysis will be performed 
once at least 50 events of disease progression or death have been observed in those randomized, or at the 
end of study which ever occurs first. Patients are anticipated to be followed for a minimum of 6 months for 
PFS. Follow-up for survival will continue for up to 5 years for each patient; patients with progression in Part 
2A will not be followed after the 30 Day Follow Up-Visit.  Patients who progress in Parts 1 and 2B will be 
followed for overall survival, see Section 8.2.3.  Please refer to schedule of events designated in Tables 1 - 3. 
The trial may be prematurely terminated if recommended by the DSMB (refer to section 9.4) 
3.3 Number of patients  
It is expected that 121 patients will be recruited into the trial; 9 in Part 1 and 112 in Part 2 
3.4 Participating Sites 
This will be initiated at M.D. Anderson Cancer Center during Part 1 and then open in Part 2 at the following 
Houston Area Locations (HALs): M.D. Anderson in Sugar Land, Katy, Woodlands, Bay Area, and Woman’s 
Hospital of Texas.  Part 2 will also open in the Cancer Network Partner M.D. Anderson Cooper Hospital, as 
well as two outside institutions, the University of Texas Southwestern Medical Center and the University of 
Oklahoma for Part 2A & 2B.   
3.5 Randomization and stratification 
Eligible patients will be allocated in Part 2B in a randomized fashion (1:1 ratio) to receive paclitaxel plus 
bevacizumab (Arm 1) or paclitaxel plus bevacizumab plus emactuzumab (Arm 2). To ensure the equal 
distribution of prognostic factor in the two study arms, patients will be stratified according to the following 
parameters 
•
Platinum-free interval (TFI) < 3 months vs 3 to 6 months.
Note: PFI is assessed according to the last platinum-based regimen administered (defining the patient as
“platinum-resistant” as per inclusion number 4). PFI is calculated from the date of that last platinum 
treatment to the date of the subsequent disease progression. 
A Patient Enrollment and Identification Code List must be maintained by the investigator.  
All patients must commence treatment within 7 days following randomization; otherwise, the screening 
assessments will need to be repeated. Please note that subject to the availability of study medication at 
site, the first dose of study treatment (Cycle 1 Day 1) may also be the day of randomization. 
 STUDY POPULATION 
4.1 Overview 
The REDIRECT study will enroll adult patients with epithelial ovarian cancer (EOC), fallopian tube 
carcinoma (FTC) or primary peritoneal carcinomas (PPC) who have undergone an appropriate attempt at, or 
completed primary platinum resistant therapy, as deemed by the investigator, for their initial disease.  
Patients will be considered eligible for enrollment in this trial if they fulfil the inclusion criteria and none of the 
exclusion criteria as defined below. 
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4.2 Inclusion criteria 
1.
Signed informed consent obtained prior to initiation of any study-specific procedures and treatment as
confirmation of the patient’s awareness and willingness to comply with the study requirements (inclusive
of 2 biopsies, one at baseline and if they qualify, one pre-randomization for part 2B).
2.
Women 18 years of age or older.
3.
Histologically confirmed and documented disease to include: adenocarcinoma NOS, clear cell
adenocarcinoma, endometrioid adenocarcinoma, malignant Brenner’s tumor, mixed epithelial
carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, transitional cell carcinoma, and
undifferentiated carcinoma.
4.
Patients must have undergone an appropriate attempt at, or completed, primary platinum based therapy,
as deemed by the investigator, for their initial disease. Patient must have recurrent disease documented
by imaging or elevated CA-125 within 6 months of last dose of platinum treatment.
5.
Patients must have disease that is measurable according to RECIST 1.1. If no measureable disease is
present, patients should have assessable disease such as pleural effusion, ascites, with  GCIG CA-125
criteria and require chemotherapy treatment.
Part 1: Patients must have have one or more measurable target lesion or assessable disease such as
pleural effusion, ascites with GCIC CA-125 criteria.Patients with non-measureable disease but evaluable
solid tumors may be deemed eligibile contingent upon PI review.
Part 2: Patients must have two or more measurable target lesions or assessable disease such as pleural 
effusion, ascites with GCIC CA-125 criteria. Patients with non-measureable disease but evaluable solid 
tumors may be deemed eligibile contingent upon PI review. 
a.
Measurable disease is defined as at least one lesion that can be accurately measured in at
least one dimension (longest dimension to be recorded).  Each “target” lesion must be >20
mm when measured by conventional techniques, including palpation, plain x-ray, CT, and
MRI, or >10 mm when measured by spiral CT.
6.
Have a performance status of 0 or 1 on the ECOG Performance Scale.
7.
Newly obtained core or excisional biopsy of a tumor lesion for Part 2A and if they qualify, one pre-
randomization biopsy for part 2B.
8.
Adequate organ function as determined by the following laboratory values:
a.
Absolute neutrophil count ≥1,500 /mcL.
b.
Platelets ≥100,000 / mcL.
c.
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L.
d.
Creatinine Clearance ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
e.
Total Bilirubin ≤ 1.5 X ULN
OR  Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN. 
f.
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
OR ≤ 5 X ULN for subjects with liver metastases. 
g. INR/PT
≤1.5 
X 
ULN 
(unless 
subject 
is 
receiving 
anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended use of anticoagulants). 
h.
PTT ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is
within therapeutic range of intended use of anticoagulants.
9.
Life expectancy of 12 weeks.
4.3 Exclusion criteria 
Cancer-related  
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1.
Patients who have disease progression prior to an appropriate attempt at, or completed primary
platinum based therapy, as deemed by the investigator, for their initial disease, including patients
demonstrating disease progression after interval cytoreduction.
2.
Non-epithelial, including malignant mixed Müllerian tumors.
3.
Ovarian tumors with low malignant potential (i.e. borderline tumors).
4.
For Part 2 patients only: History of other clinically active malignancy within 5 years of enrollment, except
for tumors with a negligible risk for metastasis or death, such as adequately controlled basal-cell
carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix or breast, or early
stage endometrial cancer (stage IA/B, Grade 1 or 2, endometrioid histology).
Prior, current or planned treatment: 
5.
Previous treatment with >2 anticancer chemotherapy regimens for ovarian cancer.
6.
Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to
initiation of study treatment, with the following exceptions:
-
Hormone-replacement therapy or oral contraceptives.
o
Tyrosine kinase inhibitors (TKIs) that have been discontinued > 7 days prior to Cycle 1, Day 1;
screening scans must be obtained after discontinuation of prior TKIs.
7.
Any prior radiotherapy to the pelvis or abdomen.
8.
Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major
surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to study
enrollment, or anticipation of need for major surgical procedure during the course of the study. Minor
surgical procedures including placement of a vascular access device, within 2 days of the first study
treatment.
9.
Previous exposure to murine CA-125 antibody (only applicable to those patients with non-measurable
disease by RECIST).
10. Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment with aspirin
(>325 mg/day).
11. Current or recent treatment with another investigational drug within 30 days of first study treatment
dosing or earlier participation in this study.
12. Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone,
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within 2 weeks prior to
Cycle 1, Day 1. Patients who have received acute and/or low-dose systemic immunosuppressant
medications or anticipation of need for major surgery, a one-time dose of dexamethasone for nausea or
chronic use of ≤ 10 mg/day of prednisone or dose-equivalent corticosteroid) may be enrolled in the study
after discussion with and approval by the IND Office Medical Monitor. The use of inhaled corticosteroids
and mineralocorticoids (e.g., fludrocortisone) is allowed. Prior corticosteroids as anti-cancer therapy
within a minimum of 14 days of first receipt of study drug.
13. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving
prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary
disease) are eligible.
14.
Patients with urine dipstick for proteinuria >2+. Patients with 2+ proteinuria on baseline dipstick
analysis should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein in the 24-hour
urine. Alternatively, proteinuria testing can be performed according to local standards.
Prior or concomitant conditions or procedures: 
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15. Patients with known auto-immune disease.
16. Patients with known history of HIV, HBV and HCV infection.
17. Patient has received an organ transplant.
18. Patient has a history of hematological malignancy within the last 5 years prior to study entry, prior
allogeneic bone marrow transplantation or prior solid organ transplantation.
19. History of or active autoimmune disease including, but not limited to, systemic lupus erythematous,
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome,
multiple sclerosis, and vasculitis or glomerulonephritis. Patients with autoimmune thyroid disease on a
stable thyroid replacement regimen; controlled vitiligo, eczema, psoriasis, or seborrhoic dermatitis with
only dermatologic manifestations; or controlled Type I diabetes on a stable insulin regimen may be
eligible for the study with approval by the Medical Monitor.
20. History or evidence upon physical / neurological examination of CNS disease unrelated to cancer,
unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
21. Symptomatic CNS metastasis.
22. Pre-existing peripheral neuropathy ≥ CTC grade 2 for those patients who received prior paclitaxel.
23. Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed
and treated spinal cord compression without evidence that disease has been clinically stable for ≥ 2
weeks prior to screening.
24. Increased corrected QT (QTc) interval (QTc > 470 ms), patients with baseline resting bradycardia < 45
bpm, or baseline resting tachycardia > 100 bpm.
25. Family history of long QT syndrome or other risk factors for torsades de pointes, and/or the use of
concomitant medications that prolong the QT/QTc interval.
26.
Signs or symptoms of serious active infection requiring oral or i.v. antibiotics within 2 weeks prior to
Cycle 1 Day 1 and/or hospitalization at study entry including, but not limited to, hospitalization for
complications of infection, bacteremia, active tuberculosis or severe pneumonia.
27. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study
treatment start.
28. For women who are not postmenopausal (<12 months of non therapy-induced amenorrhea, with no
identified cause other than menopause) and have not undergone surgical sterilization (removal of
ovaries and/or uterus):  agreement to remain abstinent (refrain from heterosexual intercourse) or use
two adequate non hormonal methods of contraception, including at least one method with a failure rate
of <1% per year, during the treatment period and for at least 4 months after the last dose of study drug.
Examples of non-hormonal contraceptive methods with a failure rate of <1% per year include bilateral
tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of
sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 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.
29. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) /
stroke or transient ischemic attack (TIA) or sub-arachnoid hemorrhage within ≤6 months prior to the first
study treatment.
30. Uncontrolled hypertension (sustained systolic >150 mmHg and/or diastolic >100 mmHg despite
antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including:
o
myocardial infarction or unstable angina within ≤6 months prior to the first study treatment.
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o
New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF).
o
serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or
paroxysmal supraventricular tachycardia).
o
Significant  vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral
arterial thrombosis) within 6 months prior of study enrollment.
o
Prior history of hypertensive crisis or hypertensive encephalopathy.
31. History of bowel obstruction, including sub-occlusive disease, related to the underlying disease and
history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-
sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of
bowel obstruction.
32. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic
anticoagulation).
33. History of hemoptysis ( 1/2 teaspoon of bright red blood per episode) within 1 month of study
enrollment for any tumor type.
34. Non-healing wound, ulcer or bone fracture.
35. Known hypersensitivity to any of the study drugs or excipients.
36. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical
examination or laboratory findings that may interfere with the planned treatment, affect patient
compliance or place the patient at high risk from treatment-related complications.
4.4 Concomitant medication and treatment 
All concomitant medications must be recorded in the eCRF, Prometheus. Throughout the study, investigators 
are permitted to use their clinical judgement when prescribing concomitant medications and treatments 
for trial patients. Local prescribing information and institutional guidelines should be followed as 
applicable. In all cases, concomitant medications and treatments should only be used with the intention 
of either maintaining existing medical conditions, or controlling cancer-related symptoms or treatment-
related complications. Caution should be exercised when using treatments that could potentially interfere 
with any of the study medications or the interpretation of the study results. For specific information, please 
refer to the paclitaxel and bevacizumab product package inserts for prescribing information and the 
emactuzumab Investigator’s Brochure. 
For example, prophylactic pre-medication for prevention of treatment-related side effects like nausea or 
hypersensitivity reactions has to be distinguished from new supportive medication used to maintain 
existing medical conditions (e.g. prophylactic heparin for prior DVT), to control cancer-related symptoms 
(e.g. pain killers) or for treatment-related complications (e.g. platelet transfusion in case of severe 
thrombocytopenia or G-CSF support in case of severe neutropenia). Prophylactic pre-medication does 
not need to be documented whereas supportive medication should be documented within eCRF. 
4.4.1 
Permitted Therapy 
Patients are allowed full supportive care therapies concomitantly during the study. 
No other anti-cancer therapy will be permitted while the patients are receiving study therapy. 
After Cycle 2, palliative radiation is permitted for irradiating small areas of painful metastases that cannot be 
managed adequately by systemic or local analgesics. Before initiation of palliative radiation therapy, a bone 
metastatic work up should be repeated to rule out disease progression. 
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Any disease progression that requires other forms of specific anti-tumor therapy will be cause for early 
discontinuation of study treatment. 
4.4.2 
Prohibited Therapy 
Patients should be treated for all concomitant medical conditions and adverse events according to accepted 
standards of medical care at the discretion of the investigator. The following treatments are not permitted 
during the study: 
•
Any other investigational therapy
•
Cytotoxic chemotherapy agents
•
Radiotherapy (as per inclusion criteria). After Cycle 2, certain forms of radiotherapy may be considered
for pain palliation (e.g., treatment of known bony metastases).
•
Immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine,
methotrexate, and thalidomide. Systemic corticosteroids, TNF-α inhibitors, mycophenolate, and other
immune suppressants may be administered for the treatment of immune-related toxicities at the discretion
of the treating physician after consultation with the Medical Monitor.
•
Other systemic anti-neoplastic agents and targeted therapies
If any anti-neoplastic or investigational therapies listed above are needed, the patient will be considered to 
have evidence of progressive neoplastic disease and have experienced treatment failure with study 
treatment and should be withdrawn from study treatment. 
Patients who experience a mixed response that requires local therapy (e.g., surgery, stereotactic radiosurgery, 
radiotherapy, and/or radiofrequency ablation) for control of three or fewer lesions may still be eligible to 
continue study treatment. Patients who receive local therapy directed at a target lesion will no longer be 
evaluable for radiographic response but will remain evaluable for progression. Such cases must be 
discussed with and approved by the IND Medical Monitor. 
4.5 Criteria for premature withdrawal 
Patients have the right to withdraw from the study at any time for any reason. The investigator also has the 
right to withdraw patients from the study in the event of intercurrent illness, AEs, treatment failure after a 
prescribed procedure, protocol violation, cures, administrative, or other reasons. Should a patient decide 
to withdraw, all efforts will be made to complete and report the observations as thoroughly as possible.  
The investigator should contact the patient or a responsible relative by telephone or through a personal visit 
to establish as completely as possible the reason for the withdrawal. A complete final evaluation at the 
time of the patient’s withdrawal should be made with an explanation of why the patient is withdrawing from 
the study.  If the reason for removal of a patient from the study is an AE, the principal specific event will 
be recorded on the eCRF.  
In case the patient decides to prematurely discontinue study treatment (“refuses treatment”), the patient should 
be asked if they can still be contacted for further information. The outcome of that discussion should be 
documented in both the medical records and in the eCRF. 
4.6 Replacement policy 
An excessive rate of patient withdrawals can render the study uninterpretable; therefore, unnecessary 
withdrawal of patients should be avoided. For additional information, please refer to Section 9.4.  Patients 
who prematurely withdraw from the study will not be replaced. The study sample size has been adjusted 
to accommodate an estimated 15% drop out rate for progressive disease/toxicity. Only patients amenable 
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to continued therapy after induction (8 weeks) in whom disease has neither progressed nor responded 
(RECIST criteria) will be randomized. 
 SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Please refer to Tables 1 - 3 detailing the schedule of assessments for Part 1 and Part 2 of the study. 
5.1 Screening examination and eligibility screening form 
All patients must provide written informed consent before any study-specific assessments or procedures are 
performed.  Patients who fulfil all the inclusion and none of the exclusion criteria will be accepted into the 
study. 
A screening physical examination should be performed within 7 days prior to the first day of treatment. Please 
refer to schedule of events designated in Tables 1 and 2.  
A study entrance note documenting the investigator’s assessment of each screened patient with regard to the 
protocol’s inclusion and exclusion criteria is to be completed by the investigator and placed in the patient’s 
electronic medical record 
A screen failure log will be maintained by the investigator. 
5.2 Procedures for enrollment of eligible patients 
Once a patient has fulfilled the entry criteria, they will be assigned a unique patient identification number when 
enrolled into the study. A patient enrollment list will be maintained by the investigator.  
5.3 Clinical assessments and procedures 
5.3.1 
Tumor response criteria  
Tumor response will be evaluated according to RECIST, CA-125 (http://www.gcig.igcs.org/CA-125.html ) 
and clinical criteria (see Appendix 1).  
In this study, disease progression is defined as per RECIST guidelines on radiological, clinical or symptomatic 
progression. CA-125 elevation alone is not defined as disease progression unless accompanied by clear 
radiological, clinical or symptomatic progression. Patients on treatment who are well but have rising CA-
125 levels should continue protocol treatment until RECIST defined radiological, clinical or 
symptomatic progression of disease. 
5.3.2 
Tumor imaging 
Tumor assessments for response and progression require CT scans of the pelvis and abdomen and (by X-ray 
or preferably by CT-scan) of the chest. MRI scans can be used for patients who are allergic to radiographic 
contrast media. Throughout the study, the same assessment technique must be used. Ultrasound scanning 
is not an acceptable substitute for CT scanning. 
Evaluation of response by RECIST criteria should be performed at baseline then every 8 weeks. A second CT 
scan performed not earlier than 4 weeks after the criteria for response are first met will confirm responses. 
Please refer to schedule of events designated in Tables 1-3.  
5.3.3 
CA-125 
Serum CA-125 will be assessed per standard of care. Please refer to schedule of events designated in Tables 
1-3.  The same laboratory throughout the study period should assess CA-125 and centers are required to
submit the normal ranges for CA-125 for the laboratories they use. CA-125 measurement is not required
following disease progression. Please refer to http://www.gcig.igcs.org/CA-125.html.
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5.3.4 
Scheduling of tumor assessments 
Baseline assessments require CT scans of the pelvis and abdomen and (by X-ray or preferably by CT-scan) 
of the chest.  MRI scans can be used for patients who are allergic to radiographic contrast media. Patients will 
be assessed for disease response or progression throughout the study according to RECISTusing the same 
imaging modality as used during screening. If the patient inadvertently misses a prescribed tumor evaluation 
or a technical error prevents the evaluation, the patient may continue treatment until the next scheduled 
assessment, unless signs of clinical progression are present.  Please refer to schedule of events designated 
in Tables 1-3. 
5.3.5 Physical examination and measurement of vital signs 
Patients will undergo a complete physical examination (including observable tumor measurements), weight 
and measurement of vital signs (blood pressure) per timepoints designated in Tables 1-3.   
5.3.6 Performance status 
PS will be measured using the ECOG performance status scale (see Appendix 2). It is recommended, where 
possible, that a patient’s PS be assessed by the same person throughout the study.  Please refer to schedule 
of events designated in Tables 1-3. 
5.3.7 Clinical safety assessments 
The NCI CTC-AE version 4.03 will be used to evaluate the clinical safety of the treatment in this study. Patients 
will be assessed for AEs at starting at the time of signed informed consent and throughout the study.  Please 
refer to schedule of events designated in Tables 1-3. 
5.4 Laboratory assessments 
Laboratory safety assessments will be performed per the schedules of events designated in Tables 1-3. All 
testing will be conducted locally.  Outside labs will be allowable, however the PI/treating physician must review, 
determine clinical significance, and sign and date these reports.  The total volume of blood taken will be 
approximately 15 ml per visit.  
5.4.1 Efficacy laboratory assessments 
As described in Section 5.3.1.2, CA-125 will be monitored over the course of the study in order to assess 
responses.  
5.4.2 Safety laboratory assessments 
Laboratory tests should be performed as per local standard of care in order to monitor patient safety.  However, 
as a guide, this could include the following assessments:  
•
Hematology (hemoglobin, platelet count, full white blood count, including differential)
•
Biochemistry (sodium, potassium, calcium, blood urea nitrogen (BUN), uric acid, total protein (or albumin
only), alkaline phosphatase, creatinine kinase, AST/SGOT, ALT/SGPT, GGT, LDH, total bilirubin, blood
glucose, creatinine)
•
Coagulation tests (INR and aPTT)
•
Urinalysis by dipstick:  Proteinuria testing can be performed according to local standards.
•
Pregnancy test in women of child-bearing potential: Serum pregnancy test within 7 days prior to the first
study treatment or within 14 days with a confirmatory urine pregnancy test within 7 days prior to the first
study treatment.
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•
ECGs will be performed at baseline and repeated during the study as clinically indicated.
•
Note:  Only AEs grade 2–5 will need to be recorded in the eCRF.
5.5 Pharmacodynamic and Biomarker Assessments 
To fully assess the utility of surrogate biomarkers and the anti-tumor response to therapy with the combination 
treatment of bevacizumab and emactuzumab, we will draw 20 ml blood for plasma markers (VEGF, VEGFR, 
IL6, IL8, FGF, PDGFAA, CSF1, and IL34) and other chemokines identified by secretome proteomics) and 
potential exosomal markers (M2-like markers VEGFR1-3, CD11b +CD68, CD11b+CD14/CD15/CD33, 
CD11b+CD11c, MHCII), prior to initiation of paclitaxel/bevacizumab/emactuzumab and at time points noted in 
Table 4 for the patient safety lead-in (Part 1), and induction and randomized therapy (Part 2A & 2B). All PD 
blood draws are mandatory.  In Part 2A, there will be one mandatory pre-treatment biopsy and one optional 
biopsy at progression. In the Part 2B, we will seek to obtain 2 biopsies, one at pre-treatment tissue biopsy prior 
to initiation of bevacizumab (Part 2A portion) and one pre-randomization tissue biopsy following 4 weeks from 
last dose of bevacizumab (at pre-infusion of emactuzumab), and optionally at progression. These biopsied 
tissues will be used for monitoring dynamic changes in adapted macrophages (with phenotype of M2-like: 
VEGFR1-3+, CD markers (e.g. +CD68, CD163+), CSF1/CSF1R+ and MHCIIlow), and hypoxia markers as well 
as CD4/CD8, NK, and T-reg.   Please refer to schedule of events designated in Tables 1-4. 
In addition to IHC assays, DNA/RNA next generation sequencing may be performed for genotype-protein 
expression. Internal/External Sequencing may be done here at MDACC, in one of the Core labs such as the 
Cancer Genomics Lab, but in some cases samples may be sent to outside collaborators for sequencing and/or 
analysis such as Broad Institute. Any sharing or sequencing of samples performed by Broad or any other 
external collaborator will be conducted under specific contract or Material Transfer Agreement (MTA). We will 
protect participant’s privacy by coding samples and keeping the master list of identifiers accessible to only key 
project staff. Data will be kept on secure computers and samples will be kept in freezers in locked laboratories 
and buildings. Additionally in some other cases, samples may be provided from outside collaborators or 
institutions for discovery and research purposes. In such cases, the samples should be obtained under IRB-
approved protocols at these outside collaborators and institutions to allow them for participation in this protocol 
and under a specific grant/ contract or Material Transfer Agreement (MTA) with MDACC. 
5.5.1 Handling of Specimens 
Biopsies: Biopsies will be obtained directly or by image guided techiniques in study Parts 2A & 2B. A simple 
biopsy will be obtained for each time point when possible. Ideally, 5 pass needle samples will be obtained using 
a 22 gauge or larger needle at the discretion of the interventional radiologist for each time point in order to 
obtain adequate tissue. Ideally a 16 gauge needle will be utilized. A portion of each biopsy sample (4 cores) 
will be snap-frozen immediately, then the remainder of the biopsy sample (1 core) will be collected into a 2mL 
cryotube for further analysis. PD blood & tissue samples will be shipped to M.D. Anderson Cancer Center and 
stored in the laboratory of Dr. Anil Sood. Shipping, collection, and processing instructions are found in Appendix 
E (Lab Manual). 
Blood Plasma: 10 ml of venous blood plasma is collected in a lavender top (EDTA) Vacutainer tube. 
  Blood Serum: 10 ml of venous blood is collected in a red top (serum) Vacutainer tube. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
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5.5.2 
Storage of Specimens 
PD blood and tissue samples will be stored and analyzed in the laboratory of Dr. Anil Sood, M.D. at MD Anderson 
Cancer Center.  
Contacting Dr. Anil Sood’s laboratory for analyses: 
Attn: Anil Sood and Nicholas Jennings 
Department of Gynecologic Oncology and Reproductive Medicine 
1881 East Road 
3SCR3.4640 
Houston, TX 77054 
5.5.3 Labeling of Specimens 
Each specimen will be labeled with a study bank ID number, a specimen code, and the collection date. The 
specimen code will be assigned sequentially and FFPE will be used for the FFPE archived tissue.  Please 
reference Appendix E (Lab Manual) for detailed instructions. 
5.6 
End of Treatment Visit 
An end of treatment evaluation should be performed within 4 weeks of the last dose of study drug for Part 1 
and both arms of Part 2 of the study. Please refer to schedule of events designated in Tables 1-3. 
5.7 
Safety follow-up 
Patients enrolled in the trial will remain on treatment until disease progression, unacceptable toxicities or 
patient request for withdrawal.  
5.7.1 30-Days Safety Follow-Up 
All patients must undergo a 30 Day Safety Follow-Up assessment 30 days +/- 5 days after the last dose of 
therapy.  Please refer to schedule of events designated in Tables 1-3.  
5.8 
Survival follow-up 
Patients with complete response will be followed for up to 5 years; patients with progression in Part 2A will not 
be followed after the 30 Day Follow Up-Visit.  Patients who progress in Parts 1 and 2B will be followed for 
overall survival, see Section 8.2.3.  Please refer to schedule of events designated in Tables 1 - 3. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
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Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
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5.9 
Study exit 
Once the patient has completed all study visits and exited the study, they will be managed by their physician 
in accordance with local standards of care.  
 INVESTIGATIONAL MEDICINAL PRODUCTS 
In this study, emactuzumab is considered to be the ‘investigational study drug’. Paclitaxel and bevacizumab 
are considered to be standard-of-care ‘non-investigational combination drugs’.  Collectively, they will be known 
as the ‘study treatments’.  
6.1 Dose and schedule of study treatments 
This trial consists of 2 Parts:  
Part 1: safety assessment in 9 patients of paclitaxel plus bevacizumab plus emactuzumab. Doses to be 
used in this cohort will mimic the starting doses in Part 2B outlined in the next section. Specifically: 
• 
Paclitaxel 80 mg/m2 as a 1-hour i.v. infusion on days 1, 8, 15 and 22 q4w 
• 
Bevacizumab 10 mg/kg i.v. on days 1 and 15 
• 
Emactuzumab 1000 mg i.v. on days 1 and 15 
 
Emactuzumab infusion should be given first.  
Patients will be evaluated for tolerance of the triplet through 4 weeks of therapy. While a dose modification 
will be provided to account for toxicity, the non-overlapping adverse events seen in the paclitaxel plus 
emactuzumab phase I provide some confidence this triplet will be well tolerated as the doublet of paclitaxel 
plus bevacizumab. Patients in this Part will stay on therapy until progression, intolerable toxicity or confirmed 
RECIST complete response.  
 
Part 2A (see Study Schema, Section 3.1): Induction: all enrollees will receive paclitaxel plus bevacizumab 
for 2 cycles (8 weeks) and undergo evaluation for response (RECIST) 
• 
Paclitaxel 80 mg/m2 as a 1-hour i.v. infusion on days 1, 8, 15 and 22 q4w. 
• 
Bevacizumab 10 mg/kg i.v. on days 1 and 15 
Part 2B (see Study Schema, Section 3.1): Randomized phase II. Patients with stable disease will be 
randomized 1:1 to continued paclitaxel plus bevacizumab (Arm 1) or paclitaxel plus bevacizumab plus 
emactuzumab (Arm 2).  
Arm 1 (Paclitaxel plus bevacizumab): 
Eligible patients will receive:  
• 
Paclitaxel 80 mg/m2 as a 1-hour i.v. infusion on days 1, 8, 15 and 22 q4w. 
• 
Bevacizumab 10 mg/kg i.v. d1,15 
These doses were chosen from the AURELIA trial, which shares identical eligibility to the current trial and is 
the FDA approved doses for this chemotherapy backbone.  
Pre-medication should be implemented according to local practices. For premedication for emactuzumab 
please see section 4.4.1 and 6.6.3 
Upon disease progression patients in Arm 1 will receive:  
• 
Standard of care.      
                   
Arm 2 (Paclitaxel plus bevacizumab plus emactuzumab): 
Eligible patients will receive: 
• 
Arm 1 therapy and schedule will be used plus Emactuzumab 1000 mg i.v. q2w over 90 
minutes  
• 
Emactuzumab dose was chosen from the phase I dose escalation and confirmed in the 
phase I combination trial with paclitaxel. Emactuzumab should be administered before 
bevacizumab and then paclitaxel at the first and all subsequent cycles 
In case chemotherapy is discontinued before diagnosis of progressive disease, patients should continue to 
receive emactuzumab at 1000 mg i.v. q 2 wks and bevacizumab 10 mg/kg i.v. q2w 
After disease progression, patients will receive standard of care treatment. 
Upon clear evidence of disease progression, study therapy should be discontinued permanently. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
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Date:  
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Oncology  REDIRECT v.9 
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6.2 Dose modifications and delays 
 
In general, a dosing delay of up to 3 weeks is allowed in case of grade 3 or greater non-hematologic toxicity 
including laboratory abnormalities or any hematologic toxicity including Grade 4 thrombocytopenia, Grade 3 
thrombocytopenia with bleeding, Grade 4 neutropenia persisting > seven days, febrile neutropenia, or Grade 
4 anemia to reduce toxicity to baseline or grade 0-1. Dose delays greater than 3 weeks will lead to the 
withdrawal of the patient from the treatment.  
  
Patients experiencing asymptomatic elevation of liver enzymes may continue on study however, close 
monitoring of liver function parameters is required. Refer to section 6.3.9.2.2 for management guidelines for 
hepatic events.  Dose levels will be adjusted only for paclitaxel in Section 6.5.1. No dose modifications will 
be made for bevacizumab or emactuzumab, please refer to Sections 6.3.9 and 6.4.3 for dose holding rules. 
No dose re-escalations are planned following dose reduction for toxicity for any of the study treatments. 
6.3 Emactuzumab: Preparation and Administration of  
6.3.1 
Formulation, Packaging and Labeling of Emactuzumab 
Emactuzumab is provided as a sterile, preservative-free liquid, in single dose 10 mL glass vials buffered 
histidine solution (pH 6.0) containing, trehalose dihydrate, polysorbate 20 and water for injection. The 
approximate concentration of emactuzumab in the vials is 25 mg/mL. The study drug must be stored 
according to the details on the product label and in the container provided. Upon arrival of investigational 
products at the site, site personnel should check them for damage and verify proper identity, quantity, and 
temperature conditions, confirm receipt and report any deviations or product complaints upon discovery to 
the monitor. 
6.3.2 
Preparation of Emactuzumab 
The infusion volume is 250 mL. After withdrawal of an appropriate volume based on the patient’s dose level, 
emactuzumab should be further diluted in 0.9% (w/v) sodium chloride solution prior to administration as an iv 
infusion at room temperature (18 °C - 24 °C). Before adding the appropriate volume of emactuzumab to the 
0.9% (w/v) sodium chloride infusion bag the respective volume of 0.9% (w/v) sodium chloride solution is 
withdrawn from the infusion bag and discarded. 
The final emactuzumab drug solution will be administered intravenously using an inline filter (0.2 µm) and 
should be used immediately. If not used immediately, in-use storage times and conditions prior to use are 
the responsibility of the user and should not be longer than 24 hours at 2 to 8°C or 4 hours at ambient 
temperature (180C to 240C). Potential drug products should be inspected visually for particulates prior to 
administration. Partially used vials MUST NOT be re-used. DO NOT SHAKE AND DO NOT FREEZE VIAL 
CONTENTS. 
Chemical and physical in-use stability for emactuzumab dilutions in 0.9% sodium chloride have been 
demonstrated for 24 hours at 2 to 8C and/or at ambient temperature (18 °C - 24 °C).  From a 
microbiological point of view, the product should be used immediately. If not used immediately, in-use 
storage times and conditions prior to use are the responsibilities of the user and would normally not be 
longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic 
conditions.  
Details on the recommended product contact surfaces for inline filter, administration set and infusion bag, as 
well as the tested emactuzumab concentrations and infusion speed are described separately in the 
investigator binder provided to the clinical centers.  
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 48 of 108 
Details regarding preparation of emactuzumab for infusion will be provided in the Drug Procedures Manual, 
which will be provided to sites prior to the start of the study. 
6.3.3 
Premedication 
Specific premedication for emactuzumab infusion is not necessary. No premedication will be allowed for the 
first dose of study treatment. Premedication is required for patients with a prior infusion reaction. 
Premedication may be administered starting at Cycle 2 at the discretion of the treating physician. A 
recommended treatment plan for premedication would be an anti H3, such as famotidine given at 25mg i.v.; 
Benadryl given at 25mg i.v.; and a steroid, such as dexamethasone given at 10mg i.v. or their equivalents. If 
hypersensitivity occurs despite premedication, the patient must be removed from study.  
6.3.4 
Administration of Emactuzumab (Parts 1 and 2B) 
Emactuzumab will be administered as a flat (absolute) dose of 1000 mg as i.v. infusion over 90 mins. All 
patients will receive their assigned dose of emactuzumab. A central line is required prior to treatment. 
During infusion, vital signs (including supine blood pressure, respiratory rate, pulse rate and temperature) 
have to be monitored pre-infusion, every 15 minutes until the end of infusion, and thereafter, every 30 
minutes until the infusion line is removed. After the end of infusion, the i.v. line should remain in place for 2 
hours. If no infusion-related symptoms occur after 2 hours, the infusion line may be removed. For 
subsequent infusions, the i.v. line should remain in place for 1 hour from the end of infusion and if no AEs 
occur after 1 hour, the infusion line may be removed. If an infusion reaction develops, the infusion should be 
temporarily slowed down or interrupted according to section 6.3.9.1. 
For the management of infusion reaction and hypersensitivity reactions, see Section 6.3.9.1. 
6.3.5 
Rate of Infusion of Emactuzumab  
Dose, date and time of the infusion commencement, date and time of end of infusion (EOI), interruption or 
adjustment in infusion rate, Arm, and the reason will be recorded for each patient. If infusion is interrupted, 
the date and time of stopping and resuming infusion will be recorded. 
6.3.6 
Assessment of Compliance 
Accountability and patient compliance will be assessed, by maintaining adequate “drug dispensing” and 
return records. 
Accurate records must be kept for each study drug. These records must contain the following information: 
• 
documentation of drug shipments received from the sponsor (date received and quantity) 
• 
disposition of unused study drug not dispensed to patient 
A Drug Dispensing Log must be kept current and should contain the following information: 
• 
the identification of the patient to whom the study medication was dispensed  
• 
the date(s), quantity of the study medication dispensed to the patient 
This inventory must be available for inspection. Copies of the Emactuzumab dispensing & inventory logs 
must be maintained by each site’s Investigational Pharmacy and made available upon request.  
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 49 of 108 
6.3.7 
Destruction of Emactuzumab 
Local or institutional regulations may require immediate destruction of used investigational product for safety 
reasons e.g., cytotoxicity. In these cases, it may be acceptable for investigational site staff to destroy 
dispensed investigational product before a monitoring inspection provided that source document verification 
is performed on the remaining inventory and reconciled against the documentation of quantity shipped, 
dispensed, returned and destroyed. Written authorization must be obtained from the drug supplier at study 
start up before destruction. 
Written documentation of destruction must contain the following: 
•
Identity (batch numbers or patient numbers) of investigational product(s) destroyed
•
Quantity of investigational product(s) destroyed
•
Date of destruction (date discarded in designated hazardous container for destruction)
•
Method of destruction (the site must provide the sponsor with documentation of their institutional policy
and procedures for handling and disposing of hazardous drugs)
•
Name and signature of responsible person who discarded the investigational product in a hazardous
container for destruction
Per the institutional site’s policy, all empty or partially used containers of investigational agents are to be 
treated as hazardous substances with disposal occurring immediately after use into the chemotherapy 
waste-stream containers.  MDACC Pharmacy will not retain or store used vials of investigational injectable 
or liquid oral medications for accountability purposes.  Medications that expire will be held for 30 days from 
date of expiration for sponsor disposition.  At the end of 30 days, any remaining expired drug will be 
destroyed per the Chemotherapy and Hazardous Substance Waste Stream Disposal Policy.  Please refer to 
MD Anderson Investigational Pharmacy policy.   
6.3.8 
Reconciliation 
MD Anderson agrees to conduct reconciliation for the product. Genentech and MD Anderson will agree to the 
reconciliation periodicity and format, but agree at minimum to exchange quarterly line listings of cases received 
by the other party.  
If discrepancies are identified, the MD Anderson study team and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case basis until 
satisfactory resolution.  The MD Anderson study team shall receive reconciliation guidance documents within 
the ‘Activation Package 
6.3.9 
Dose Modifications and Delays 
Part 1: After the toxicity assessment period has been completed, a delay of Emactuzumab administration for 
up to 3 weeks will be acceptable. Dose reductions are not permitted in the toxicity assessment interval of the 
first cycle.  Infusions/cycles will not be considered as missed but as delayed if a patient does not meet 
parameters for treatment.  In case of a delay of an administration of more than 21 days for any reason, 
additional doses will not be administered and the patient will be withdrawn from all study treatment: 
Paclitaxel, Bevacizumab, and Emactuzumab. After the first cycle toxicity assessment period is complete 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
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Oncology  REDIRECT v.9 
Page 50 of 108 
dose reductions for Emactuzumab will be allowed, refer to Table 7 for hepatic toxicities and Table 8 for 
Dermatological toxicities. 
Patients may continue on treatment for Grade 3 or 4 laboratory parameters that may be elevated due to 
decreased clearance in the liver due to Kupffer cell depletion including CK, LDH and transaminases 
(ALT/AST), if not associated with clinical signs and symptoms (see section 6.3.9.2.2 for details on expected 
asymptomatic decreases in hepatic clearance). Close monitoring of liver function parameters (including 
Total Bilirubin, Creatinine Kinase, LDH, AST, ALT, Alkaline Phosphatase, Albumin, GGT, aPTT/INR) is 
required to ensure that the asymptomatic increases in LFTs due to Emactuzumab are not masking signs of 
true liver damage due to other reasons. If ALT/AST elevation is 3x ULN in combination with elevation in T 
Bili above 2.0x UNL, the patient has reached threshold for Hy’s Law and all treatment will be permanently 
discontinued.  Refer to Table 7 and section 6.3.9.2.2 for management guidelines for hepatic events. 
Initial 
First Dose Reduction 
Second Dose 
Reduction 
Dose Level of 
Emactuzumab 
1000mg 
670mg 
500mg 
Part 2B: If treatment is delayed for any reason infusions/cycles will not be considered as missed but as 
delayed. If all treatment including Emactuzumab is held for more than 21 days due to toxicity patient may 
continue on Taxol and Bevacizumab if criteria for re-starting is met (see Table 7). Patients whose dose is 
missed for reasons other than study drug related toxicity should receive this dose as soon as possible.  
Patients may continue on treatment for any Grade 3 laboratory parameters that may be increased due to 
decreased clearance in the liver, for example, but not limited to, CK, LDH and transaminases (ALT/AST), if 
not associated with clinical signs and symptoms (see section 6.3.9.2.2 for details on expected asymptomatic 
decreases in hepatic clearance). Close monitoring of liver function parameters (including Total Bilirubin, 
Creatinine Kinase, LDH, AST, ALT, Alkaline Phosphatase, Albumin, GGT, aPTT/INR) is required to ensure 
that the asymptomatic increases in LFTs due to Emactuzumab are not masking signs of true liver damage 
due to other reasons. If ALT/AST elevation is 3x ULN in combination with elevation in T Bili above 2.0x UNL 
patient has reached threshold for Hy’s Law and all treatment will be permanently discontinued.  Refer to 
Table 7 and section 6.3.9.2.2 for management guidelines for hepatic events and Emactuzumab dose 
reduction schedule and Table 8 for management of Dermatological toxicities and dose reduction schedule.  
A patient with any > Grade 3 electrolyte, calcium, phosphorus, or magnesium abnormality which does not 
correct to < Grade 1 within 14 days with adequate repletion, must be discussed with the principal 
investigator to determine subject removal. For any other non-Hematological > Grade 3 toxicities not listed 
above, believed to be related to Emactuzumab, the investigator will hold the dose of Emactuzumab until 
toxicity reverts to ≤ grade 1 within a maximum of 21 days at which point the patient will be removed from 
treatment with Emactuzumab and can continue with Paclitaxel and Bevacizumab.   
For any Grade 4 hematological toxicity related to study therapy, study therapy will be held until toxicity 
reverts to ≤ grade 1 within a maximum of 21 days at which point the patient will be removed from treatment 
with Emactuzumab and can continue with Paclitaxel and Bevacizumab.   
6.3.9.1 During the Infusion 
6.3.9.1.1 Infusion-Related Reactions  
Infusion-related reactions may be clinically indistinguishable from allergic/anaphylactic reactions. 
Allergic/anaphylactic reactions have occurred following administration of proteins to patients. Medication 
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Investigational Drug  
Substance(s): 
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
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(including epinephrine for subcutaneous injection, corticosteroids, diphenhydramine for i.v. injection) and 
resuscitation equipment should be available for immediate use. If an infusion-related reaction (allergic 
reaction/hypersensitivity, fever, chills, pain, bronchospasm, wheezing or hypoxia) develops, the infusion 
should be temporarily slowed down or interrupted. Refer to Table 5 for guidance on the management of 
infusion-related reactions. 
Part 1 and Part 2B: In the case of a stop or interruption of Emactumuzab infusion due to adverse events 
(e.g. infusion reaction) the end of infusion will be determined per the guidelines below: 
•
If an infusion related reaction causes an infusion interruption, and Emactuzumab is able to be
restarted and completed, then the time of Emactuzumab completion will be considered the end
of infusion.
•
If an infusion related reaction causes an infusion interruption, and the reaction does not resolve
causing an incomplete treatment, then the time Emactuzumab was interrupted will be
considered the end of infusion.
TABLE 5: MANAGEMENT OF INFUSION RELATED REACTIONS
DURING TREATMENT WITH EMACTUZUMAB 
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Investigational Drug  
Substance(s): 
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Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
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Oncology  REDIRECT v.9 
Page 52 of 108 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but 
is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve 
and the subject should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but 
is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
No subsequent dosing 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
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Oncology  REDIRECT v.9 
Page 53 of 108 
Infusion related guidance: 
If a patient develops a grade 1 infusion reaction, the infusion rate should be slowed down by up to 50%. 
Patient should be monitored closely until complete resolution of the symptoms. Upon resolution of 
symptoms, the infusion rate may be re-escalated to 100% after an observation time of 30 minutes. 
If a patient develops a grade 2 infusion reaction, infusion should be slowed down by 50% or interrupted. 
Patient should be monitored closely until complete resolution of the symptoms and treated as clinically 
indicated. If a patient promptly responds as per the investigator, to medical intervention, the infusion may be 
restarted at 50% of the previous infusion rate and the infusion rate may be re-escalated to 100% after an 
observation time of 30 minutes and in the absence of recurrence of infusion-related symptoms. If the 
infusion cannot be restarted the infusion should be repeated if the patient received  50% of scheduled dose 
and the IRR has resolved completely. In the event that >50% of the dose was received prior to interruption, 
the infusion may be repeated at the investigator’s discretion.  The actual dose received on each occasion 
should be documented in the eCRF. 
If a ≥ Grade 3 infusion reaction occurs during the infusion, the infusion should be stopped immediately and 
not re-started.  The patient should be monitored closely until complete resolution or stabilization of the 
symptoms and receive appropriate treatment as clinically indicated.  The actual dose received on each 
occasion should be documented in the eCRF. 
With the exception of any grade 3 or 4 infusion reaction, patients may resume treatment when the infusion 
reaction resolves.  Hypersensitivity reactions will be considered as treatment limiting toxicities and not dose-
limiting toxicities.  
6.3.9.2 After Infusion 
6.3.9.2.1 Management of Diarrhea 
All subjects who experience diarrhea should be advised to drink liberal quantities of clear fluids.  If sufficient 
oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion.  For Grade 2 or 
higher diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
Patients should receive clear instructions regarding the treatment of diarrhea and the necessity to contact 
the treating physician. To avoid complications of diarrhea such as electrolyte imbalance, dehydration, and 
renal dysfunction, early intervention with loperamide should be started for diarrhea ≥ Grade 1. Patients 
should receive loperamide capsules 4 mg followed by 2 mg with every unformed stool.  The maximum daily 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 54 of 108 
dose of loperamide should not exceed 16 mg. Loperamide can be stopped after the patient is free of 
diarrhea for 12 hours.  Electrolyte repletion and i.v. fluids should be administered on an as needed basis. 
If diarrhea is reported frequently as an adverse event, investigators may also consider premedicating 
patients with loperamide prior to start of emactuzumab infusion. 
 
• 
If a patient in Part I of the trial experiences Grade 3-4 diarrhea for >2 days, despite adequate 
treatment (defined as a SAE), no further doses will be administered and the patient will be observed 
for resolution of toxicity.  
 
See below in table 6, a summary of dose-delay criteria for diarrhea (if occurring despite adequate 
treatment and considered related to the study medication): 
 
TABLE 6: DOSE-DELAY CRITERIA FOR DIARRHEA DURING 
TREATMENT WITH EMACTUZUMAB 
 
Grade 2 
Grade 3 
Grade 4 
 (or SAE) 
1st  
occurrence 
Delay infusion for up to 2 weeks.  
Resolution to ≤ G1: continue at 
same dose. When symptoms 
improve to grade 1 or less, steroid 
taper should be started and 
continued over no less than 4 
weeks.  
If diarrhea persists greater than 3 
days, administer oral 
corticosteroids. 
  
No resolution to ≤ G1: discontinue 
medication 
IV hydration is required.  
Delay infusion for up to 2 weeks. 
Resolution to ≤ G1: continue at 
same dose. When symptoms 
improve to grade 1 or less steroid 
taper should be started and 
continued over no less than 4 weeks. 
 If diarrhea persists greater than 1 
week, treat with intravenous steroids 
followed by high dose oral steroids. 
 
No resolution to ≤ G1: 
discontinue medication 
IV hydration is required.  
 
Discontinue 
medication 
 
2nd  
occurrence 
Delay infusion for up to 2 weeks. 
 Resolution to ≤ G 1 continue at 
same dose. When symptoms 
improve to grade 1 or less, steroid 
taper should be started and 
continued over no less than 4 
weeks. 
 
Delay infusion for up to 2 weeks. 
Resolution to ≤ G1: continue at 
same dose. When symptoms 
improve to grade 1 or less, steroid 
taper should be started and  
continued over no less than 4 weeks. 
 
 
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Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
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Grade 2 
Grade 3 
Grade 4 
 (or SAE) 
If diarrhea persists greater than 3 
days, administer oral 
corticosteroids. 
No resolution to ≤ G1: discontinue 
medication 
If diarrhea persists greater than 1 
week, treat with intravenous steroids 
followed by high dose oral steroids. 
No resolution to ≤ G1: 
discontinue medication 
3rd 
occurrence 
Delay infusion for up to 2 weeks. 
Resolution to ≤ G 1 continue at 
same dose. When symptoms 
improve to grade 1 or less, steroid 
taper should be started and 
continued over no less than 4 
weeks. 
If diarrhea persists greater than 3 
days, administer oral 
corticosteroids. 
No resolution to ≤ G1: discontinue 
medication 
Discontinue medication 
4th 
occurrence 
Discontinue medication 
6.3.9.2.2 
Management Guidelines for Hepatic Events 
Inhibitors of CSF-1R have been associated with depletion of Kupffer cells in the liver. Kupffer cells play an 
important role in the clearance of serum enzymes, including AST, ALT, LDH, and CK. Increased levels of 
AST, ALT, LDH, and CK have been observed in patients treated with emactuzumab. In the majority of 
patients, the increase in AST, ALT, LDH, and CK level was 2- to 3-fold above baseline. Patients who 
experienced an elevation in liver enzymes remained asymptomatic; laboratory work up revealed no 
evidence for damage to the liver.  Therefore, the observed elevation in liver enzyme levels is consistent with 
delayed clearance of liver enzymes secondary to emactuzumab-induced inhibition of Kupffer cells. 
However, in combination with bevacizumab and paclitaxel patients may experience a true liver toxicity which 
could be masked by emactuzumab mediated AST, ALT, LDH, and CK elevations. Eligible patients must 
have adequate liver function, as manifested by measurements of total bilirubin, PT and INR (levels are 
independent of emactuzumab mediated depletion of Kupffer cells) as well as hepatic transaminases, and 
liver function will be monitored throughout study treatment. 
In patients treated with emactuzumab, bilirubin, alkaline phosphatase, and PT/PTT remain within 
normal range; thus, elevations in these liver function parameters should prompt a work-up for 
hepatocyte damage.  Similarly, large increases in CK and LDH are also commensurate with 
emactuzumab-induced Kupffer cell depletion; thus, in the absence of elevations of bilirubin, alkaline 
phosphatase and PT/PTT, elevations in these two parameters do not reflect damage to the liver.  
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Bevacizumab 
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While in this study, patients who present with right upper-quadrant abdominal pain and/or unexplained 
nausea or vomiting should have liver function tests (LFTs to include AST, ALT, LDH, CK, alkaline 
phosphatase, PT, INR, albumin and bilirubin) performed immediately and reviewed before administration of 
the next dose of study drug. 
If LFTs increase, concurrent medications, viral hepatitis, and toxic or neoplastic etiologies should be 
considered and addressed, as appropriate. Imaging of the liver, gall bladder, and biliary tree should be 
performed to rule out neoplastic or other causes for increased LFTs. Anti-nuclear antibody, perinuclear anti-
neutrophil cytoplasmic antibody, anti-liver kidney microsomal antibodies, and anti-smooth muscle antibody 
tests should be performed if an autoimmune etiology is considered. 
Guidelines for the management of liver toxicity during treatment with emactuzumab plus bevacizumb and 
paclitaxel are provided below in Table 7. 
TABLE 7: GUIDELINES ON THE MANAGEMENT AND REPORTING OF ELEVATED LIVER ENZYMES
DURING TREATMENT WITH EMACTUZUMAB 
Toxicity 
NCI CTCAE Grade 
Paclitaxel 
Bevacizumab 
Emactuzumab 
Reporting 
ALT/AST (u/L) 
Grade 1: 
(>ULN – 3.0x ULN) 
Continue study treatment 
No action 
Grade 2:  
(>3.0x – 5.0x ULN) 
Grade 3:   
(>5.0x – 20.0x ULN) 
Hold all treatment; investigate to exclude alternate 
causes of abnormal LFTs. To rule-out autoimmune 
etiology consider Anti-nuclear antibody, 
perinuclear anti-neutrophil cytoplasmic antibody, anti-
LKM, and anti−smooth muscle antibody tests. Repeat 
lab work daily, when investigator has assessed 
alkaline phosphatase, bilirubin and PT/PTT as stable, 
resume treatment at one dose reduction with weekly 
labs.  
If asymptomatic and 
INR, PT, alkaline 
phosphatase, total 
bilirubin within normal 
range: attributed to 
Kupffer cell depletion 
and will not be 
reported as a serious 
adverse event.  
If symptomatic and 
abnormal PT, INR, 
alkaline phosphatase 
and/or bilirubin 
increases hold all 
treatment: expedited 
reporting as serious 
adverse event and 
assess causality. 
DLT in Part 1 if 
unable to restart in 
21 days. 
Grade 4: 
(>20.0x ULN) 
 Hold all treatment; investigate to exclude alternate 
causes of abnormal LFTs. To rule-out autoimmune 
etiology consider Anti-nuclear antibody, 
perinuclear anti-neutrophil cytoplasmic antibody, anti-
LKM, and anti−smooth muscle antibody tests. Repeat 
lab work daily, when investigator has assessed 
alkaline phosphatase, bilirubin and PT/PTT as stable, 
If asymptomatic and 
INR, PT, alkaline 
phosphatase, total 
bilirubin within normal 
range: attributed to 
Kupffer cell depletion 
and will not be 
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Oncology  REDIRECT v.9 
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resume treatment at one dose reduction with weekly 
labs. 
reported as a serious 
adverse event.  
If symptomatic and 
abnormal PT, INR, 
alkaline phosphatase  
and/or bilirubin 
increase hold all 
treatment: expedited 
reporting as adverse 
event. 
 DLT in Part 1 if 
unable to restart in 
21 days. 
Bilirubin (mg/dL) 
Grade 1:  
(ULN – 1.5x ULN) 
Continue study treatment 
No action 
Grade 2: 
(1.5x – 2.0x ULN) 
Above 2.0x ULN 
meets criteria for Hy’s 
Law if Grade 2 or 
higher ALT/AST 
Continue study treatment. Investigator review lab 
work, AST/ALT  
Monitor lab work 
every day until 
assessed as stable 
by investigator.  
Grade 2: (Hy’s Law) 
2.0 – 3.0x ULN 
Grade 3: 
(3.0x – 10.0x ULN) 
Hold treatment. Consult Hepatology. 
Discontinue all 
treatment. Monitor 
liver function tests 
daily until assessed 
as stable by 
investigator. 
Grade 4: 
(>10.0x ULN) 
CK (u/L) (CPK) 
Grade 1: 
(ULN – 2.5x ULN) 
Continue study treatment 
No action 
Grade 2:  
(2.5x – 5.0x ULN) 
Monitor weekly lab 
work. 
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Grade 3: 
(5.0x – 10.0x ULN) 
Continue study treatment with daily alkaline 
phosphatase, bilirubin and PT/PTT until investigator 
assesses as stable, then monitor weekly lab work. 
If asymptomatic and 
INR, PT, alkaline 
phosphatase, total 
bilirubin within normal 
range: attributed to 
Kupffer cell depletion 
and will not be 
reported as a serious 
adverse event.  
If symptomatic and/or 
abnormal PT, INR, 
alkaline phosphatase  
and/or bilirubin 
increases hold all 
treatment: expedited 
reporting as serious 
adverse event and 
assess causality. 
Grade 4: 
(> 10.0x ULN) 
Continue study 
treatment on 
Part 2B with 
daily alkaline 
phosphatase, 
bilirubin and 
PT/PTT until 
investigator 
assesses as 
stable, then 
monitor weekly 
lab work. 
Part 1 hold all 
treatment 
Resume 
Emactuzumab 
at one dose 
reduction when 
levels resolve to 
< grade 2 
Continue study 
treatment on 
Part 2B with 
daily alkaline 
phosphatase, 
bilirubin and 
PT/PTT until 
investigator 
assesses as 
stable, then 
monitor weekly 
lab work.  
Part 1 hold all 
treatment 
Resume 
Emactuzumab 
at one dose 
reduction when 
levels resolve to 
< grade 2 
Hold treatment 
on Part 2B with 
daily alkaline 
phosphatase, 
bilirubin and 
PT/PTT until 
investigator 
assesses as 
stable. Resume 
Emactuzumab 
at one dose 
reduction when 
levels resolve to 
< grade 2 with 
weekly labs.   
On Part 1 hold 
all treatment 
Resume 
Emactuzumab 
at one dose 
reduction when 
levels resolve to 
< grade 2 
If asymptomatic and 
INR, PT, alkaline 
phosphatase, total 
bilirubin within normal 
range: attributed to 
Kupffer cell depletion 
and will not be 
reported as a serious 
adverse event.  
If symptomatic and/ 
or abnormal PT, INR, 
alkaline 
phosphatase, and/or 
bilirubin increase 
hold all treatment: 
expedited reporting 
as adverse event. 
. 
 DLT in Part 1 if 
unable to restart 
within 21 days. 
LDH (u/L) 
Grade 1: 
ULN-2.5x ULN 
Continue study treatment 
No action 
Grade 2: 
2.5xULN-5.0x ULN 
Grade 3: 
5.0xULN-20.0x ULN 
Hold all treatment. Monitor lab alkaline phosphatase, 
bilirubin and PT/PTT  daily until stable, then resume 
Emactuzumab at one dose reduction when levels 
resolve to < grade 2 with weekly labs. 
Investigator to 
assess lab work, 
stable patient will be 
followed with weekly 
lab work and may be 
treated after AST, 
ALT, PT, PTT, 
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alkaline 
phosphatase, total 
bilirubin reviewed by 
investigator 
Grade 4:  
Above 20.0x ULN 
Hold all treatment. Monitor lab alkaline phosphatase, 
bilirubin and PT/PTT daily until stable, then resume 
Emactuzumab at one dose reduction when levels 
resolve to < grade 2 with weekly labs. 
In Part 2B: daily lab 
work until stable, 
then weekly. If stable, 
may restart treatment 
after clearance by 
investigator and 
medical monitor & 
AST, ALT, PT, INR, 
alkaline 
phosphatase, 
bilirubin within normal 
limits. 
DLT in Part 1 in 
unable to restart 21 
days 
Investigations should be conducted to exclude alternate causes of the abnormal LFTs, e.g.. 
progression of underlying disease, infections or other diseases affecting liver function, concomitant 
medication and nutrition.  Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, 
anti-LKM, and anti-smooth muscle antibody tests should be evaluated if an autoimmune etiology is 
considered. 
For patients with documented liver metastasis and elevated LFT results at baseline, further 
elevations of LFT results may not require dose interruptions if there are no progressive changes in 
the ALT and/or AST (less than a doubling) and if there are no progressive elevations in total bilirubin 
or INR. Regular monitoring of LFTs, bilirubin, coagulation parameters will be conducted throughout 
the study. Please refer to the Schedule of Assessments.  
Patients who, upon restarting study treatment after resolution, experience another dose delay due to 
elevations of LFTs with concomitant increase of bilirubin and/or abnormal coagulation parameters 
should permanently discontinue treatment. 
Study treatment should be discontinued for life-threatening immune study related hepatic events. 
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6.3.9.2.3 
Neutrophil Count 
If a patient experiences an Absolute Neutrophil Count (ANC) of  ≤ 1.5 x 109/L prior to any infusion, the 
patient will be observed and the infusion will be delayed for up to 3 weeks until resolution. 
6.3.9.2.4 
Periorbital Edema 
Periorbital edema has been documented in agents that interfere with the CSF-1 pathway.  In the GLP 
toxicology study, treatment-related periorbital swelling was noted in all except two dosed animals. This 
finding persisted through recovery. Histologically, only edema was noted, with no inflammatory infiltrates or 
endothelial alterations. No specific therapy is required for mild periorbital edema in patients receiving 
Emactuzumab, however, cold eye cell eye masks may be used during infusion and at night. In more severe 
cases, a short pulse of diuretics and occasional use of topical treatment with 1% hydrocortisone plus 0.25% 
phenylephrine may be beneficial. Symptomatic patients may be referred to an ophthalmologist for further 
examination. 
6.3.9.2.5 
Dermatologic Toxicity 
Treatment with emactuzumab may cause dermatologic toxicity in some patients. In some patients who 
developed skin rash under treatment with emactuzumab, further workup disclosed a diagnosis of cutaneous 
lupus erythematosus. In an attempt to reduce the risk of dermatologic toxicity, patients may consider the 
following precautions:  
•
Patients should be advised to avoid manipulation of lesions, as this may potentially induce
new skin lesions.
•
Patients should avoid sun exposure and use sunscreens effective against ultraviolet A and
ultraviolet B irradiation. Sufficient amounts of sunscreen with a sun protection factor of at
least 50 should be applied 20−30 minutes prior to expected exposure. Physical sunscreens,
such as titanium dioxide or zinc oxide, provide broad-spectrum protection.
•
Patients should be advised to avoid tanning studios, sunbathing, and outdoor activities. It is
important to consider the risk of vitamin D deficiency in sun-avoiding patients, as sunlight is
required for vitamin D synthesis. 25-Hydroxyvitamin D levels may be monitored and
supplementation with at least 400 IU of vitamin D3, or cholecalciferol may prevent vitamin D
deficiency.
A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should be performed 
unless contraindicated. Low-grade rash and pruritus immune-related adverse events have been treated with 
symptomatic therapy (e.g., antihistamines). 
Guidelines for the management of dermatologic toxicity are provided in Table 8 below. 
TABLE 8: MANAGEMENT GUIDELINES FOR POTENTIAL
DERMATOLOGICAL TOXICITY/ RASH DURING TREATMENT
WITH EMACTUZUMAB 
Toxicity 
Description 
Management 
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Investigational Drug  
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Oncology  REDIRECT v.9 
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6.4 
Bevacizumab 
Bevacizumab will be obtained from the institutional pharmacy through standard mechanisms. 
Formulation/packaging/storage 
Dermatologic 
toxicity/rash 
(e.g. maculopapular or 
purpura) 
Grade 1 mild < 10% BSA 
• Continue all study treatment.
Symptomatic therapy with antihistamine PRN.
• Consider topical steroids and/or other
symptomatic therapy (e.g., antihistamines).
Grade 2 moderate 
10%−30% BSA 
•
After Cycle 1 toxicity assessment period: hold
all study medication until resolved to Grade 1 or
baseline then resume one dose level lower of
Emzactuzumab.
•
Consider dermatologist referral.
•
Administer topical steroids.
•
Consider higher potency topical steroids if
rash unresolved.
Grade 3 severe 
> 30% BSA
•
Hold all study treatment
•
Consult dermatologist.
•
Administer oral prednisone 10 mg or
equivalent.  If rash unresolved after 48−72
hours, administer oral prednisone 60 mg or
equivalent.
•
Restart Bevacizumab and Taxol at previous
dose and reduce one dose level of Emactuzumab
if rash resolved and systemic dose is ≤10mg
oral prednisone equivalent per day.
Grade 4 skin toxicity: 
•
Permanently discontinue emactuzumab for
life-threatening immune-related dermatologic
toxicity.
Continue Paclitaxel and Bevacizumab 
BSA = body surface area; PRN = as needed. 
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Oncology  REDIRECT v.9 
Page 62 of 108 
Per manufacturer’s guidelines. 
Product preparation  
Per manufacturer’s guidelines. 
Dose administration  
Per manufacturer’s guidelines. 
Bevacizumab is manufactured by recombinant DNA technology, using a genetically engineered Chinese 
hamster ovary (CHO) cell line. The protein is purified from the cell culture medium by routine methods of 
column chromatography and filtration. The final product is tested for quality, identity, safety, purity, 
potency, strength, and excipient/chemical composition according to International Conference on 
Harmonisation (ICH) guidelines. The purity of bevacizumab is > 95%. 
Bevacizumab may be supplied in 6-cc (100-mg) and 20-cc (400-mg) glass vials containing 4 mL or 16 
mL of bevacizumab, respectively (all at 25 mg/mL). Vials contain bevacizumab with phosphate, 
trehalose, polysorbate 20, and sterile water for injection (SWFI). Vials contain no preservative and are 
suitable for single use only.  For further details and molecule characterization, see the bevacizumab 
Investigator Brochure. 
6.4.1 
Bevacizumab Administration 
Bevacizumab should be prepared using aseptic technique.  Withdraw the necessary amount of 
bevacizumab and dilute to the required administration volume with 0.9% Sodium Chloride Injection, 
USP.  Administration will be as a continuous IV infusion.  Anaphylaxis precautions should be observed 
during study drug administration.  
The initial dose will be delivered over 9015 minutes.  If the first infusion is tolerated without 
infusion-associated adverse events (fever and/or chills), the second infusion may be delivered over 
6010 minutes.  If the 60-minute infusion is well tolerated, all subsequent infusions may be delivered 
over 3010 minutes.   
If a patient experiences a grade 1 or 2 infusion–associated adverse event, she may be premedicated for 
the next study drug infusion; however, the infusion time may not be decreased for the subsequent 
infusion.  If the next infusion is well tolerated with premedication, the subsequent infusion time may then 
be decreased by 3010 minutes as long as the patient continues to be premedicated.  If a patient 
experiences an infusion-associated adverse event with the 60-minute infusion, all subsequent doses 
should be given over 9015 minutes.  Similarly, if a patient experiences an infusion-associated adverse 
event with the 30-minute infusion, all subsequent doses should be given over 6010 minutes. 
6.4.2 
Bevacizumab Storage 
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 NOT SHAKE. 
Keep vial in the outer carton due to light sensitivity.  
VIALS ARE FOR SINGLE USE ONLY.  Vials used for 1 subject may not be used for any other subject.  
Chemical and physical in-use stability has been demonstrated for 48 hours at 2C–30C in 0.9% Sodium 
Chloride solution.  If not used immediately, in-use storage times and conditions are the responsibility of 
the user and would normally not be longer than 24 hours at 2C–8C, unless dilution has taken place in 
a controlled and validated aseptic conditions. 
Body weight at baseline is to be used to calculate the required dose, and no dose modifications are 
foreseen unless the patient’s body weight changes by ± 10% from baseline. 
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Oncology  REDIRECT v.9 
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A rounding up or down of the dose is acceptable to allow practical ease of administration. Rounding of 
the dose is optional and if the treating physician decides to round the total dose of bevacizumab, it 
should be rounded to the nearest 5 mg. 
The bevacizumab dose (10 mg/kg) should not be reduced or modified due to toxicity. 
6.4.3 
Management of Bevacizumab Toxicities 
In cases of toxicity, please refer to the latest version of the bevacizumab Investigator Brochure for 
guidance.   
As described below, bevacizumab treatment may be either temporarily or permanently suspended in the 
case of hypertension, proteinuria, thrombosis/embolism, hemorrhage, CHF or wound healing 
complications in addition to any other serious bevacizumab-related toxicity (grade 3 or 4). 
Bevacizumab should be temporarily withheld in the event of febrile grade 4 neutropenia and/or grade 4 
thrombocytopenia (regardless of the relationship to treatment), since these conditions are predisposing 
factors for an increased bleeding tendency. In general, appropriate management for grade 3 or 4 
bevacizumab-related events is described in Table 9. Additionally, guidance on the management of 
infusion related reactions is described in Table 5.  
TABLE 9 MANAGEMENT OF GRADE 3 OR 4 BEVACIZUMAB-
RELATED AES 
First occurrence 
Permanently discontinue bevacizumab treatment 
Second occurrence 
In addition, bevacizumab treatment should be permanently discontinued in patients experiencing any of 
the following events: 
•
Reversible Posterior Leucoencephalopathy Syndrome (RPLS).
•
Grade 3/4 hemorrhagic/bleeding events.
•
Grade 4 venous thromboembolism
•
Any grade CNS bleeding
•
Any grade of arterial thromboembolism.
•
Grade 4 hypertension (hypertensive crisis).
•
Grade 4 proteinuria (nephrotic syndrome).
•
Grade 3/4 left ventricular dysfunction (CHF).
•
Any grade of gastrointestinal perforation.
•
Any grade of tracheo-esophageal fistula.
•
Grade 4 non-gastrointestinal fistula.
•
Grade ≥ 2 hemoptysis (hold temporarily or permanently discontinue)
6.4.3.1 
Reversible Posterior Leucoencephalopathy Syndrome
There have been rare reports of patients treated with bevacizumab that develop signs and symptoms
consistent with RPLS, a rare neurological disorder, which can present with following signs and symptoms
among others: seizures, headache, confusion, visual disturbance or cortical blindness, with or without
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associated hypertension. Brain imaging confirms the diagnosis of RPLS. Bevacizumab treatment should 
be discontinued in patients who develop signs/symptoms consistent with RPLS and the specific symptoms 
should be appropriately treated, including control of hypertension. 
6.4.3.2 
CNS Bleeding 
Patients should be monitored for signs and symptoms of CNS bleeding, and bevacizumab treatment 
discontinued in case of intracranial bleeding of any grade. Patients with untreated CNS metastases were 
routinely excluded from clinical trials with bevacizumab, based on imaging procedures or signs and 
symptoms. Therefore, the risk of CNS hemorrhage in such patients has not been prospectively 
evaluated in randomized clinical studies. Patients should be monitored for signs and symptoms of CNS 
bleeding, and bevacizumab treatment discontinued in case of intracranial bleeding of any grade. 
6.4.3.3 
Hypertension 
Patients must be closely monitored on study for the development or worsening of hypertension. Blood 
pressure measurements should occur after the patient has been in a resting position for ≥5 minutes. If 
the initial BP reading is ≥140 mmHg systolic and/or ≥90 mmHg diastolic pressures, the result should be 
verified with a repeat measurement. If hypertension occurs, bevacizumab treatment should be managed 
as described in Table 10. 
TABLE 10. BEVACIZUMAB TREATMENT MANAGEMENT FOR
HYPERTENSION 
NCI CTCAE 
v4.03 grading 
Hypertension pattern 
Treatment action 
Grade 1 
Prehypertension (systolic BP 120-139 
mm Hg or diastolic BP 80-89 mm Hg) 
Give bevacizumab. 
Grade 2 
Stage 1 hypertension (systolic BP 
140-159 mm Hg or diastolic BP 90-99
mm Hg); medical intervention
indicated; recurrent or persistent
(>=24 hrs); symptomatic increase by
>20 mm Hg (diastolic) or to >140/90
mm Hg if previously WNL;
monotherapy indicated
Withhold bevacizumab 
and all treatment. Start 
antihypertensive therapy. 
Once BP is <150/100 
mmHg, patients may 
continue bevacizumab 
therapy. 
Grade 3 
Stage 2 hypertension (systolic BP 
>=160 mm Hg or diastolic BP >=100 
mm Hg); medical intervention 
indicated;  more than one anti-
hypertensive drug or more intensive 
therapy than previously used 
indicated. 
Hold bevacizumab and all 
treatment for persistent or 
symptomatic hypertension 
and discontinue 
permanently if 
hypertension is not 
controlled according to 
Investigator judgment. 
Grade 4 
Life-threatening consequences (e.g. 
malignant hypertension, transient or 
permanent neurological deficit, 
Permanently discontinue 
bevacizumab.  
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hypertensive crisis); urgent 
intervention indicated 
6.4.3.4 
Proteinuria 
Proteinuria will be assessed within 48 hours before each bevacizumab treatment by dipstick method 
unless assessed by 24-hour urine collection. Alternatively, proteinuria testing can be performed 
according to local standards. Proteinuria should be managed according to Table 11 below. 
TABLE 11. BEVACIZUMAB TREATMENT MANAGEMENT FOR
PROTEINURIA
NCI CTCAE 
v4.03 
grading 
Proteinuria Pattern 
Treatment action 
Grade 1 
1+ proteinuria; urinary protein 
<1.0 g/24 hrs 
No bevacizumab dose 
modifications 
Grade 2 
2+ proteinuria; urinary protein 
1.0-3.4 g/24 hrs 
Suspend bevacizumab and all 
treatment for urine protein level ≥ 
2 g/24 hrs and resume when 
proteinuria is < 2 g/24 hours. 
For 2+ dipstick: may administer 
bevacizumab; obtain 24-hour 
protein urine prior to next 
bevacizumab dose. 
For 3+ dipstick: obtain 24-hour 
urine prior to bevacizumab 
administration.  
Grade 3 
Urinary protein >=3.5 g/24 hrs 
Suspend bevacizumab and all 
treatment.  Resume when 
proteinuria is < 2 g/24 hrs, as 
determined by 24-hrs urine 
collection < 2 g. 
Grade 4 
(Nephrotic 
syndrome) 
- 
Permanently discontinue 
bevacizumab. 
If bevacizumab treatment is delayed for more than 2 cycles, continuation of treatment must be 
discussed with the Genentech medical monitor or designee.  
Nephrotic syndrome: Bevacizumab must be permanently discontinued if nephrotic syndrome (grade 4 
per NCI CTCAE v4.03) is detected at any time.  
6.4.3.5 
Dose interruption due to infusion-associated reactions 
If ≤ grade 3 infusion-associated reaction (cytokine release syndrome/acute infusion reaction or allergic 
reaction/hypersensitivity such as fever, rash, urticaria or bronchospasm) occurs, pre-medication should 
be given with the next dose, but the infusion time may not be decreased for the subsequent infusion. If 
the next dose is well-tolerated with pre-medication, the subsequent infusion time may be decreased by 
30 ±10 minutes as long as pre-medication continues to be used. If infusion-related AEs occur with the 
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Oncology  REDIRECT v.9 
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60-minute infusion, all subsequent doses should be given over 90 ±15 minutes (with pre-medication). If
infusion-related AEs occur with the 30-minute infusion, all subsequent doses should be given over 60 ±
10 minutes (with pre-medication). For patients with grade 3 or 4 reactions, the bevacizumab infusion
should be permanently discontinued.
6.4.3.6 
Surgical procedures and wound healing complications 
Bevacizumab therapy should be withheld for an interval of at least four weeks (28 days) before 
conducting elective surgery. In the case of unplanned surgical procedures, bevacizumab should be 
stopped as soon as the indication for surgery is identified. Emergency surgery should be performed as 
appropriate without delay after a careful risk benefit assessment.  
Bevacizumab therapy should be restarted ≥28 days and ≤42 days following major surgery. In patients 
who experience wound healing complications during bevacizumab treatment, bevacizumab should be 
withheld until the wound is fully healed. If the wound is not fully healed within 42 days, bevacizumab 
treatment should be discontinued. 
Continuation of study treatment in patients who have had bevacizumab therapy delayed for more than 2 
treatment cycles due to surgical procedures or wound healing must also be discussed with the 
Genentech medical monitor or his/her designee. 
6.4.3.7 
Thrombosis/embolism 
Arterial thromboembolism: If a patient experiences any grade of arterial thromboembolism during the 
study treatment period, bevacizumab should be discontinued permanently. 
A history of arterial thromboembolic events or age greater than 65 years has been associated with an 
increased risk of arterial thromboembolic events during bevacizumab therapy. Patients receiving 
bevacizumab plus chemotherapy with a history of arterial thromboembolism and age greater than 65 
years have a higher risk. Caution should be taken when treating these patients with bevacizumab.  
Venous thromboembolism:  
Bevacizumab should be held in patients developing a grade 3 thrombosis/embolism. Bevacizumab may 
be resumed once the patient is adequately anti-coagulated and on a stable level of anticoagulation for at 
least 2 weeks prior to restarting study drug treatment. Patients on heparin treatment should have an 
aPTT between 1.5-2.5 x ULN (or patient value before starting heparin treatment). Patients on coumarin 
derivatives should have an INR between 2.0 and 3.0 assessed in two consecutive measurements 1-4 
days apart. Patients on full dose low molecular weight heparins should receive the appropriate dose 
based on the weight of the patient according to package insert. 
An increased risk of venous thromboembolic events and bleeding in patients receiving anti-coagulation 
therapy after first venous thromboembolic event while receiving bevacizumab has been observed. 
In the event of recurrent grade 3 thrombosis/embolism, the patient should be discontinued from 
bevacizumab. 
Bevacizumab should be discontinued in patients with life-threatening (grade 4) pulmonary embolism. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 67 of 108 
6.4.3.8 
Hemorrhage 
An increased incidence of bleeding events was observed in study patients treated with bevacizumab as 
compared to control treatment arms. The hemorrhagic events observed in bevacizumab studies were 
predominantly tumour-associated hemorrhage and minor mucocutaneous hemorrhage.   
If grade 3 or 4 bleeding of any kind occurs during the study treatment period bevacizumab should be 
permanently discontinued. 
If hemorrhagic complications occur in patients on full dose anticoagulation therapy, permanently 
discontinue bevacizumab treatment and follow guidelines of the institution. Standard procedures such as 
antagonization with protamine or vitamin K, infusion of vitamin K dependent factors or insertion of a 
vena cava filter should be considered dependent on the severity of the bleeding and thrombotic events 
and the organ affected. 
Bevacizumab should be temporarily held or permanently discontinued for grade ≥ 2 haemoptysis 
(defined as ≥ 2.5 mL bright red blood per episode). The safety of re-initiating bevacizumab in patients 
previously experiencing grade ≥ 2 haemoptysis has not been evaluated. 
6.4.3.9 
Gastrointestinal Perforation and Fistula 
Bevacizumab has been associated with serious cases of GI perforation in patients with mCRC and a few 
reports of gallbladder perforation have been reported from the post-marketing experience. The 
presentation of these events has varied in type and severity, ranging from free air seen only on the plain 
abdominal X-ray, which resolved without treatment, to a colonic perforation with abdominal abscess and 
fatal outcome. The common feature among these cases was intra abdominal inflammation, either from 
gastric ulcer disease, tumour necrosis, diverticulitis or chemotherapy-associated colitis.  Nevertheless, a 
causal association of an intra-abdominal inflammatory process and GI perforation to treatment with 
bevacizumab has not been established. However, caution should be exercised when treating patients 
with intra-abdominal inflammatory process with bevacizumab. 
Bevacizumab should be permanently discontinued in patients who develop GI perforation. 
Bevacizumab use has been associated with serious cases of fistulae including events resulting in death. 
Fistulae within the GI tract or GI tract and skin are common in patients with mCRC and ovarian cancer, 
but are uncommon or rare in other indications. Other fistulae (e.g. tracheoesophageal, bronchopleural, 
urogenital, biliary) have been reported uncommonly in bevacizumab clinical trials patients and in post-
marketing reports. 
Temporarily discontinue bevacizumab in patients with grade 2 or 3 non- tracheoesophageal fistula until 
resolution to ≤ grade 1.  
Permanently discontinue bevacizumab in patients with tracheoesophageal fistula or any grade 4 fistula. 
Limited information is available on the continued use of bevacizumab in patients with other fistulae. In 
cases of internal fistula not arising in the GI tract, discontinuation of bevacizumab should be considered. 
6.4.3.10 
Congestive Heart Failure 
Events consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic 
declines in left ventricular ejection fraction (LVEF) to symptomatic CHF, requiring treatment or 
hospitalisation. Most of the patients who experienced CHF had metastatic breast cancer and had 
received previous treatment with anthracyclines, prior radiotherapy to the left chest wall or other risk 
factors for CHF were present.  
Caution should be exercised when treating patients with clinically significant cardiovascular disease 
such as pre-existing coronary artery disease, concomitant cardiotoxic therapy or CHF with 
bevacizumab.   
Bevacizumab should be permanently discontinued in patients with ≥ grade 3 CHF. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 68 of 108 
6.4.3.11 
Hypersensitivity/Allergic Reactions and Infusion-Associated Reactions 
Bevacizumab should be permanently discontinued in patients exhibiting hypersensitivity/allergic 
reactions. 
The NCI CTCAE distinguish between hypersensitivity reactions and acute infusion reactions induced by 
cytokine release. Despite the different possible mechanisms underlying hypersensitivity and infusion 
reactions, the clinical signs and symptoms associated with these reactions overlap.  
Patients may be at risk of developing infusion reactions to bevacizumab. Close observation of the 
patient during and following the administration of bevacizumab is recommended as expected for any 
infusion of a therapeutic humanised monoclonal antibody. If an infusion reaction occurs, the infusion 
should be discontinued and appropriate medical therapies should be administered. A systematic 
premedication is not warranted. 
6.4.3.12 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw was reported in patients receiving bevacizumab mainly in combination with 
bisphosphonates in the post-marketing setting.  The pathogenesis of the osteonecrosis is unclear.  For 
further information, please refer to the Avastin® Investigator’ Brochure. 
6.5 
Paclitaxel  
Paclitaxel will be obtained from the institutional pharmacy through standard mechanisms. 
Formulation/packaging/storage 
Per manufacturer’s guidelines.  
Product preparation  
Per manufacturer’s guidelines. 
Dose administration  
Per manufacturer’s guidelines. 
6.5.1 
Dose Modifications 
Up to 2 dose reductions (70mg/m2 and 60mg/m2) are acceptable for paclitaxel. For patients who have 
one dose omitted in one cycle of treatment, the patient may be maintained at 70mg/m2 for 1-hour i.v. 
infusion in subsequent cycles.  If there is a second omission, then the second dose reduction of 60 
mg/m2 for 1-hour i.v. infusion will be allowed.   
6.5.2 
Management of Paclitaxel Toxicities 
6.5.2.1 
Hematological toxicity 
Dose reductions for next course will be performed according to following guidelines for nadir: 
TABLE 12. SUMMARY OF PACLITAXEL DOSE REDUCTIONS 
WBC [109/L] 
ANC1 [109/L] 
Platelets 
[109/L] 
Dose modification 
< 1.0 lasting > 7 
days 
< 0.5 lasting > 5 
days 
< 25 
Decrease 1 dose 
level 
Febrile 
Neutropenia2 
Severe 
bleeding 
Decrease 1 dose 
level 
Febrile 
Neutropenia2 
Severe 
bleeding 
Discontinue 
paclitaxel 
1.
ANC - Absolute Neutrophil Count
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 69 of 108 
2.
Febrile neutropenia: Fever > 38,5°C associated with ANC  < 1.0 x 109/L
Hematological recovery (values at day of scheduled retreatment)
The WBC count must be  3.0 x 109/L or ANC  1.0 x 109/L and the platelet count  80 x 109/L prior to
the beginning of the following course of treatment.  For patients who do not achieve hematological
recovery on scheduled day of the course, complete blood counts should be performed twice weekly until
the above defined limits are achieved.
If hematological recovery is achieved within 14 days after the scheduled day of the course, the full dose
of paclitaxel adjusted for the previous nadir should be administered immediately.
If hematological recovery is not achieved 14 days or more after the scheduled day of the course, the
patient will discontinue treatment.
Administration of G-CSF or EPO is permitted according to approved indications and scientific
recommendations.
6.5.2.2 
Non-hematological toxicity 
6.5.2.2.1 
Mucositis and cutaneous toxicity 
The occurrence of mucositis CTCAE grade > 2 leads to a dose reduction of one level. 
6.5.2.2.2 
Neurological toxicity 
In case of: 
•
CTCAE grade 2: Reduce dose of one level.
•
CTCAE grade 3/4: Withhold paclitaxel treatment and follow patient as per protocol.
6.5.2.2.3 
Hypersensitivity premedication 
Premedication prior to paclitaxel should be administered in accordance with local standard of care in 
order to prevent grade 3 or higher hypersensitivity reactions. An example of premedication is as follows: 
Dexamethasone    20 mg IV 
30 minutes prior to paclitaxel 
Clemastine * 
   2 mg IV 
30 minutes prior to paclitaxel 
Ranitidine * 
   50 mg IV 
30 minutes prior to paclitaxel 
5HT3 Antagonist * Single dose IV 
  30 minutes prior to paclitaxel 
*Alternative compounds of the same classes can be used
Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be 
available. 
Significant hypersensitivity reactions as characterised by dyspnoea and hypotension requiring treatment, 
angioedema, and generalised urticaria have occurred in <1% of patients receiving paclitaxel after 
adequate premedication. These reactions are probably histamine-mediated.  
In the case of grade 3 or higher hypersensitivity reactions, paclitaxel infusion should be discontinued 
immediately, symptomatic therapy should be initiated and the patient should not be rechallenged with 
paclitaxel. 
Thirty-four percent of patients receiving paclitaxel (17% of all courses) experienced minor 
hypersensitivity reactions. These minor reactions, mainly flushing and rash, did not require therapeutic 
intervention nor did they prevent continuation of paclitaxel therapy. 
6.5.2.2.4 
Other Major Organ Toxicity (not evaluated as disease related) 
If the patient has any clinically significant non-hematological drug related toxicity CTCAE grade > 3, the 
treatment course will be delayed until the toxicity is no longer clinically significant or the patient will go off 
protocol treatment according to investigator evaluation. In case of absence of recovery from 
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Investigational Drug  
Substance(s): 
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Bevacizumab 
Study Number: 
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Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 70 of 108 
hematological and non-hematological toxicity for 2 weeks or more (counted from planned day 1 of 
treatment course) the patient will go off protocol treatment and will be followed up as any other patient. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
AEs and laboratory abnormalities 
7.1.1 
Clinical AEs 
In accordance with the International Conference of Harmonization (ICH), an AE is any untoward medical 
occurrence in a patient or clinical investigation patient who receives a pharmaceutical product. The 
event does not necessarily have to have a causal relationship with this treatment to be known as an AE. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. Pre-existing 
conditions which worsen during a study are to be reported as AEs.  The investigator or physician 
designee is responsible for providing source documentation and assigning attribution for all AEs. 
7.1.1.1 
Intensity 
The Intensity of AEs are usually graded according to the NCI Common Toxicity Criteria for Adverse 
Events v 4.03 (CTCAE) on a five-point scale (grade 1–5). In this study, AEs grade 2–5 occurring during 
the study and up to 30 days after the last dose of study medication will need be recorded in the eCRF.   
AEs not listed on the CTCAE should be graded as follows:  
TABLE 13. GRADING OF AES ACCORDING TO NCI CTCAE V 4.03 
CTC 
Grade 
Equivalent To: 
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal 
daily activity. 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily 
activity; no treatment or medical intervention 
is indicated although this could improve the 
overall well-being or symptoms of the patient. 
Grade 3 
Severe 
Inability to work or perform normal daily 
activity; treatment or medical intervention is 
indicated in order to improve the overall well-
being or symptoms; delaying the onset of 
treatment is not putting the survival of the 
patient at direct risk. 
Grade 4 
Life 
threatening/disabling 
An immediate threat to life or an event that 
leads to permanent mental or physical 
conditions that prevents work or the 
performance of normal daily activities; 
treatment or medical intervention is required 
in order to maintain survival. 
Grade 5 
Death 
AE resulting in death. 
7.1.1.2 
Drug – AE relationship 
The causality relationship of the (combination of) study drug to the AE will be assessed by the 
investigator as either: 
Yes or No 
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Investigational Drug  
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 71 of 108 
If there is a reasonable, suspected, causal relationship to the study medication, i.e. there are facts 
(evidence) or arguments to suggest a causal relationship, a drug-event relationship should be assessed 
as Yes. 
The following criteria should be considered in order to assess the relationship as Yes: 
•
Reasonable temporal association with drug administration.
•
It may or may not have been produced by the patient’s clinical state, environmental or toxic factors, or
other modes of therapy administered to the patient.
•
Known response pattern to suspected drug.
•
Disappears or decreases on cessation or reduction in dose.
•
Reappears on rechallenge.
The following criteria should be considered in order to assess the relationship as No: 
•
It does not follow a reasonable temporal sequence from administration of the drug.
•
It may readily have been produced by the patient’s clinical state, environmental or toxic factors, or other
modes of therapy administered to the patient.
•
It does not follow a known pattern of response to the suspected drug.
•
It does not reappear or worsen when the drug is re-administered.
7.1.1.3 
SAEs (immediately reportable to Genentech/Genentech) 
A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution. It 
is any AE that at any dose fulfils at least one of the following criteria: 
•
It is fatal; (results in death; NOTE: death is an outcome, not an event).
•
Life-threatening; (NOTE: the term "Life-threatening" refers to an event in which the patient was at
immediate risk of death at the time of the event; it does not refer to an event which could hypothetically
have caused a death had it been more severe).
•
Required in-patient hospitalization or prolongation of existing hospitalization.
•
Results in persistent or significant disability/incapacity.
•
Is a congenital anomaly/birth defect.
•
Is medically significant or requires intervention to prevent one or other of the outcomes listed above.
The study will comply with all local regulatory requirements and adhere to the full requirements of the 
ICH Guideline for Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, 
Topic E2. 
7.1.1.4 
Progression of underlying malignancy 
Progression of underlying malignancy is not reported as an AE if it is clearly consistent with the 
suspected progression of the underlying cancer as defined by RECIST criteria, or other criteria as 
determined by protocol. Hospitalization due solely to the progression of underlying malignancy should 
NOT be reported as a SAE. Clinical symptoms of progression may be reported as AEs if the symptom 
cannot be determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study. 
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 tumor measurements. Or, the disease 
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 72 of 108 
progression is so evident that the investigator may elect not to perform further disease assessments. In 
such cases, the determination of clinical progression is 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. 
If there is any uncertainty about an AE being due only to the disease under study, it should be reported 
as an AE or SAE. 
7.1.2 
Treatment and follow-up of AEs 
After at least 30 days following the last study drug intake/administration, continue to follow up AEs 
(grades 2–5) every 2 months as follows: 
Related AEs: Follow until one of the following occurs: 
•
Resolved or improved to baseline.
•
Relationship is reassessed as unrelated.
•
Death.
•
Start of new anti-cancer regimen.
•
Investigator confirms that no further improvement can be expected.
•
Clinical or safety data will no longer be collected or final database closure.
Unrelated severe or life threatening AEs: Follow until one of the following occurs: 
•
Resolved or improved to baseline.
•
Severity improved to grade ≤2.
•
Death.
•
Start of new anti-cancer regimen.
•
Investigator confirms that no further improvement can be expected.
•
Clinical or safety data will no longer be collected or final database closure.
Unrelated grade 1 AEs: These events should be managed in accordance with local practice; however, 
they are not recorded in the eCRF. The final outcome of each AE must be recorded on the eCRF.  
7.1.3 
Laboratory test abnormalities 
Laboratory tests should be performed as per local standard of care. Laboratory test results of ≥grade 2, 
or clinically significant results, will be recorded on the Adverse Events pages of the eCRF.  
Any laboratory result abnormality fulfilling the criteria for a SAE should be reported as such, in addition 
to being recorded as an AE in the eCRF.  
Not every laboratory abnormality qualifies as an adverse event. Clinically significant treatment-emergent 
abnormal laboratory results are those meeting one or more of the following conditions: 
•
Accompanied by clinical symptoms.
•
Leading to a change in study medication (e.g. dose modification, interruption or permanent
discontinuation).
•
Requiring a change in concomitant therapy (e.g. addition of, interruption of, discontinuation of, or any other
change in a concomitant medication, therapy or treatment).
•
Clinically significant in the investigator’s judgment
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Investigational Drug  
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 73 of 108 
It is the investigator’s responsibility to review all laboratory findings.  Medical and scientific judgment 
should be exercised in deciding whether an isolated laboratory abnormality should be classified as an 
adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 times the upper limit of normal (ULN) associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result from tests 
performed after the first dose of study medication, which falls outside the laboratory reference range and 
meets the clinical significance criteria. 
This does not apply to any abnormal laboratory result which falls outside the laboratory reference range 
but which does not meet the clinical significance criteria (which will be analysed and reported as 
laboratory abnormalities); those which are considered AEs of the type explicitly exempted by the 
protocol; or those which are a result of an AE which has already been reported. 
7.1.3.1 
Follow-up of abnormal laboratory test values 
In the event of medically significant unexplained abnormal laboratory test values, the tests should be 
repeated and followed until they have returned to the normal range, baseline value and/or an adequate 
explanation of the abnormality is found. If a clear explanation is established it should be recorded on the 
eCRF for all grade 2–5 laboratory AEs. 
7.2 
Handling of safety parameters 
7.2.1 
Reporting of AEs 
The investigator or qualified designee will be responsible for collecting and tracking all new or worsening 
protocol-defined AEs originating from the study in accordance with the schedule of assessments and 
more frequently if clinically indicated.  
The investigator or qualified designee will be responsible for the evaluation of AEs originating from the 
Study for the Products. AEs will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.03. All grade 2–5 related and unrelated AEs occurring during 
the study and up to 30 days after the last dose of study medication will be recorded on the AE page(s) of 
the eCRF and followed until resolution, or until adequate due diligence with regard to obtaining follow-up 
information. After 30-days post-treatment, AEs will not be collected unless they are serious/clinically 
relevant and are considered to be related to the study drug. 
All AEs of unknown etiology associated with emactuzumab exposure should be evaluated to determine 
if it is possibly an event of clinical interest (ECI). 
MD Anderson PI will forward monthly listings of non-serious AEs originating from the study to the 
Genentech contact listed below:  
Genentech Drug Safety at: (650)-225-4682 OR (650)-225-4630. Please use the “Genentech Safety 
Reporting Fax Cover Sheet” provided at the end of the protocol (see Appendix 7). 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 74 of 108 
Emactuzumab Safety at: new_york.ml29802predcontactsd@Genentech.com 
The investigator or qualified designee will ensure that all single case reports have been 
adequately received by Genentech, via the exchange of a de-identified periodic line-listing documenting 
single case reports in the preceding time period (monthly).  
7.2.1.1 
AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product  
The Avastin Events of Special Interest are: 
Hypertension > grade 3 
Proteinuria > grade 3 
GI perforation, abscesses and fistulae (any grade) 
Wound healing complications > grade 3 
Haemorrhage > grade 3 (any grade CNS bleeding; > grade 2 haemoptysis) 
Arterial thromboembolic events (any grade) 
Venous thromboembolic events > grade 3 
PRES (any grade) 
CHF > grade 3 
Non-GI fistula or abscess > grade 2 
7.2.1.1.1 Special Situation Reports 
Special situation reports 
In addition to all AEs, pregnancy reports and AESIs, the following Special Situations Reports should be 
collected and transmitted to Genentech even in the absence of an Adverse Event within thirty (30) 
calendar days: 
•
Data related to the Product usage during pregnancy or breastfeeding
•
Data related to overdose, abuse, off-label use, misuse, inadvertent/erroneous administration,
medication error or occupational exposure, with or without association with an AE/SAE unless
otherwise specified in the protocol
•
Data related to a suspected transmission of an infectious agent via a medicinal
product (STIAMP)
•
Lack of therapeutic efficacy
In addition, reasonable attempts should be made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular population 
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Investigational Drug  
Substance(s): 
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Bevacizumab 
Study Number: 
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Version Number: 
9 
Date: 
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Oncology  REDIRECT v.9 
Page 75 of 108 
7.2.2 
Reporting of SAEs (immediately reportable) 
Any clinical AE or abnormal laboratory test value that is serious or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study that occurs to any 
subject from the time the consent is signed through 30 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to study drug, must be 
reported to Genentech within one working day of the investigator becoming aware of the event 
(expedited reporting). 
Non-serious Events of Clinical Interest will be forwarded by MD Anderson to Genentech and will be handled 
in the same manner as SAEs.  
Additionally, any serious adverse events, considered by an investigator who is a qualified physician to 
be related to Genentech product that is brought to the attention of the investigator at any time outside of 
the time period specified in the previous paragraph also must be reported immediately to Genentech. 
TABLE 14 SAE COLLECTION BEFORE, DURING AND AFTER-STUDY
DRUG DOSING
Related SAEs MUST be collected and reported regardless of the time elapsed from the last study drug 
administration, even if the study has been closed.  
Unrelated SAEs must be collected and reported during the study and for up to 30 days after the last dose of 
study medication. 
The definition and reporting requirements of ICH Guideline for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2 will be adhered to.  Complete information can be found in 
Appendix 3. 
Before Investigational 
Medicinal Product dosing 
Collect all SAEs occurring from the start of study screening 
procedures per the schedule of assessments Table 1. 
During Investigational 
Medicinal Product dosing 
Collect all SAEs occurring during use of the IMP. 
After Investigational 
Medicinal Product dosing 
Collect all SAEs from the last dose of the IMP up to 0 
days, after last IMP dose taken. Collect all SAEs 
considered having a causal relationship to the IMP (as 
considered by the investigator), regardless of time elapsed 
since last IMP dose, even if study has stopped, including 
SAEs related to trial (study) procedures. 
After Investigational 
Medicinal Product dosing, 
when the product is no 
more an Investigational 
Medicinal Product as per 
definition 
SAEs are collected via spontaneous reporting procedures. 
However, if SAEs are received from patients that have 
participated in a clinical trial via the clinical study route in 
error, process the SAEs via the clinical study route as for 
clinical study SAEs. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 76 of 108 
Serious adverse events (SAEs), and AEs of special interest (AESIs), where the patient has been exposed to 
the Products, will be sent on a Genentech Approved Site Specific Safety Reporting Form to the Genentech 
contact listed below. Transmission of these reports (initial and follow-up) will be either electronically or by fax 
and within one working day of the awareness date. 
Genentech 
Genentech Drug Safety at: (650)-225-4682 OR (650)-225-4630. Please use the “Genentech Safety 
Reporting Fax Cover Sheet” provided at the end of the protocol. 
Emactuzumab Safety at: new_york.ml29802predcontactsd@roche.com 
7.2.3 
Reporting to Regulatory Authorities, Ethics Committees, and Investigators 
Additional Reporting Requirements for IND Holders (if applicable): For Investigator-Initiated IND Studies, 
some additional reporting requirements for the FDA apply in accordance with the guidance set forth in 21 
CFR § 600.80. 
Events meeting the following criteria need to be submitted to the Food and Drug Administration (FDA) as 
expedited IND Safety Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is unexpected 
and assessed by the Investigator to be possibly related to the use of emactuzumab.  An unexpected 
adverse event is one that is not already described in the emactuzumab Investigator Brochure. Such 
reports are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning 
of the event. 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written IND Safety 
Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use of 
emactuzumab. An unexpected adverse event is one that is not already described in the emactuzumab 
investigator brochure. 
Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 21 CFR 
§ 312.32. All safety reports previously filed by the investigator with the IND concerning similar events should
be analyzed and the significance of the new report in light of the previous, similar reports commented on.
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Genentech, and all 
participating investigators within 15 calendar days of first learning of the event. The FDA prefers these reports 
on a MedWatch 3500 form, but alternative formats are acceptable (e.g., summary letter). 
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Investigational Drug  
Substance(s): 
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Bevacizumab 
Study Number: 
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Version Number: 
9 
Date: 
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Oncology  REDIRECT v.9 
Page 77 of 108 
M.D. Anderson will be responsible for the distribution of safety information to its own investigators, where
relevant, in accordance with local regulations. Any required development safety update reports for the study
will be handled by M.D. Anderson and submitted to regulatory authorities and ethics committees of the
concerned participating sites, where applicable. The Principal Investigator will provide Genentech with the
safety information provided for any development safety update report as soon as reasonably possible after
completion.
Genentech agrees to forward to M.D. Anderson an executive summary of the Genentech Development 
Safety Update Report (DSUR) upon request from M.D. Anderson. Furthermore, Genentech agrees that M.D. 
Anderson may cross-reference the executive summary of the Genentech DSUR, as applicable.  
Genentech will provide M.D. Anderson with amendments to the Investigator’s Brochure or the applicable 
Reference Safety Information generated for the Emactuzumab product. 
7.2.4 
Pregnancy 
A female patient must be instructed to stop taking the study drug and immediately inform the investigator 
if she becomes pregnant during the study. All participating sites should report all pregnancies within 24 
hours to Genentech. The investigator should counsel the patient, and discuss the risks of continuing with 
the pregnancy and the possible effects on the fetus. Pregnancies occurring up to 30 days after the 
completion of the study drug must also be reported to the investigator. Monitoring of the female patient 
should continue until conclusion of the pregnancy or until adequate due diligence with regard to 
obtaining follow-up information. 
M. D. Anderson will be responsible for collecting, tracking and evaluating pregnancy reports where the
patient has been exposed to the investigational product. Pregnancy reports will be sent on a MDACC
SAE  Reporting Form to the Genentech contact listed below. Transmission of these reports (initial and
follow-up) will be either electronically or by fax and within 24 hours of the awareness date.
Genentech 
Genentech Drug Safety at: (650)-225-4682 OR (650)-225-4630. Please use the “Genentech Safety 
Reporting Fax Cover Sheet” provided at the end of the protocol. 
Emactuzumab Safety at: new_york.ml29802predcontactsd@.roch.com 
7.2.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special warnings or 
precautions were appropriate, other than those noted in the bevacizumab and emactuzumab 
Investigators’ Brochure.  
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Investigational Drug  
Substance(s): 
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 78 of 108 
7.2.6 
Safety Crisis Management 
In case of a safety crisis, e.g. where safety issues have a potential impact on the indication(s), on the 
conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict the way in 
which the investigational agents are used, or where there is media involvement, the participating site 
where the crisis originates will contact M.D. Anderson as soon as possible. M.D. Anderson will confirm 
details regarding safety issues with Genentech as soon as possible. 
M.D. Anderson and Genentech and other participating sites (as appropriate) will discuss and coordinate
any safety crisis issue; the overall principal investigator will have the final say and control over safety
crisis management issues relating to the study with reasonable consideration of Genentech’s comments.
Any queries from media and other sources that are not regulatory authorities relating to the
investigational agent used in the study (except for queries relating to MDACC’s participation in the Study
or a participating site’s participation in the study) shall be discussed between MD Anderson’s
Communications Office and  the Genentech contact listed below before any response is given.
Genentech 
Genentech Drug Safety at: (650)-225-4682 OR (650)-225-4630. Please use the “Genentech Safety 
Reporting Fax Cover Sheet” provided at the end of the protocol. 
Emactuzumab Safety at: new_york.ml29802predcontactsd@Genentech.com 
7.2.7 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-sponsored Multicenter IND Protocols
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
•
Death
•
A life-threatening adverse drug experience – any adverse experience that places the patient, in the
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It
does not include an adverse experience that, had it occurred in a more severe form, might have
caused death.
•
Inpatient hospitalization or prolongation of existing hospitalization
•
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life
functions.
•
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
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Investigational Drug  
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Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 79 of 108
•
Important medical events as defined above, may also be considered serious adverse events.
Any important medical event can and should be reported as an SAE if deemed appropriate by
the Principal Investigator or the IND Sponsor, IND Office.
•
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be
reported to the IRB in accordance with the timeframes and procedures outlined in “University of Texas
M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting
Unanticipated Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, all
SAEs, expected or unexpected, must be reported to the IND Office, regardless of attribution (within 5
working days of knowledge of the event).
Reporting for all sites: 
•
A written report should be submitted to the Institutional Review Board (IRB) according to the
requirements of the assigned IRB for patients enrolled at each site. (The MD Anderson site will utilize
the electronic SAE application (eSAE) for reporting SAEs.)
•
SAEs will be reported to the sponsor on a template form that will be provided to each site.  If
needed, a copy of all relevant examinations that have been carried out and the dates on which
these examinations were performed should be attached. For laboratory results, normal ranges
should be included. Patient name should be marked out and initials and study number included on
all attachments.
•
In case of a serious adverse event, the following actions must be undertaken by the investigator:
(Please note that these are in addition to reporting that is required by the local IRB and supporting
company.) Complete the SAE form immediately and then fax and overnight mail the signed and
dated SAE form to the sponsor representative within two working days to the following address:
The University of Texas M.D. Anderson Cancer Center 
IND Office 
Attention: Dr. Agueda Cohen, Medical Monitor, IND Office 
7007 Bertner, 1MC12.2225 
Houston, Texas  77030 
Tel no.: 713-563-5466  
Fax no.: 713-792-8987     
e-mail:  mdaccsafetyreports@mdanderson.org
A copy of the tracking receipt should be kept and filed in the study regulatory binder at the site. The research 
team may e-mail or call the sponsor to confirm receipt of the SAE fax or mailed form. 
•
Death or life-threatening events that are possibly, probably or definitely related to drug must be
reported within 24 hours.  The sponsor IND safety coordinator must be notified by phone immediately, in
addition to fax or overnight mail as listed above.
•
All life-threatening or fatal events, expected or unexpected, and regardless of attribution to the
study drug, must have a written report submitted within 24 hours (next working day) of knowledge of
the event to the Safety Project Manager in the IND Office.
•
Serious adverse events will be captured from the time of the first protocol-specific
intervention, unless the protocol states otherwise, and be reported until 30 days after the last
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 80 of 108 
dose of drug. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
•
Additionally, any serious adverse events that occur after the 30 day time period that are related
to the study treatment must be reported to the IND Office. This may include the development
of a secondary malignancy.
•
All events reported the supporting company must also be report to the IND Office.
Reporting to FDA: 
•
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND
Office) according to 21 CFR 312.32.
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
7.2.8 
Study Monitoring 
The University of Texas MD Anderson Cancer Center IND Office will monitor the study investigators to 
assure satisfactory enrollment rate, data recording, and protocol adherence. The site principal investigator 
and staff are expected to cooperate and provide all relevant study documentation in detail at each site 
visit on request for review. MD Anderson Cancer Center will monitor and/or audit the other participating 
sites to assure satisfactory protocol adherence and enrollment. The site will be visited on a regular basis 
by the Clinical Study Monitor, who will check completed source documentation, discuss the progress of 
the study and monitor drug according to good clinical practice (GCP). The monitoring will also include 
source data verification (SDV). 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
8.1 
Safety Decision Rule for Lead in: Part 1 
Part 1 participants will be treated with the triplet combination of paclitaxel plus bevacizumab plus 
Emactuzumab. The primary endpoint is safety defined as no required dose alterations during the first 
cycle (4 wks) of therapy due to a Dose Limiting Toxicity (DLT). A dose limiting toxicity for this trial is 
defined as any Grade 4 hematologic toxicity including Grade 4 thrombocytopenia, Grade 3 
thrombocytopenia with bleeding, Grade 4 neutropenia persisting > seven days, febrile neutropenia, or 
Grade 4 anemia. A dose limiting toxicity is also defined as grade 3 or greater non-hematologic toxicity 
including laboratory abnormalities, however, for patients receiving Emactuzumab, any laboratory 
parameters that may be increased due to decreased clearance in the liver, for example, but not limited 
to, CK, LDH and transaminases (ALT/AST; see section 6.3.9.2.2 for details on expected asymptomatic 
decreases in hepatic clearance), if not associated with clinical signs and symptoms, will not be 
considered a dose limiting toxicity and also do not require expedited reporting as SAE’s. See section 
6.3.9 Dose Modifications and Table 7 for further guidance on managing toxicities related to Hepatic lab 
values. Close monitoring of liver function parameters (e.g. bilirubin elevation) is required to ensure that 
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Investigational Drug  
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 81 of 108 
Number of Patients with DLT 
the asymptomatic increases in LFTs due to emactuzumab are not masking signs of true liver damages 
due to other reasons. If Total Bilirubin is elevated to 2.0 xUNL in combination with elevated ALT/AST the 
criteria for Hy’s Law may be met.  Refer to section 6.3.9.2.2 for management guidelines for hepatic 
events. A total of 9 evaluable patients will be enrolled. The following decision rule will be followed: 
  Number of Patients at Current Dose 
0 
3 
P 
6 
P 
9 
A 
1 
S 
P 
A 
2 
U 
U 
A 
3 
  U 
U 
U 
P = proceed to treat additional patients 
S = stay at the current dose – treat 3 more patients 
A = Acceptable to open enrollment beyond patient safety lead-in 
U = the current dose is unacceptably toxic, halt all enrollment 
*Exclude lab abnormalities that don’t meet criteria for AE reporting and observed increases in liver enzymes (e.g., AST, ALT,
CK, LDH) due to known emactuzumab PD effect. LFT increases should count as a DLT only if there is true evidence of toxicities 
(e.g., increase in bilirubin)
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 82 of 108 
§ If 3 DLT’s are observed before 9 patients are enrolled, recruitment will stop and a new cohort of up to 9
additional patients will enrolled at emactuzumab at a dose confirmed after discussion with Genentech on
days 1 and 15 on a 28-day cycle.  If 3 or more DLT’s are observed at this level, a discussion with Genentech,
will be undertaken to consider other dosing/schedule opportunities.
Investigations should be conducted to exclude alternate causes of the abnormal LFTs, e.g.progression of 
underlying disease, infections or other diseases affecting liver function, concomittant medication and 
nutrition.  Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-LKM, and anti-
smooth muscle antibody tests should be evaluated if an autoimmune etiology is considered. 
For patients with documented liver metastasis and elevated LFT results at baseline, further elevations of 
LFT results may not require dose interruptions if there are no progressive changes in the ALT and/or 
AST (less than a doubling) and if there are no progressive elevations in total bilirubin or INR. Regular 
monitoring of LFTs, bilirubin, coagulation parameters will be conducted throughout the study in 
accordance with the schedule of assessments. 
Patients who, upon restarting study treatment after resolution, experience another dose delay due to 
elevations of LFTs with concomitant increase of bilirubin and/or abnormal coagulation parameters should 
permanently discontinue treatment. 
Study treatment should be discontinued for life-threatening immune-related hepatic events. 
8.1.1 
Patient Enrollment to Safety Lead in: Part 1 
To ensure patient safety, the first three patients will be enrolled staggered with one week 
between enrollments of each patient. All three patients must complete one cycle of triplet therapy 
prior to enrollment of any additional patients on Part 1 of the study. If no dose-limiting toxicities 
are observed, the remaining six patients may be enrolled simultaneously. If any dose-limiting 
toxicity occurs in one of the first three patients enrolled, three additional patients will be enrolled 
sequentially (one week apart) and observed for one cycle (four weeks) prior to enrollment of 
additional patients. If any dose-limiting toxicity occurs in two of the first three patients enrolled in 
Part 1, the enrollment on the trial will be suspended pending a revised protocol with a new 
dosing schedule. Additionally, if a dose-limiting toxicity occurs in a second patient, even if 
enrollment of six patients has not been reached, the trial will be placed on hold and will require 
an amended protocol with a new dosing schedule. If three or more of the first nine patients 
experience any of the dose-limiting toxicities, no additional patients will be enrolled and the 
clinical trial will be halted pending a revised protocol with new dose level(s)/schedule and 
updated information regarding all toxicities observed while using the prior dose/schedule. 
8.2 
Statistical Considerations for Part 2 
8.2.1 
Induction Therapy: Part 2A 
The intent of the Part 2A is to produce a sample cohort of patients treated with paclitaxel and 
bevacizumab who achieve stable disease at the first assessment. Estimation of this sample 
was interpreted from the AURELIA trial (n=361), which recruited a cohort of 115 patients 
treated with paclitaxel, 60 of whom were randomized to additionally receive open label 
bevacizumab. The eligibility, dosing and schedule for this regimen are identical to the current 
trial (REDIRECT).  
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 83 of 108 
8.2.1.1 
Estimation of Sample size: Part 2A 
In the paclitaxel/bevacizumab cohort of AURELIA, approximately 15% of patients experienced 
an event of progression or toxicity at or before the first RECIST (v 1.0) evaluation. 
Conservatively, we would raise this estimate to 15% to account for expectations/difficulties 
with travel, etc. Although difficult to estimate, the proportion of patients experiencing objective 
response at 8 weeks was estimated at 25%. In the paclitaxel/bevacizumab cohort of the 
AURELIA trial, objective response was 53% with a median duration of chemotherapy at 6 
cycles (IQR: 4-8 cycles). The time to response by assessment cycle (every 8 weeks) is not 
available or published upon which to make this estimate. However, conservative estimates on 
a sample size at Part 2A in order to produce 80 eligible patients for randomization (Part 2B) is 
112.  
8.2.2 
Randomization Cohort: Part 2B 
The primary efficacy variable will be PFS from the date of randomization, which will occur in 
CORe. A sample size of approximately 80 patients (40 randomized to each treatment arm) 
will yield 83% power with a 2-sided significance level of 0.20 to detect an increase in the 
PFS at 32 weeks post-randomization from 50% to 75% using a log-rank test.  This 
calculation is based on nQuery Advisor. We choose the significance level of 0.2 because the 
objective of this phase II is proof of concept, rather than confirmative. 
8.2.2.1 
Estimation of Treatment Effect: Part 2B 
In the AURELIA trial (paclitaxel/bevacizumab arm), using a landmark analysis from week 8, 
the proportion of all patients being progression-free at a subsequent 32 weeks was 
approximately 61%. This analysis considers all patients not progressing at week 8, including 
those with early response. In the current trial, we will only be randomizing those patients in 
whom stable disease is the best response at week 8. Since this is unknown from the prior 
AURELIA publications, we are conservatively estimating that the PFS at 32 weeks post 
randomization will be 50% for the control arm (paclitaxel/bevacizumab). Our goal is to 
evaluate an effect size of increasing this PFS from 50% to 75%. We assume that we will 
accrue all 80 patients in 100 weeks. The maximum study duration is expected to be 127 
weeks, and we expect to observe a maximum of 50 PFS events (i.e., progressive disease or 
death). 
8.2.2.2 
Statistical Analyses: Part 2B 
We will use descriptive statistics to summarize the demographic and clinical characteristics 
of patients in the 2 treatment arms. We will estimate PFS from randomization with the 
product-limit estimator of Kaplan and Meier for each treatment arm, and we will use the 
stratified log-rank test to compare the 2 treatment arms with respect to PFS. We will use 
stratified Cox proportional hazards regression to model PFS as a function of treatment arm 
and estimate the hazard ratio with a 95% confidence interval. We will similarly analyze 
overall survival. We will tabulate tumor response by treatment arm, and we will estimate the 
rate of response (CR, PR, and CR+PR) with 95% confidence intervals. We will tabulate 
adverse events by grade and relationship to study drug for each treatment arm.  
8.2.2.2.1 
Interim Analysis: Part 2B 
We will use the methods of Lan and DeMets to perform an interim analysis for futility and for 
efficacy once we have observed 25 patients with a PFS event.  We control the overall type I 
error rate of 0.2 and power of 80%. We choose to use this relative large type I error rate 
because this is a phase II proof-of-concept trial. We assume that the PFS at 32 weeks post-
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
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Version Number: 
9 
Date: 
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Oncology  REDIRECT v.9 
Page 84 of 108 
randomization is 50% and 75% for control and experimental arms, respectively. The accrual 
rate is 80 patients in 100 weeks.  The interim analysis for efficacy will employ an O’Brien-
Fleming stopping boundary with a nominal significance level of 0.04. The interim stopping 
boundary for futility is a nominal significance level of 0.8678. The nominal significance level 
for the final analysis will be 0.188.  
For Part 2A and Part 2B, the toxicity will be monitored based on the following Bayesian rule: 
stop enrolling patients if the Pr(DLT > 25% | data) > 0.9. That is, we will stop enrolling patients 
if the data indicate that there is more than 90% chance that the true DLT rate is higher than 
25%. This decision rule gives the following stopping rule, assuming a Beta(0.1, 0.4) prior 
distribution for DLT rate,  
Stop enrolling pts if [# of pts with DLT] / [# of pts evaluated] ≥ 3/5, 5/10, 8/20, 11/30, 
and 14/40. 
In Part 2A, the first 40 patients will be monitored using the above rule. We do not provide a 
formal stopping rule after 40 patients because by that time there are enough data to confirm 
the safety of the drug. After the 40 patients, the safety procedure described in Section 7 will 
be used to monitor AE. In Part2B, the two treatment arms will be monitored independently 
using the above stopping rule. The following table shows the operating characteristics of the 
safety stopping rule: 
TABLE 15: OPERATING CHARACTERISTICS OF
SAFETY STOPPING RULE 
True DLT rate 
0.1 
0.2 
0.3 
0.4 
0.5 
Stopping 
probability 
0.008 
0.098 
0.401 
0.789 
0.967 
Average sample 
size 
39.7 
37.1 
29.7 
19.3 
11.9 
8.2.3 
Secondary efficacy variables 
The secondary efficacy variables are objective response rate, overall survival and 
safety/tolerability. 
Progression-free Survival (PFS): PFS is defined as the time from the date of 
randomization to the first documented disease progression or death, whichever occurs first. 
Progression will be based on tumor assessment made by the investigators according to the 
RECIST criteria (for patients with measurable disease), and as per Appendix 1 (for those 
with non-measurable disease). Patients who had not experienced an event at the data cut-
off date or patients who are withdrawn from the study without documented progression will 
be censored at the date of the last tumor assessment when the patient was known to be 
progression free. Patients without post baseline tumor assessments but known to be alive 
will be censored at the time of the first study drug administration. The median PFS with 95% 
confidence interval and quartiles will be reported as well as Kaplan-Meier curves. 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
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Objective response rate: ORR is determined as the rate of patients with an observed tumor 
response. ORR will be evaluated for three types of responders: 
1.
Patients who have a response as defined per RECIST and as defined using the 50%
response criteria for CA-125 (“responders”)
2.
Patients who have a response as defined per RECIST but no response as defined using
the 50% response criteria for CA-125 (“RECIST responders”)
3.
Patients who do not have a response as defined per RECIST but who do have a
response as defined using the 50% response criteria for CA-125 (“CA-125 responders”)
A detailed explanation regarding responder criteria is given in Appendix 1. Patients with no
tumor assessment after the start of study treatment are to be considered as non-responders.
The point estimate per treatment arm and the 95% Pearson-Clopper confidence interval for
the objective response rates will be provided. Logistic regression analyses will be performed
to assess the influence of baseline covariates in an exploratory manner. More details will be
defined in the statistical analysis plan.
Biological progression-free interval: PFIbio is defined on the basis of a progressive serial 
elevation of serum CA-125 at the time from the date of randomization to first documented 
increase in CA-125 levels to: 
1.
two times the ULN (for patients with normal pre-treatment CA-125 or elevated pre-
treatment CA-125 and initial normalization on-treatment) or
2.
two times the nadir value (for patients with elevated baseline CA-125 that did not
normalize on-treatment).
In patients with radiologically measurable disease according to RECIST61, progression
during protocol treatment cannot be declared on the basis of CA-125 alone.
Overall survival: This is defined as the time from the date of Part 1 commencement or date 
of randomization (Part 2B) for up to 5 years. Patients who were alive at the time of the 
analysis will be censored at the date of their last follow-up assessment. Patients without 
follow-up assessment will be censored at the day of their last dose and patients with no post 
baseline information will be censored at the time of their first study drug administration.  
The survival distribution will be summarized by Kaplan-Meier method. Medians of the overall 
survival as well as the associated 95% confidence intervals and quartiles will be provided per 
treatment arm. Kaplan-Meier curves will be used to graphically describe the observed 
distribution. 
All tests will be performed at a two-sided 5% alpha level. No adjustments for multiplicity will 
be made during the analysis of secondary variables. 
8.2.3.1 
Analyses of Biomarkers: Part 2B 
To fully assess the utility of surrogate biomarkers and the anti-tumor response to therapy with 
the combination treatment of bevacizumab and emactuzumab, we will draw 20 ml blood for 
plasma markers (VEGF, VEGFR, IL6, IL8, FGF, PDGFAA, CSF1, and IL34) and other 
chemokines identified by secretome proteomics) and potential exosomal markers (M2-like 
markers VEGFR1-3, CD11b +CD68, CD11b+CD14/CD15/CD33, CD11b+CD11c, MHCII), 
prior to initiation of paclitaxel/bevacizumab/emactuzumab and after pre-infusion every 4 weeks 
for the patient safety lead-in (Part 1), and randomized therapy (Part 2B). All PD blood draws 
are mandatory.  In Part 2A, there will be one mandatory pre-treatment biopsy, and one optional 
biopsy at progression. In the Part 2B, we will seek to obtain 2 biopsies, one at pre-treatment 
tissue biopsy prior to initiation of bevacizumab (Part 2A portion) and one pre-randomization 
tissue biopsy following 4 weeks from last dose of bevacizumab (at preinfusion of 
emactuzumab), and optionally at progression. These biopsied tissues will be used for 
monitoring dynamic changes in adapted macrophages (with phenotype of M2-like: VEGFR1-
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Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
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3+, CD markers (e.g. +CD68, CD163+), CSF1/CSF1R+ and MHCIIlow), and hypoxia markers 
as well as CD4/CD8, NK, and T-reg.  Please refer to schedule of events designated in Tables 
1-4.
8.2.4 
Safety variables 
General physical examination, measurement of vital signs, laboratory safety assessments 
(as per local standard of care) and recording of AEs/SAEs will be completed at each study 
visit. 
Clinical safety assessments will also include medical history, prior treatments for cancer and 
ECOG performance status. 
Clinical and laboratory adverse events will be reported and graded according to NCI-CTCAE 
version 4.03. Safety of the treatment in both arms will be evaluated by the frequency of 
adverse events, laboratory tests, vital signs, and ECOG performance status during the study. 
8.2.5 
Analysis populations 
The following population definitions will be used to analyze selected endpoints according 
using the appropriate subpopulation of the enrolled patients. If the need arises, additional 
subpopulations can be defined in the statistical analysis plan. 
8.2.5.1 
Safety analysis population 
The Safety Population comprises all study patients who received at least one dose of any 
study medication. The safety population will be used for the analysis of all safety parameters. 
Patients are assigned to the treatment groups based on what they actually received. 
8.2.5.2 
Efficacy analysis population(s) 
All patients who were randomized to one of the two treatment arms will be included in the 
Intent-to-treat (ITT) population and presented according to the therapy they were 
randomized to receive. 
The Per Protocol (PP) population is defined as the subset of ITT population who have 
received at least one study treatment cycle and had no major violation of the protocol 
inclusion and exclusion criteria. 
All efficacy analyses will be based on the ITT population. The primary and secondary 
efficacy analyses will be repeated using the PP population to confirm the overall study 
results.  
8.2.6 
Safety data analysis 
All safety parameters will be summarized and presented in tables based on the safety 
population described in section 8.2.5.1. 
All adverse events and abnormal laboratory variables will be assessed according to the 
CTCAE v4.03 grading system. However, only Grade 2-5 events will be captured in the eCRF 
and clinical database. Grade 2-5 adverse events and separately, serious adverse events, will 
be presented in frequency tables (overall, by intensity and by relationship to study treatment) 
by body system and preferred term, using a current MedDRA dictionary. The number of 
patients with any grade 2-5 adverse events and the number of patients with an adverse 
event of special interest will be presented together with 95% Pearson-Clopper confidence 
intervals. In addition, the number of events (grade 2-5 adverse events, serious adverse 
events, and adverse events of special interest) per patient year under treatment will be 
calculated and descriptively presented. 
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Study Number: 
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Version Number: 
9 
Date: 
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Oncology  REDIRECT v.9 
Page 87 of 108 
Selected events of particular interest (e.g. GI perforation) will be presented in summary 
tables. The time to first onset of the event and the total number of episodes will be 
presented. Every occurrence of an event in any patient will be counted in the total number of 
episodes but successive reports of an identical event in the same Phase (treatment, follow-
up) will be combined (concatenated) into one episode if the end date of the earlier event was 
the same as the start date of the later event, or if the end date of the earlier event was 
missing. 
Descriptive statistics will be used to summarize ECOG performance status. Vital signs, 
electrocardiograms, and neurological examinations will be reported in tables or listings, as 
appropriate. 
Treatment exposure will be summarized as the number of cycles received by each patient, 
the time from first to last treatment, and as the percentage of the planned dose of each agent 
given at each cycle. 
8.2.6.1 
Toxicity and Efficacy Reporting to MDACC IND Office 
The Investigator is responsible for completing toxicity and efficacy summary reports, and 
submitting them to the IND Office Medical Affairs and Safety Group, for review.  These should be 
submitted as follows:  
•
Part 1:
A Toxicity Summary report, after the first 3 evaluable subjects, complete cycle 1 of triplet
therapy, and every 3 evaluable subjects thereafter, prior to changing dose levels or
advancing to Part 2A.
•
Part 2A:
A Toxicity/Efficacy Summary report, after the first 5 evaluable subjects, complete cycle 1
of study treatment, and every 10 subjects thereafter, until the 40th evaluable patient. On
every summary submission, prior subjects’ reported best response will need to be
updated.
•
Part 2B:
An Efficacy/Toxicity summary report, after the first 5 evaluable subjects per arm, complete cycle 1 
of study treatment, and every 10 subjects thereafter, until enrollment is complete. On every report 
submission, prior subjects’ best response will need to be updated. 
DATA QUALITY ASSURANCE 
9.1 
Data collection  
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies. 
All data will be entered into the Prometheus Software Platform. Prometheus is a secure 
portal that requires users to login with validated credentials, has granular data access 
controls to ensure that the minimal amount of information required to complete a task is 
presented, handles the de-linking and de-identification of patient information to maintain 
patient confidentiality. Prometheus provides a multi-institute 21 CFR 11 compliant data 
capture portal to simplify these tasks. Standard data collection, storage procedures, and 
quality assurance procedures will be followed to ensure integrity and auditability of all 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 88 of 108 
information entered.  Accurate and reliable data collection will be assured by verification and 
cross–checking of the eCRFs against the investigator’s records by the study monitor (source 
document verification), and the maintenance of a drug–dispensing log by the investigator. 
Oversight of the MD Anderson Cancer Network sites will be handled through the Clinical 
Research Support Center utilizing the M.D. Anderson institutional SOPs that are in place. 
Monitoring of all sites will be handled by the M.D. Anderson IND office. 
9.2 
Data management 
A comprehensive validation check program utilizing front-end checks in the eCRF and back-
end checks in the Prometheus database will verify the data and discrepancies will be 
generated accordingly. These are transferred electronically to the eCRF at the site for 
resolution by the investigator.  
 
Queries related to the study at M.D Anderson will be answered by M.D Anderson. Queries 
directed to a participating site’s participation in the study will be coordinated with MD 
Anderson and answered by the participating site, this includes all safety queries from 
regulatory authorities or for publications. M.D Anderson and Genentech agree that MD 
Anderson shall have the final say and control over safety queries relating to the study at M.D 
Anderson (or the participating site, as applicable).  
 
 MD Anderson and Genentech and any participating site, as applicable, will use reasonable 
efforts to ensure that deadlines for responses to urgent requests for information or review of 
data are met. MD Anderson and Genentech and any participating site, as applicable will 
clearly indicate on the request the reason for urgency and the date by which a response is 
required; provided, however, that no such coordination effort will impair MD Anderson’s (or 
the participating site, as applicable) ability to timely respond to such query. 
 
MD Anderson Cancer Center will forward a copy of the Final Study Report and the Final IND 
Annual Report to Genentech upon completion of the Study.  
 
9.3 
Study Close Out 
MD Anderson Cancer Center will forward a copy of the Final Study Report and the Final IND 
Annual Report to Genentech upon completion of the Study.  
Additionally, any literature articles that are a result of the study should be sent to Genentech. 
Copies of such reports should be mailed to the assigned Clinical Operations contact for the 
study, see section 16.6. 
 
9.4 
Assignment of preferred terms 
For classification purposes, preferred terms will be assigned by the sponsor to the original 
terms entered on the eCRF, using the current version of MedDRA (medical dictionary for 
regulatory activities) for AEs and diseases and the INN (international non-proprietary name) 
drug terms and procedures dictionary for treatments and surgical and medical procedures.  
9.5 
Study committees  
A Data Safety Monitoring Board (DSMB) at M.D. Anderson reviews the protocol annually or if 
necessary at other times determined by the chair. The DSMB Chair or a designated member 
will notify the study team with a follow up memo following each DSMB committee review.  
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Investigational Drug  
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Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 89 of 108 
The DSMB will be responsible for independently evaluating the safety of the patients 
participating in the trial. Specifically, the DSMB will review and evaluate the safety data 
emerging from each cohort. If the DSMB has safety concerns regarding one of the treatment 
cohorts, the DSMB may recommend to close recruitment into that cohort. The 
implementation of such recommendation will disallow the data from the final primary 
analysis, however, these data will still be analyzed and reported in descriptive terms. 
ETHICAL ASPECTS 
10.1 
Local regulations/Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformance with the principles 
of the “Declaration of Helsinki” or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual.  The study 
must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” ICH 
Tripartite Guideline (January 1997) or with local law if it affords greater protection to the 
patient.  
10.2 
Informed consent 
It is the responsibility of the investigator, or a person designated by the investigator (if 
acceptable by local regulations), to obtain written informed consent from each patient 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. Patients who cannot make an unbiased decision 
or patients who are institutionalized due to regulatory or judicial order are not allowed to 
participate. For patients not qualified or incapable of giving legal consent, written consent must 
be obtained from the legally acceptable representative. In the case where both the patient and 
his/her legally acceptable representative are unable to read, an impartial witness should be 
present during the entire informed consent discussion. After the patient and representative 
have orally consented to participation in the trial, the witness’ signature on the form will attest 
that the information in the consent form was accurately explained and understood. The 
investigator or designee must also explain that the patients are completely free to refuse to 
enter the study or to withdraw from it at any time, for any reason. The eCRFs for this study 
contain a section for documenting informed patient consent, and this must be completed 
appropriately. If new safety information results in significant changes in the risk/benefit 
assessment, the consent form should be reviewed and updated if necessary. All patients 
[including those already being treated] should be informed of the new information, given a 
copy of the revised form and give their consent to continue in the study. 
In a life-threatening situation where a patient is unconscious or otherwise unable to 
communicate, the emergency is such that there is not enough time to obtain consent from the 
patient's legally acceptable representative, and there is no other or better treatment available, 
it is permissible to treat the patient under protocol with consent of the investigator, with 
appropriate documentation that the IRB had approved the procedures used to enroll patients 
in such situations.  In addition, the patient or his/her legally acceptable representative should 
be informed about the trial as soon as possible and consent to continue, giving written consent 
as described above. 
10.3 
Independent Ethics Committees 
This protocol and any accompanying material provided to the patient (such as patient 
information sheets or descriptions of the study used to obtain informed consent) as well as 
any advertising or compensation given to the patient, will be submitted by the investigator to 
the IRB.  
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Investigational Drug  
Substance(s): 
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Version Number: 
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Date:  
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Oncology  REDIRECT v.9 
Page 90 of 108 
Approval from the committee must be obtained before starting the study, and should be 
documented in a letter to the investigator specifying the date on which the committee met and 
granted the approval. 
Any modifications made to the protocol after receipt of the IRB approval must also be 
submitted by the investigator to the Committee in accordance with local procedures and 
regulatory requirements. 
 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between an 
appropriate representative of the sponsor and the investigator representative(s).  Protocol 
modifications must be prepared by a representative of the sponsor and initially reviewed and 
approved by the PI and Biostatistician. 
All protocol modifications must be submitted to the appropriate IRB for information and 
approval in accordance with local requirements, and to Regulatory Agencies if required. 
Approval must be awaited before any changes can be implemented, except for changes 
necessary to eliminate an immediate hazard to trial patients, or when the change(s) involves 
only logistical or administrative aspects of the trial (e.g. change in monitor(s), change of 
telephone number(s). 
 
CONDITIONS FOR TERMINATING THE STUDY 
Both Genentech and M.D. Anderson reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange the procedures on an individual study basis 
after review and consultation.  In terminating the study, Genentech and the 
Sponsor/investigator will ensure that adequate consideration is given to the protection of the 
patient’s interests. 
 
STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING 
13.1 
Investigator's files / retention of documents 
The Investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 
will be classified into two different separate categories [1] Investigator's Study File, and [2] 
patient clinical source documents. 
The investigator's study file will contain the protocol/amendments, independent ethics 
committee and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms and other appropriate documents, 
correspondence etc.  
The Investigator will keep the Study File and patient clinical source documents (including 
MRI/CT scans) on file for at least 15 years after completion or discontinuation of the study. 
After that period of time the documents may be destroyed, subject to local regulations.  
Should the Investigator wish to assign the study records to another party or move them to 
another location, Genentech must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site for 
any or all of the documents, special arrangements must be made between the Investigator 
and Genentech to store these in a sealed container(s) outside of the site so that they can be 
returned sealed to the Investigator in case of a regulatory audit. Where source documents are 
required for the continued care of the patient, appropriate copies should be made for storing 
outside of the site. 
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Investigational Drug  
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Study Number: 
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Version Number: 
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Oncology  REDIRECT v.9 
Page 91 of 108 
13.2 
Source documents and background data 
Patient clinical source documents shall include patient hospital/clinic records, physician's and 
nurse's notes, appointment book, original laboratory reports, ECG, CT/MRI, X-ray, pathology 
and special assessment reports, signed informed consent forms, consultant letters, and 
patient screening and enrollment logs. In no case is the eCRF to be considered as source data 
for this trial. 
The investigator shall supply Genentech, on request, any required background data from the 
study documentation or clinic records. In case of special problems and/or governmental 
queries or requests for audit inspections, it is also necessary to have access to the complete 
study records, provided that patient confidentiality is protected. 
13.3 
Audits and inspections 
The investigator should understand that source documents for this trial should be made 
available to health authority inspectors after appropriate notification.  
13.4 
Case Report Forms 
For each patient enrolled, an eCRF will be completed and signed by the principal investigator 
or authorized delegate from the study staff. For those patients who fail screening, only an ESF 
Form will be completed. If a patient withdraws from the study, the reason must be noted on 
the eCRF. If a patient is withdrawn from the study because of a treatment-limiting AE, thorough 
efforts should be made to clearly document the outcome. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported in the eCRFs and in all required reports. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
The investigator must ensure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On eCRFs or other documents submitted 
to the sponsor, patients should not be identified by their names, but by an identification code. 
The investigator should keep a patient enrollment log showing codes, names and addresses. 
The investigator should maintain documents not for submission to Genentech, e.g., patients’ 
written consent forms, in strict confidence, at the site. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Genentech prior to 
submission. 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 accord with standard editorial and ethical practice, Genentech will 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. 
Any formal publication of the study in which input of Genentech personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the 
appropriate Genentech personnel. Authorship will be determined by mutual agreement. 
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Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 92 of 108 
 
APPENDICES 
16.1 
Appendix 1 Evaluation of Residual Disease, Evaluation of and Definitions of Response 
and Progression 
 
16.1.1 
Tumor Imaging and Assessment of Disease (RECIST v1.1) 
Physical examination 
• Lesions detected by physical examination will only be considered measurable if superficial, 
e.g., skin nodules and palpable lymph nodes. Documentation by color photography including 
ruler is recommended for estimating the size of skin lesions. 
CT scan with contrast of the chest, abdomen, and pelvis 
• CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm. 
MRI scans 
• MRI of the abdomen and pelvis is acceptable for measurement of lesions provided that the 
same anatomical plane is used for serial assessments. If possible, the same imaging device 
should be used for serial evaluations. In case of MRI, measurements will be preferably 
performed in the axial (transverse) plane on contrast-enhanced T1-weighted images. 
However, there are no specific sequence recommendations. 
16.1.2 
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows: 
• Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of:  
• 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm).  
• 10 mm caliper measurement by clinical exam (when superficial).  
• Malignant lymph nodes are considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  
• Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable 
include the following: leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
• Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 
lesions per organ) representative of all involved organs should be identified as target 
lesions. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  
• Non-target Lesions - It is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).    
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Investigational Drug  
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Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 93 of 108 
16.1.3 
Response Criteria 
16.1.3.1 
Evaluation of Target Lesions 
•
Complete Response - Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may
not be “0” if there are target nodes).
•
Partial Response - At least a 30% decrease in the sum of the diameters of target lesions,
taking as reference the baseline sum diameters.
•
Progressive Disease - At least a 20% increase in the sum of diameters of target lesions,
taking as reference the smallest sum on study (this includes the baseline sum if that is the
smallest on study). In addition to the relative increase of 20%, the sum must also
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or
more new lesions is also considered progression.)
•
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, taking as reference the smallest sum of diameters while on study.
16.1.3.2 
Evaluation of Non-target Lesions 
•
Complete Response - Disappearance of all non-target lesions and normalization of
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short
axis).
•
Non-complete response/Non-progressive disease - Persistence of 1 or more non-target
lesion(s) and/or maintenance of tumor marker level above the normal limits.
•
Progressive Disease - Unequivocal progression of existing non-target lesions will be
defined as the overall level of substantial worsening in non-target disease such that,
even in presence of SD or PR in target disease, the overall tumor burden has increased
sufficiently to merit discontinuation of therapy. In the absence of measurable disease,
change in non-measurable disease comparable in magnitude to the increase that would
be required to declare PD for measurable disease. Examples include an increase in a
pleural effusion from ‘trace’ to ‘large,’ an increase in lymphangitic disease from localized
to widespread.
16.1.3.3 
Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. 
Considering the unique response kinetics that have been observed with immunotherapy, 
new lesions may not represent true disease progression. In the absence of rapid clinical 
deterioration, subjects may continue to receive emactuzumab if investigators consider that 
subjects continue to benefit from treatment. 
16.1.3.4 
Evaluation of Overall Response with Modifications 
Confirmation of CR, PR, as well as PD is required by a repeat, consecutive assessment no 
less than 4 weeks from the date of first documentation. Treatment with emactuzumab will 
continue between the initial assessment of PD and confirmation for PD. 
Tables 16 and 17 provide overall responses for all possible combinations of tumor responses 
in target and non-target lesions with or without the appearance of new lesions. 
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Investigational Drug  
Substance(s): 
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Bevacizumab 
Study Number: 
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
Page 94 of 108 
TABLE 16. EVALUATION OF OVERALL RESPONSE 
Target Lesions 
Non-target Lesions 
New 
Lesions 
Overall 
Response 
Complete 
response 
Complete response (or no non- 
target lesion) 
No 
Complete 
response 
No target lesion 
at baseline
Complete response 
No 
Complete 
response 
Complete 
response 
Not evaluable 
No 
Partial 
response 
Complete 
response 
Non-complete response / non-
progressive disease 
No 
Partial 
response 
Partial response 
Non-progressive disease and not 
evaluable (or no non-target lesion) 
No 
Partial 
response 
Stable disease 
Non-progressive disease and not 
evaluable (or no non-target lesion) 
No 
Stable disease 
TABLE 17. EVALUATION OF OVERALL RESPONSE 
Target Lesions 
Non-target 
Lesions 
New Lesions 
Overall Response 
Not all 
evaluated 
Non-progressive 
disease 
No 
Not evaluable 
No target lesion 
Not all evaluated 
No 
Not evaluable 
No target lesion 
Non-complete 
response / non-
progressive 
disease 
No 
Non-complete response / 
non-progressive disease 
Progressive 
disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive 
disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesion 
Unequivocal 
progressive 
disease 
Yes/No 
Progressive disease 
No target lesion 
Any 
Yes 
Progressive disease 
16.1.3.5 
MRI Scans 
Specific lesions must be evaluated serially, and comparative analysis of changes in the area 
of contrast enhancement, as well as the nonenhancing component, should be performed. 
The product of the maximal cross-sectional enhancing diameters will be used to determine 
the size of the contrast-enhancing lesions. 
Minimum sequences required: 
•
Pre-contrast T1, T2/ fluid attenuated inversion recovery (FLAIR)
•
Post-contrast T1, with two orthogonal planes (or a volume acquisition) recommended
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Investigational Drug  
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
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•
Recommended slice thickness ≤ 5 mm with no gap
16.1.4 
CA-125 responses 
Guidelines for using CA-125 response have been developed. Please refer to 
http://www.gcig.igcs.org/CA-125.html. Patients should have a pre-treatment CA-125 of at 
least twice the ULN in order to be considered for CA-125 response. Patients are not 
evaluable by CA 125 if they have received mouse antibodies or if there has been medical 
and/or surgical interference with their peritoneum or pleura during the previous 28 days. In 
those patients, a CA-125 response would be obtained the moment the CA-125 is reduced by 
50% and this should be confirmed with a consecutive CA-125 assessment not earlier than 
28 days after the previous one, with however the date of the first 50% reduction to be the 
reference date for the CA-125 response.  
16.1.4.1 
PROGRESSION OR RECURRENCE BASED ON SERUM CA-125 LEVELS 
Biological Progression Free Interval (PFIBIO) will be defined on the basis of a progressive serial 
elevation of serum CA-125 according to the following criteria: 
In patients with radiologically measurable disease, progression during protocol treatment 
cannot be declared on the basis of CA-125 alone.  
Patients with elevated CA-125 pre-treatment and normalization of CA-125 must show 
evidence of CA-125 greater than or equal to two times the upper normal limit on two occasions 
at least one week apart or  
Patients with elevated CA-125 pre-treatment, which never normalizes must show evidence of 
CA-125 greater than or equal to two times the nadir value on two occasions at least one week 
apart or 
Patients with CA-125 in the normal range pre-treatment must show evidence of CA 125 greater 
than or equal to two times the upper normal limit on two occasions at least one week apart. 
Elevated values must be confirmed by two separate measurements obtained at least one week 
apart. PFIBIO will be assigned the date of the first measurement that meets the criteria as noted. 
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Investigational Drug  
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Version Number: 
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Oncology  REDIRECT v.9 
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16.2 
Appendix 2 - ECOG Performance Status Scale 
-
Description
-
Scal
e
-
Normal activity
-
0
-
Symptomatic but ambulatory self-care
-
1
-
Ambulatory more than 50% of the time
-
2
-
Ambulatory 50% or less of time, nursing care needed
-
3
-
Bedridden, may need hospitalization
-
4
-
Death
-
5
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Investigational Drug  
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Oncology  REDIRECT v.9 
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16.3 
Appendix 3 – ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
a.
Diagnosis vs. Signs and Symptoms
If known at the time of reporting, a diagnosis should be reported rather than individual signs
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be
medically characterized as a single diagnosis or syndrome at the time of reporting, it is
acceptable to report the information that is currently available. If a diagnosis is subsequently
established, it should be reported as follow-up information.
b.
Deaths
All deaths that occur during the protocol-specified AE reporting period, regardless of
attribution, will be reported to the appropriate parties. When recording a death, the event or
condition that caused or contributed to the fatal outcome should be reported as the single
medical concept. If the cause of death is unknown and cannot be ascertained at the time of
reporting, report “Unexplained Death”.
c.
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study. Such
conditions should be reported as medical and surgical history. A preexisting medical
condition should be re-assessed throughout the trial and reported as an AE or SAE only if
the frequency, severity, or character of the condition worsens during the study. When
reporting such events, it is important to convey the concept that the preexisting condition has
changed by including applicable descriptors (e.g., “more frequent headaches”).
d.
Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization should be documented and
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure
as a result of an AE, the event responsible for the procedure, not the procedure itself, should
be reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass
surgery, record the heart condition that necessitated the bypass as the SAE.
Hospitalizations for the following reasons do not require reporting: 
•
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures
for preexisting conditions
•
Hospitalization or prolonged hospitalization required to allow efficacy measurement for
the study or
•
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease
of the study.
A SAE is any experience that suggests a significant hazard, contraindication, side effect or 
precaution. An SAE is any AE that at any dose fulfils at least one of the following criteria: 
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•
is fatal; (results in death) [NOTE: death is an outcome, not an event]
•
is life-threatening  [NOTE: the term "life-threatening" refers to an event in which the patient
was at immediate risk of death at the time of the event; it does not refer to an event which
could hypothetically have caused a death had it been more severe]
•
required in-patient hospitalization or prolongation of existing hospitalization
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect
•
is medically significant or requires intervention to prevent one or other of the outcomes
listed above.
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
to the sponsor is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the outcomes listed in the definitions 
above. These situations should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the applicable 
product information. 
Causality is initially assessed by the investigator. For SAEs, possible causes of the event are 
indicated by selecting one or more options (check all that apply). 
•
Pre-existing/Underlying disease - specify
•
Study treatment – specify the drug(s) related to the event
•
Other treatment (concomitant or previous) – specify
•
Protocol-related procedure
•
Other (e.g. accident, new or intercurrent illness) - specify
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For 
example, nausea of several hours' duration may be rated as severe, but may not be clinically 
serious. 
A SAE occurring during the study or within 15 days after stopping the treatment, or during the 
protocol-defined follow-up period must be reported.  In addition, a SAE that occurs after this 
time, if considered related to the study drug should also be reported. 
Such preliminary reports will be followed by detailed descriptions which will include copies of 
hospital case reports, autopsy reports and other documents when requested and applicable. 
For SAEs, the following must be assessed and recorded on the AEs page of the CRF: intensity, 
relationship to test substance, action taken, and outcome to date. 
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Investigational Drug  
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Version Number: 
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Date: 
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Oncology  REDIRECT v.9 
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The investigator must notify the Ethics Review Committee/Institutional Review Board of a SAE 
in writing as soon as is practical and in accordance with international and local laws and 
regulations. 
GENENTECH LOCAL COUNTRY CONTACT for SAEs: Local Monitor  
GENENTECH HEADQUARTERS CONTACT for SAEs: Clinical Operations/Clinical Science 
16.3.1 
MD Anderson Cancer Center SAE Reporting Guidelines 
MDACC SAE form Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description of the MDACC SAE form: 
• Protocol description (and number, if assigned)
• Description of event, severity, treatment, and outcome if known
• Supportive laboratory results and diagnostics
• Investigator’s assessment of the relationship of the adverse event to each
investigational product and suspect medication
Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MDACC SAEreport and submitting it as follow-up
• Adding supplemental summary information and submitting it as follow-up with the
original MDACC SAEform
• Summarizing new information and faxing it with a cover letter including patient
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if
assigned, brief adverse event description, and notation that additional or follow-up
information is being submitted (The patient identifiers are important so that the new
information is added to the correct initial report)
Occasionally Genentech may contact the reporter for additional information, clarification, 
or current status of the patient for whom an adverse event was reported. For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative 
noted above or the MSL assigned to the study. Relevant follow-up information should be 
submitted to Genentech Drug Safety as soon as it becomes available and/or upon request. 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 100 of 108 
16.4 
Appendix 4: NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased. 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 101 of 108 
16.5 
Appendix 5: PROCEDURE FOR OBTAINING A URINE PROTEIN: 
Procedure for Obtaining a Urine Protein / Creatinine Ratio 
1) Obtain at least 4 ml of a random urine sample (does not have to be a 24 hour urine)
2) Determine protein concentration (mg/dL)
3) Determine creatinine concentration (mg/dL)
4) Divide #2 by #3 above:
 urine protein / creatinine ratio = protein concentration (mg /dL) 
/ creatinine concentration (mg /dL) 
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs (i.e. a 
UPC of 1 should be equivalent to 1g protein in a 24hr urine collection) 
Protein and creatinine concentrations should be available on standard reports of urinalyses, 
not dipsticks. If protein and creatinine concentrations are not routinely reported at an 
Institution, their measurements and reports may need to be requested. 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 102 of 108 
 
 
 
 
16.6 
Appendix 6- Genentech Contacts 
GENENTECH CONTACTS 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel,  
Bevacizumab 
Study Number: 
2015-0647 
 
Version Number: 
9 
Date:  
18 July 2020 
 
Oncology  REDIRECT v.9 
Page 103 of 108 
Activity 
Person Responsible 
Clinical Operations Contact 
Dianne Tuccillo 
Clinical Study Manager 
P: 781-859-5413  
E: tuccillo.dianne@gene.com 
General Queries/Aggregate 
Reports  
To:  
Drug Safety Contact Line Mailbox: 
contact_line.drug_safety@roche.com 
Tel: + 41 61 68 78841  
Single Case Management 
Single Case Reports To Genentech:  
Central Operations Mailbox: welwyn.pds-pc@roche.com 
Fax (Clinical): +44 1707 377 967/ 373 779/ 373 793/ 390 959 
Fax (Spontaneous): +44 1707 390 904 
 
Queries on Single Case Reports/Reconciliation: 
Regional Center Europe (RCE) mailbox: 
welwyn.contact_line_rce@roche.com 
 
CC: Avastin 
Katherine Y.  Look M.D. 
Senior Medical Director - Avastin Medical Affairs/GYN 
Genentech BioOncology 
P: 650-225-7832 
E: look.katherine@gene.com 
 
CC: Emactuzumab 
Dominik Rüttinger, M.D., Ph.D. 
Translational Medicine Leader - Genentech Pharmaceutical Research 
and Early Development (pRED) Innovation Center Penzberg 
P: +49 8856 60 19705 
E: new_york.ml29802predcontactsd@Genentech.com  
Safety Crisis Management 
Final Study Report 
SDEA 
Avastin 
Katherine Y.  Look M.D. 
Senior Medical Director - Avastin Medical Affairs/GYN 
Genentech BioOncology 
P: 650-225-7832 
E: look.katherine@gene.com 
 
Emactuzumab 
Dominik Rüttinger, M.D., Ph.D. 
Translational Medicine Leader - Genentech Pharmaceutical Research 
and Early Development (pRED) Innovation Center Penzberg 
P: +49 8856 60 19705 
E: new_york.ml29802predcontactsd@Genentech.com  
IB updates for Emactuzumab 
 
 
 
 
 
 
 
Emactuzumab 
Dominik Rüttinger, M.D., Ph.D. 
Translational Medicine Leader - Genentech Pharmaceutical Research 
and Early Development (pRED) Innovation Center Penzberg 
P: +49 8856 60 19705 
E: new_york.ml29802predcontactsd@Genentech.com  
 
 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 104 of 108 
16.7 
Appendix 7- Safety Reporting Fax Cover Sheet 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-4630 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
Initial Report Date 
[INSERT investigational product name] / [INSERT 
investigational product name] / [INSERT 
investigational product name] 
Follow-up Report Date 
[INSERT investigational product name] / [INSERT 
investigational product name] / [INSERT 
investigational product name] 
Subject Initials 
(Enter a dash if patient has no middle 
name) 
[INSERT investigational product name] - [INSERT 
investigational product name] - [INSERT 
investigational product name] 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 105 of 108 
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Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 106 of 108 
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Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 107 of 108 
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Proprietary of MD Anderson Cancer Center

Investigational Drug  
Substance(s): 
Emactuzumab, Paclitaxel, 
Bevacizumab 
Study Number: 
2015-0647 
Version Number: 
9 
Date: 
18 July 2020 
Oncology  REDIRECT v.9 
Page 108 of 108 
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