Assessing REsponse to Neoadjuvant Taxotere and Trastuzumab in Nigerian Women With HER2-positive Breast Cancer (ARETTA)
Phase: PHASE2
Conditions: Breast Cancer, Breast Cancer Female, HER2-positive Breast Cancer, Breast Cancer Stage II, Breast Cancer Stage III
Sponsor: University of Chicago

 
 
 
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Protocol No. CABC123D4567 
 
Assessing REsponse to neoadjuvant Taxotere and TrAstuzumab in Nigerian women with 
HER2-positive breast cancer (ARETTA) 
 
Document type 
 
Oncology Synopsis 
EUDRACT number  
Not applicable 
Study phase 
 
 
II 
Document status 
 
Final 
Release date  
 
January 30, 2019 (new protocol) 
Revisions 
 
 
 
 
 
 
 
 
University of Chicago IRB# IRB18-1178  
NCT03879577 
 
 
 
 
 
 
 
 
 

 
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Protocol No. CABC123D4567 
 
SPONSOR:  
 
University of Chicago  Center for Global Health  (UC CGH) 
 
 
Participating Centers: 
University College Hospital, Ibadan, Nigeria (UCH Ibadan) 
Lagos University Teaching Hospital (LUTH) Idi-Araba Lagos 
Lagos State University Teaching Hospital, Ikeja, Lagos State, Nigeria (LASUTH Lagos) 
Obafemi Awolowo University Teaching Hospitals Complex, Ile Ife, Nigeria (OAUTHC Ile Ife) 
University of Chicago Medical Center, Chicago, IL, USA (UCMC Chicago) 
 
Principal Investigator: 
Prof. Olufunmilayo I. Olopade, MD 
University of Chicago Medical Center, 
5841 S. Maryland Avenue, MC2115 
Tel: (01) (773) 702-1632 
Fax: (773) 702-0963 folopade@medicine.bsd.uchicago.edu 
 
Study Co-PI (UCH Ibadan) 
Dr Atara Ntekim MBBCh, MRes, FWACS, FMCR 
Department of Radiation Oncology, College of Medicine, 
University College Hospital, Ibadan, Nigeria 
Tel +2348023059292 
tarantekim@yahoo.com 
 
Study Co-PI (LASUTH Lagos) 
Dr. Abiodun O. Popoola, MBBS, FWACS 
Department of Radiology (Oncology Unit) 
Lagos State University College of Medicine 
Ikeja, Lagos State, Nigeria 
Tel: 234-8033021434 
Email: pabiodun@yahoo.com 
 
Study Co-PI (OAUTH Ile Ife) 
Dr Olukayode. A. Arowolo MBBS, FWACS, FICS 
Department of Surgery, 
Obafemi Awolowo University Teaching Hospital (OAUTH) 
Ile Ife Nigeria 
Tel:+2348037171477 
Email:   arowolodoctor1@yahoo.com 
 
Study Co-PI (LUTH) 
Dr Anthonia Sowunmi MBBS, FMCR, FWACS 
Department of Radiotherapy, Lagos University Teaching Hospital (LUTH) 
Idiaraba Lagos 
Tel +2348037216723 
Email: toniaso@yahoo.com 
 
 
 
 
 
 

 
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Protocol No. CABC123D4567 
 
Co-Investigators:  
 
Christopher Sola Olopade MD, PhD 
Professor, Director of International Programs,                         
University of Chicago 
5841 S Maryland Avenue MC 6076, Chicago, IL 60637 
Tel: +1 (773) 702-6479  
Email: solopade@bsd.uchicago.edu 
 
 
Theodore Karrison, PhD 
Research Professor 
                               
 
 
Director of Biostatistics Laboratory                              
 
 
Department of Public Health Sciences                            
 
 
University of Chicago, 5841 S. Maryland Ave.  
 
 
MC 2000, R314 
Chicago, Illinois 60637 
 
 
                           
 
 
Tel: 1+(733) 702-9326 
 
 
 
                  
Email: karr@uchicago.edu 
 
Abiola Ibraheem, MD 
Research Associate, Center for Global Health 
The University of Chicago 
5841 S Maryland Avenue MC 2115, Chicago, IL 60637 
Tel: +1 (773) 834-9014  
Email: aibraheem@medicine.bsd.uchicago.edu 
 
Staff:  
 
 
Toshio Yoshimatsu, BS 
Laboratory Informatics Specialist                                                                                                            
Knapp Center for Biomedical Discovery 
900 E. 57TH Street, Room 8240D, Chicago, IL  60637 
Tel: +1(773) 834-8336 
Email: tyoshima@medicine.bsd.uchicago.edu 
 
Ilona Siljander, RN, MS 
Clinical Research Coordinator/Project Manager 
Center for Glinical Cancer Genetics & Global Health 
The University of Chicago 
5841 S Maryland Avenue MC 2115, Chicago, IL 60637 
Tel: +1 (773) 702 4298  
Email: isiljander@medicine.bsd.uchicago.edu 
 
 
 
 
 
 
 
 
 

 
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Investigation Site UCH, Ibadan 
Site  Number 002 
 
Project Site Director  (UCH Ibadan) 
Prof. Oladosu Ojengbede, MD 
Professor of Obstetrics and Gynecology 
Director, Centre for Population & 
Reproductive Health 
College of Medicine, UCH,  
Ibadan, Nigeria 
Tel: 234-805-599-3211; 234-803-442-
6047; 
Email: ladosu2002@yahoo.co.uk  
 
Investigation Site LASUTH Lagos 
Site Number 003 
 
Project Site Director (LASUTH Lagos) 
Prof. John O. Obafunwa, MD 
Department of Forensic Pathology 
Lagos State University College of Medicine 
P.M.B 2266, Ikeja 
Lagos State, Nigeria 
Tel: 234-803-396-6199 
Email: joobafunwa@hotmail.com 
 

 
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Clinical Oncology Co-Investigator (UCH 
Ibadan) 
Dr Ayorinde Folasire ( Site Co-PI) 
Department of Radiation Oncology 
University College Hospital Ibadan 
Tel: 2348028879622 
Email: ayofolayemisi@gmail.com  
 
 
Surgery  Co-investigators (UCH Ibadan) 
Prof. Temidayo Ogundiran 
Department of Surgery, UCH, Ibadan 
Tel : 234-803-715-5946 
Email: toogundiran@yahoo.co.uk  
 
Dr. Adeyinka Ademola 
Department of Surgery 
University College Hospital 
Ibadan, Oyo State, Nigeria  
Tel: 2348055267072 
Email: deoluyinka@yahoo.com 
 
Dr Bolaji Ayandipo 
Department of Surgery 
University College Hospital 
Ibadan, Oyo State, Nigeria  
Tel: 2348051249319 
 
Pathology Co-investigators (UCH Ibadan) 
Dr. Ayodeji Salami MBBS, FWACP 
Pathology Department 
College of Medicine 
University of Ibadan  
P.M.B. 5116 
Ibadan, Nigeria 
Tel: 234-8057072670 
Email: ayodejisalami@gmail.com 
 
 
 
 
 
Surgery  Co-investigators (LASUTH Lagos) 
Dr. Nasiru Ibrahim 
Department of Surgery 
Lagos State College of University of 
Medicine 
Ikeja 
Tel: 234-8023044971 
Email: ibrahimakanmu@yahoo.com 
 
Dr. Foluso Omodele 
Department of Surgery 
Lagos State University College of Medicine 
Ikeja 
Tel: 234-8033061296 
Email: omodelefolusho@yahoo.com  
 
Dr. Oludara  Mobolaji 
Department of Surgery 
LASUTH, Lagos 
Telephone: 234-8033093296 
Email: boludara2001@yahoo.com 
 
Clinical Oncology Co-Investigator 
Dr Omolara Fatiregun  
Department of Radiology 
Oncology unit 
Tel 08035858071 
Email:omolarafatiregun@yahoo.com 
 
 
Pathology Co-Investigator (LASUTH 
Lagos) 
Dr. Ayodele Sanni                                           
Department of Forensic Pathology 
Lagos State College of University of 
Medicine 
Ikeja 
Tel: 234-8024412629 
Email: ayodele_sanni@ymail.com 
 
 

 
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Dr. Mustapha Ajani 
Department of Pathology, 
College of Medicine 
University of Ibadan  
Ibadan, Oyo State, Nigeria 
Phone: 234-33776720 
Email: ajanimustapha@yahoo.com 
 
Dr. Ebenezer O Fatunla 
Department of Pathology 
University College Hospital 
Ibadan, Oyo State, Nigeria 
Tel: 234-8035502787; 234-8155563273 
Email: ebenezerfat@gmail.com 
 
Radiology Co-Investigators (UCH Ibadan) 
Dr. Milicent Obajimi  
(BS,MBBS,FWACS,FMCR,DMRD) 
Professor, Department of Radiology  
Head, Breast Imaging Suite 
University 
College 
Hospital, 
Ibadan, 
Nigeria 
Email: millieobaj@yahoo.com  
 
Dr. A T Adenii–Sofoluwe MBBCh, 
FWACS , MSc Department of Radiology, 
University College Hospital Ibadan, 
Nigeria 
Email: omoba30732003@yahoo.com 
 
Study Coordinators (UCH Ibadan) 
Chibuzor Afolabi 
Tel: 234-803-727-2413 
Email: gafolabi08@gmail.com 
 
Toyin Aniagwu RN MPH 
Department of Nursing  Education 
UCH Ibadan 
Tel: 234-8033535370 
Email: taniagwu@yahoo.com 
 
Research Nurse (UCH Ibadan) 
Omolara Fagbenle RN, BSc 
Department of Radiation Oncology 
Radiology Coinvestigators  
Prof. G.O. G. Awosanya (LASUTH Lagos) 
Department of Radiology 
Lagos State University Teaching Hospital 
Ikeja, Lagos, Nigeria 
Tel: 234-8033069983 
Email: gog_awosanya@yahoo.com 
 
Dr. Babajide Balogun (LASUTH Lagos) 
Department of Radiology 
Lagos State University Teaching Hospital 
Ikeja, Lagos, Nigeria 
Tel: 234-8056522232 
Email: babajide_balogun@yahoo.com 
 
Study Nurse (LASUTH Lagos) 
Daphne Chibuzor Oguntuwo 
 Lagos State University Teaching Hospital 
Ikeja, Lagos 
Tel: 08036160181 
Email: daphnelawrence95@gmail.com 
  
Okechukwu  Emeruwa, 
Lagos State University Teaching Hospital 
Ikeja, Lagos 
Tel: 2347035245618 
Email: emexokey@yahoo.com,                
  
Pharmacy (LASUTH Lagos) 
Mr Muri Olayinka  
Pharmacy Dept 
Lagos State University Teaching Hospital 
Ikeja, Lagos 
Tel: 2348023294952 
murilanre2000@yahoo.com 
 
Study Coordinator (LASUTH Lagos) 
Stella O.  Odedina  
Lagos State University Teaching Hospital 
Ikeja, Lagos 
Tel: 234-8035762998 
Email: stellakinleye@yahoo.com 
 
Data Manager (LASUTH Lagos) 
Felix Sanni                           

 
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UCH Ibadan 
Tel:2348037127561 
Email: fabenleomolara@yahoo.com 
 
Folake Olahansoye RN 
Department of Radiation Oncology 
UCH Ibadan 
Tel:2348032146942 
Email:folahansoye@gmail.com 
  
Dasola Ogungbade 
Department of Radiology 
UCH Ibadan 
Tel:2348033890637 
Email: dasolaogungbade@gmail.com 
 
Study Monitors 
Healthy Life for All Foundation (HLF)  
 UCH Ibadan, P.O. Box 30175                       
Secretariat Ibadan, Nigeria 
 
            
Tel: +234-80 344 98945 
 
Clinical Pharmacology/Pharmacy (UCH 
Ibadan) 
Mrs. Olayinka Adejoke Kotila B. Pharm 
PhD 
Department of Pharmaceutical Chemistry 
Faculty of Pharmacy 
University of Ibadan 
Ibadan, Nigeria  
Tel: 234-8037018797, 234-8078979327 
Email: olayinkakotila@yahoo.com 
 
Mrs Helen. Oduntan, BPharm, MPSN 
(Pharm) 
Department of Pharmacy,  
University College Hospital Ibadan, 
Nigeria 
Email: hoduntan@yahoo.com 
 
Adepoju Toyosi Michael B. Pharm 
Clinical Oncology Pharmacist 
Pharmacy Department, 
University College Hospital, 
Ibadan , Nigeria. 
Lagos State University Teaching Hospital 
Ikeja, Lagos 
Tel: 234-8060085465 
Email: fescosof@yahoo.com 
 
Investigation Site OAUTH Ile-Ife  
Site Number 004 
 
Project Site Director  (OAUTHC Ile - Ife)  
Professor Muheez Durosinmi 
Department of Haematology and 
Immunology 
Faculty of Basic Medical Sciences 
Obafemi Awolowo University 
Ile-Ife, Nigeria 
Tel: 234-8033298205 
Email: mdurosin@gmail.com 
 
Clinical Pharmacology/Pharmacist 
(OAUTHC Ile –Ife) 
Lanrewaju Adebayo Ayoola  ( FPCP ) 
Departmentof Pharmacy 
Obafemi Awolowo University Teaching 
Hospitals Comples. Ile – Ife. 
Tel: +2348036720112 
Email : blanrewaju@yahoo.com. 
 
Pathology Co – Investigator (OAUTHC Ile- 
Ife) 
Dr. Akinwunmi. O. Komolafe (M.B.Ch.B), 
FMCPath 
Department of Morbid Anatomy and 
Forensic Medicine.  
Obafemi Awolowo University (OAU). 
Ile- Ife.  
Tel : +2348033557741 
Email: akinkomo1@yahoo.com   
 
Ganiyat. O. Omoniyi - Esan 
Department of Morbid Anatomy and 
Forensic Medicine.  
Obafemi Awolowo University (OAU). 
Ile- Ife. 
Tel : +2348033536852 
Email : gomoniyi_esan@yahoo.com 

 
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Email:toyosi.adepoju@yahoo.com 
tadepoju@bsd.uchicago.edu 
 
Dr Michael Obaro MBBS, MSc, FMCP 
Department of Clinical Pharmacology and 
Therapeutics 
University College Hospital Ibadan 
Nigeria 
Tel: 234803337112 
Email: micobaro@yahoo.com 
 
Laboratory Co-Investigator (UCH Ibadan) 
Professor Chinedum P Babalola 
Head of Unit  
Genetic and Bioethics Research Unit 
IMRAT, College of Medicine 
Tel: 234-8055224989 
Email: peacebab2001@yahoo.com   
 
Psycho-Oncology/Counselling  Co-
Investigators 
Prof Prisca Adejumo PhD 
Department of Nursing 
University of Ibadan 
Tel: 2348033923260 
Email: bisiandbayo@yahoo.com 
 
Dr Chioma Asuzu PhD 
Department of Radiation Oncology, UCH 
Ibadan 
Tel: 2348023288134 
Email:chiomazuzu20@yahoo.com 
 
Telemedicine (UCH Ibadan) 
Dr Simpa Dania 
Lead Consultant/CEO,  
Sabaoth Technologies Consultant Health 
Informatics,  
University College Hospital Ibadan,  
Tel: 234-803-664-8712 
Email:dania@sabaothtechnologies.com 
 
 
 
 
 
Surgery Co – Investigator  OAUTHC Ile- 
Ife. 
Prof Oladeje. O. Lawal (FMCS) 
Department of Surgery 
Obafemi Awolowo University Teaching 
Hospitals Complex (OAUTHC) Ile –ife. 
Nigeria 
Phone: +2348033802362 
Email: lawal_08@yahoo.com 
 
Dr. Olusegun. I Alatise (FMCS, FWACS) 
Department of Surgery 
Obafemi Awolowo University Teaching 
Hospitals Complex (OAUTHC). 
Ile –ife. Nigeria 
Phone: +2348033859387. 
Email: segunalatishe@yahoo.co.uk 
 
Dr. Adewale. O. Adisa. (FWACS) 
Department of Surgery 
Obafemi Awolowo University Teaching 
Hospitals Complex (OAUTHC). 
Ile –ife. Nigeria 
Phone: +2348033889425 
Email: wadisc@gmail.com 
 
Dr. Akinbolaji. A. Akinkuolie (FWACS) 
Department of Surgery 
Obafemi Awolowo University Teaching 
Hospitals Complex (OAUTHC). 
Ile –ife. Nigeria 
Phone: +2348034548855  
Email: akinjts@yahoo.com 
 
Dr. Olasehinde Olalekan (FWACS ) 
Department of Surgery 
Obafemi Awolowo University Teaching 
Hospitals Complex (OAUTHC). 
Ile –Ife. Nigeria 
Phone: +2348060716670 
Email: lekanolasehinde@yahoo.com 
 
 
 

 
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Laboratory Research Technologists (UCH 
Ibadan) 
Mr. Abayomi  B. Odetunde 
Medical Laboratory Scientist 
Genetic and Bioethics Research Unit 
IMRAT, College of Medicine 
Tel: 234-8055265706; 234-98112770 
Email: abayomiodetunde@gmail.com 
 
Babajide Okedere 
Research technologist 
Genetic and Bioethics Research Unit 
IMRAT, College of Medicine 
Tel: 234-7043192557 
Email: jendorok@gmail.com 
 
Project Manager (UCH Ibadan) 
Omobolanle Oyedele 
University of Ibadan 
Tel: (234) 0802 365 9278 
Email: omob_oye@yahoo.com 
 
Project Manager II (UCH Ibadan) 
Mrs  Olufadekemi Ajani  
University College Hospital Ibadan 
Tel:2348033085831 
Email: olufadekemiajani@gmail.com 
 
Program Officer (Nigeria) 
Mr.  Dayo Adepoju 
Healthy Life For All Foundation 
Idi Ape, Ibadan, 
Tel:234-805-660-2274   
Email: dayoadepoju@yahoo.com    
 
Radiology Co-investigators (LUTH) 
Dr Adekunle  O.  Adeyomoye  MBBS, 
FWACS, FMCR 
Department of Radiodiagnosis 
College of Medicine, University of Lagos/ 
Lagos University Teaching Hospital, 
Lagos Nigeria 
Tel +2348023101718, +2347034081270 
Email: kunleadeyomoye@yahoo.com 
 
Research Cordinator  
Dr. Fehintoluwa Okunade (MBChB ) Ile- 
Ife) 
Obafemi Awolwowo University Teaching 
Hospitals Complex 
Phone : +2348063608920 
E mail : fehintay@gmail.com  
 
Data Manager (OAUTHC Ile- Ife ) 
Mrs. Awodele Olubunmi J. (HND )  
Health Information management  
OAUTHC Ile – Ife 
Tel : +2348039674550 
E mail : awodeleo95@gmail.com 
 
Investigation Site LUTH Lagos 
Site Number 005 
 
Project Site Director   
Prof Fatimah Abdulkareem 
Department of Pathology 
Lagos University Teaching Hospital 
Idi-Araba Lagos Nigeria 
Tel:2348023093852 
Email: biade64@yahoo.co.uk 
 
Clinical Oncology Co-investigators 
Dr Adewumi O Alabi MBBS,FWACS, 
FMCR 
Department of Radiotherapy &Clinical 
Oncology 
Lagos University Teaching Hospital 
Idi-Araba Lagos Nigeria 
Tel +2348052843206 
Email: adewumialabi@gmail.com 
 
Dr Olukiran Gbenro MBBS, MWACS 
Department of Radiotherapy and Clinical 
Oncology 
Lagos University Teaching Hospital 
Idi-Araba Lagos Nigeria 
Tel: 2348052574406; 2347034206181 
Email: droluiran@gmail.com 
 

 
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Dr Nicholas Irurhe MBBS, MSc, FMCR 
Department of Radiology 
College of Medicine, University of Lagos 
Lagos Nigeria 
Tel: 2348023450029 
Email:nick3irurhe@gmail.com 
 
Pharmacokinetics Co-investigators LUTH 
Dr Olufunso Awodele B. Pharm,MSC, 
Fwacp, MPH, PhD Pharm, FASI, DSc 
(alternate medicine)  
Department 
of 
Pharmacology 
, 
Therapeutics and Toxicology 
College of Medicine, University of Lagos, 
Lagos Nigeria 
Tel:+2348023624044 
Email:  
 
Dr Adedunni Wumi Olusanya MBBS, MSC 
FMCP 
Department of Pharmacology , 
Therapeutics and Toxicology 
College of Medicine, University of Lagos, 
Lagos Nigeria 
Tel:+2348126648460 
Email: dedunolusanya@gmail.com 
            adeolusanya@unilag.edu.ng 
 
Study Nurses ( LUTH Lagos) 
Ola Grace Aladesida 
Department of Surgery, LUTH 
Tel: 2348033459137;2348055677269 
Email: galadesida@yahoo.com 
 
Anastasia Okudo 
Department of Radiotherapy, LUTH 
Tel: 2348027305255 
Email: maryann2967@gmail.com 
 
Research Assistant Data Entry (LUTH) 
Isaac Ademola 
Tel: +2348027540009 
Email: olaisaac2014@yahoo.com 
Dr Okoro Uchenna 
Department of Radiotherapy and Clinical 
Oncology 
Lagos University Teaching Hospital 
Idi-Araba Lagos Nigeria 
Tel: 2348065836326 
Email: okoro.uche@gmail.com 
 
Surgical Oncology Co-investigators 
Dr AbdulRazzak O Lawal FWACS 
Department of Surgery,  
Lagos University Teaching Hospital 
Idi-Araba Lagos Nigeria 
Tel +234803383776 
Email: razzaklawal@gmail.com 
 
Dr Thomas Olagboyega Olajide  FWACS 
Department of Surgery,  
Lagos University Teaching Hospital 
Idi-Araba Lagos Nigeria 
Tel +2348028534450 
Email: seyiolajide@gmail.com 
 
Pathology Co-investigators LUTH 
Prof Adetola O Daramola 
Department of Anatomic and Molecular 
Pathology  
College of Medicine, University of Lagos/ 
Lagos University Teaching Hospital Idi-
Araba Lagos Nigeria 
Tel: +2348127869798 
Email:detoladaramola@gmail.com 
 
Dr Olakanmi Ralph Akinde  
MBBS,FMCPath, MSc  
Department of Anatomic and Molecular 
Pathology  
College of Medicine, University of Lagos/ 
Lagos University Teaching Hospital Idi-
Araba Lagos Nigeria 
Tel: +2348023426396 
Email:akindior@gmail.com 
 
Dr Oyetunji O. Soriyan MBBS, MWAP, 
FMCPath 

 
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Study Coordinating Center (UCMC 
Chicago) 
 
Co –investigators 
Christopher Sola Olopade MD, PhD 
Professor, Director of International 
Programs,                          
University of Chicago 
5841 S Maryland Avenue MC 6076, 
Chicago, IL 60637 
Tel: +1 (773) 702-6479  
Email: solopade@bsd.uchicago.edu 
 
 
 
Theodore Karrison, PhD 
Research Professor 
                            
Director of Biostatistics Laboratory               
Department of Public Health Sciences           
University of Chicago, 5841 S. Maryland 
Ave., MC 2000, R314 
Chicago, Illinois 60637 
Tel: 1+(733) 702-9326 
                        
Email: karr@uchicago.edu 
 
Babatunde Adedokun, MBBS, PhD 
Postdoctoral Fellow  
Knapp Center for Biomedical Discovery 
900 E. 57TH Street, Chicago, IL  60637 
Tel: +1 (773) 834-3518 
Email: tukankar@gmail.com 
 
Project Manager (UCMC Chicago) 
Kristyna Hulland  
University of Chicago Medical Center 
5841 S. Maryland Ave, MC 1140 
Chicago, IL 60637 USA 
Email: 
khulland@medicine.bsd.uchicago.edu 
 
Regulatory Coordinator (UCMC Chicago) 
Amanda Spratt 
University of Chicago Medical Center 
5841 S. Maryland Ave, MC 1140 
Chicago, IL 60637 USA 
Tel: +1 773 834 4031 
Department of Clinical Pathology 
College of Medicine, University of Lagos , 
Lagos Nigeria 
Tel: +2348023143447; 2348065437112 
Email:tunjisoriyan@gmail.com 
 
Dr Gbenga Mary FMCPath 
Department of Haemato-Oncology  
Lagos University Teaching Hospital  
Tel 2348028293668 
Email;  
 
Cardiology Coinvestigators (LUTH) 
Dr Olagoke Korede Ale MBBS, MPH , 
FMCP 
Department of Medicine, 
College of Medicine, University of Lagos/ 
Lagos University Teaching Hospital, Lagos 
Nigeria 
Tel +2348033447099 
Email: gokeale@yahoo.com 
 
Pharmacy Co-investigators LUTH 
Mr Oladeide Olagbenga Adeoye B Pharm, 
MSC, FWACP 
Department of Oncology Pharmacy 
Lagos University Teaching Hospital, Lagos 
Nigeria 
Tel: +2348034717853, +2348072930295 
Email: adexg2001@yahoo.com 
 
Psychooncology Co-Investigators (UCMC 
Chicago) 
David Beiser, MD 
5841 S. Maryland Ave. 
MS 5068 
Chicago, IL 60637 
 
Robert Gibbons PhD 
5841 S.Maryland Avenue 
MC 2007 office W260 
Chicago, IL 60637 
Tel: +1 773 834 8692 
Email: rdg@uchicago.edu 
 

 
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Email: aspratt@bsd.uchicago.edu 
Bioinformatics Support (UCMC Chicago) 
Toshio Yoshimatsu 
Knapp Center for Biomedical Discovery 
900 E. 57TH Street, 8th Floor Room 
#8240D,  
Chicago, IL  60637 
Tel: (01) 773-834-8336 
Email: 
tyoshima@medicine.bsd.uchicago.edu 
 
 
 
Study Statistician LUTH 
Dr Adedoyin Ogunyemi MBBS, MPH 
MWACP MA (Bradford), FMCPH 
Department of Community Health and 
Primary Care  
College of Medicine, University of Lagos, 
Lagos Nigeria 
Tel: 2348063068858 
Email: aoogunyemi@comul.edu.ng 
            doyinogunyemi@gmail.com 
 
COLLABORATING INSTITUTIONS: 
 
F. Hoffmann-La Roche Ltd 
Roche 
Regional 
Medical 
Lead, 
Gyn 
Oncology,               EEMEA Region, Africa 
Strategy Team (AST)                                   Tel: 
+41 79 604 78 32; + 1(415) 690-6591 
 
Coordinating Center:                                 
Healthy Life for All Foundation (HLF)     
UCH Ibadan, P.O. Box 30175                         
Secretariat Ibadan, Nigeria 
 
             
Tel: +234-80 344 98945 

 
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Steering Committee: 
 
Dr. Atara Ntekim, MBBCh, FWACS, FMCR (UCH Ibadan) 
Dr. Abiodun O. Popoola, MBBS, FWACS   (LASUTH Lagos) 
                                                                       . 
Dr Adeola  O. Arowolo, MBBS, FWACS OAUTH Ile Ife) 
 
Dr Anthonia Sowunmi MBBS, FWACS, FMCR (LUTH Lagos) 
 
Prof. Olufunmilayo I. Olopade, MD, FACP (UCMC Chicago) -Chairman 
 

 
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Data Safety and Monitoring Board (DSMB) 
 
Professor M. Asuzu  
                                      
Department of Community Medicine  
 
    
University College Hospital Ibadan Nigeria   
               
Tel: 2348033467670   
 
 
 
                   
Email: mcasuzu2003@yahoo.com 
 
Professor G. Gbotosho  
 
 
 
 
   
Department of Pharmacology and Therapeutics,  
    
University of Ibadan, Nigeria  
 
 
 
2348030757071 
 
 
 
                      
Email: solagbotosho@yahoo.co.uk  
 
Professor B. Fawole   
 
 
 
 
  
Department of Obstetrics and Gynecology   
    
University College Hospital Ibadan Nigeria   
 
   
Tel: 2348033182802  
 
 
 
 
 
Email: fawoleo@yahoo.co.uk  
 
Prof  A. Adenipekun,   
 
 
 
 
  
Department of Radiation Oncology,   
 
    
University College Hospital Ibadan, Nigeria    
 
    
Tel: 2348033583256   
 
 
 
          
Email: adenipek2000@yahoo.com 
 
Dr Tosin Awolude,   
 
 
 
  
Department of Obstetrics and Gynaecology,   
          
College of Medicine, University of Ibadan,   
               
Tel: 08032222986  
 
 
          
          
Email: tosinawolude@yahoo.com  
 
Toyosi Odenike 
 
 
 
 
University of Chicago 
 
                                                Dezheng Huo, M.D., Ph.D.  
                                                Department of Public Health Sciences (Epidemiology) 
 
 
 
University of Chicago  
dhuo@health.bsd.uchicago.edu 
 
 

 
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Protocol No. CABC123D4567 
 
 
Signatures: 
 
Investigator 
I have read and agree to the protocol ‘Assessing REsponse rate to neoadjuvant Taxotere 
and TrAstuzumab in Nigerian women with HER2-positive breast cancer ‘(Version ___, 
dated __________). I am aware of my responsibilities as an Investigator under the guidelines 
of GCP, local regulations (as applicable) and the study protocol. I agree to conduct the study 
according to these responsibilities and to appropriately direct and assist the staff under my 
control, who will be involved in the study. 
 
Clinical Site: University of Chicago Center for Global Health (UC CGH)  
Site Number: 001 
Site Principal Investigator: Prof Olufunmilayo I. Olopade 
 
Print Name Title:  
 
Signature:                              Date: 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents 
 
Participating Centers: .............................................................................................................. 2 
List of abbreviations ................................................................................................................. 22 
Glossary of terms ...................................................................................................................... 25 
Protocol summary ..................................................................................................................... 28 
1 Introduction ........................................................................................................................... 31 
1.1 Breast cancer overview .................................................................................................... 31 
1.2 Breast cancer burden in Nigeria and Sub-Saharan Africa .......................................... 31 
1.3 Treatment options for breast cancer .............................................................................. 33 
1.4 Neoadjuvant chemotherapy ............................................................................................. 33 
1.5 Introduction to investigational treatment(s) and other study treatment(s) ................ 34 
1.5.1 Docetaxel (TXT) ..................................................................................................... 34 
1.5.2 5-Fluorouracil, Epirubicin, Cyclophosphamide (FEC) ...................................... 35 
1.5.3. Herceptin  (Trastuzumab) (H) ............................................................................. 35 
1.5.5 Tamoxifen (TAM), letrozole (LET) and Luteinizing Hormone Releasing 
Hormone (LHRH) agonist. ............................................................................................. 36 
2 Rationale ................................................................................................................................ 36 
2.1 Study rationale and purpose ............................................................................................ 36 
2.2 Rationale for choice of drug and schedule ..................................................................... 38 
2.2.1 Docetaxel (TXT) and Trastuzumab ...................................................................... 38 
3. Objectives and endpoints ...................................................................................................... 39 
4. Study design ......................................................................................................................... 45 
4.1 Overview ............................................................................................................................ 45 
4.2 Definition of end of study ................................................................................................. 47 
4.3 Early study termination ................................................................................................... 47 
5. Patient population ................................................................................................................. 47 
5.1 Inclusion criteria ............................................................................................................... 48 
5.2 Exclusion criteria .............................................................................................................. 48 
5.3 Recruitment process ......................................................................................................... 49 
6. Treatment .............................................................................................................................. 50 

 
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6.1 Study treatment ................................................................................................................ 50 
6.2 Dosing guidelines .............................................................................................................. 51 
6.3 Ultrasound evaluation of response .................................................................................. 52 
6.4 Dosing regimen ................................................................................................................. 52 
6.5 Treatment duration .......................................................................................................... 52 
6.6 Pretreatment considerations: .......................................................................................... 53 
6.7 Guidelines for continuation of treatment ....................................................................... 54 
6.8 Dose modification and dose delay ................................................................................... 54 
AST or ALT.............................................................................................................................. 58 
AST or ALT and Bilirubin ....................................................................................................... 58 
6.9 Disease progression during study .................................................................................... 61 
6.10 Follow-up for toxicities ................................................................................................... 61 
6.11 Anticipated risks and safety concerns of the study treatments .................................. 61 
6.12 Concomitant medications............................................................................................... 61 
6.13 Prohibited concomitant therapy .................................................................................... 61 
6.14 Patient numbering .......................................................................................................... 62 
6.14.1 Patient numbering ................................................................................................ 62 
6.14.2 Treatment assignment.......................................................................................... 62 
6.14.3 Treatment blinding .............................................................................................. 62 
6.15 Study drug preparation and dispensation .................................................................... 62 
6.16 Drug supply and storage ................................................................................................ 62 
6.17 Study drug accountability and compliance .................................................................. 63 
7. Study flow and visits schedule ............................................................................................. 63 
7.1 Screening ........................................................................................................................... 63 
Bone scan .................................................................................................................................. 68 
CT scan of brain ....................................................................................................................... 68 
CT scan of chest, abdomen, pelvis ........................................................................................... 68 
7.1.2 HLF Data Submission ............................................................................................ 71 
7.1.4 Patient demographics and other baseline characteristics .................................. 73 
7.2 Treatment period .............................................................................................................. 73 
7.3 End of treatment visit including study completion and premature withdrawal ........ 73 
7.4 Criteria for premature patient withdrawal .................................................................... 73 

 
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7.4.1 Replacement policy ................................................................................................ 74 
7.5 Follow up period ............................................................................................................... 74 
7.5.1 30 - day safety follow up period ............................................................................ 74 
7.5.2 Survival follow up period ...................................................................................... 74 
7.6 Assessment types ............................................................................................................... 74 
7.6.1 Efficacy assessments ............................................................................................... 74 
7.6.2 Safety and tolerability assessments ....................................................................... 75 
7.7 Patient reported outcomes ............................................................................................... 77 
7.7.1 The EORTC Quality of Life questionnaire.......................................................... 77 
8. Safety monitoring and reporting ........................................................................................... 77 
8.1 Adverse events................................................................................................................... 77 
8.1.1 Definitions ............................................................................................................... 77 
8.2 Serious adverse event ....................................................................................................... 78 
8.2.1 Definition ................................................................................................................. 78 
8.2.2 Reporting ................................................................................................................. 79 
8.3 Pregnancies........................................................................................................................ 80 
8.4  
Routine Adverse Event Reporting ............................................................................. 80 
8.5  
Serious Adverse Event Reporting to the Coordinating Center ............................... 82 
8.6 
Serious and Unexpected Adverse Event reporting by the Coordinating Center ... 82 
8.7 Warnings and precautions ............................................................................................... 83 
9. Statistical methods and data analysis.................................................................................... 83 
9.1 Analysis sets....................................................................................................................... 83 
9.1.1 Full Analysis Set (FAS) .......................................................................................... 83 
9.1.2 Safety Set ................................................................................................................. 83 
9.2 Patient demographics and other baseline characteristics ............................................. 83 
9.3 Treatment (study treatment, concomitant therapies, compliance) .............................. 84 
9.4 Primary objective ............................................................................................................. 84 
9.5 Primary Outcome Measure ............................................................................................. 84 
9.6 Handling the missing values; censoring and discontinuations ..................................... 85 
9.7 Secondary objectives ........................................................................................................ 85 
9.8 Secondary efficacy objectives .......................................................................................... 85 
9.8.1 Invasive disease-free survival (iDFS).................................................................... 85 

 
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9.8.2 Subgroup analysis .................................................................................................. 86 
9.9 Safety objectives ................................................................................................................ 86 
9.9.1 Analysis set and grouping for the analysis ........................................................... 86 
9.9.2 Adverse events (AEs) ............................................................................................. 86 
9.9.3 Laboratory abnormalities ...................................................................................... 87 
9.9.4 Other safety data .................................................................................................... 87 
9.10 Patient-reported outcomes ............................................................................................. 88 
10 Biospecimens management and biomarker analysis ........................................................... 88 
10.1 Biospecimens ................................................................................................................... 88 
10.2 Pathology consideration ................................................................................................. 89 
10.3 Biomarkers, correlative and special studies ................................................................. 89 
11   STUDY MANAGEMENT AND REGULATORY AFFAIRS ......................................... 90 
11.1 Multicenter Guidelines ..................................................................................................... 90 
11.2  Institutional Review Board (IRB) Approval and Consent............................................... 90 
11.3 Required Documentation .................................................................................................. 91 
11.4  Data and Safety Monitoring ............................................................................................ 91 
11.5 Data Safety Monitoring Board ...................................................................................... 93 
11.6 Auditing ......................................................................................................................... 93 
11.7 Amendments to the Protocol ......................................................................................... 93 
11.8 Annual IRB Renewals, Continuing Review and Final Reports..................................... 94 
11.9 Record Retention ........................................................................................................... 94 
11.10 
Obligations of Study Site Investigators ..................................................................... 94 
11.11 Study finance and sponsorship .................................................................................... 95 
11.12 Steering Committee ...................................................................................................... 95 
11.13 Coordinating Center and Sponsor .............................................................................. 96 
12 References (hard copy available upon request) ................................................................... 96 
APPENDICES ........................................................................................................................ 104 
APPENDIX A. ECOG Performance Status ....................................................................... 104 
APPENDIX B.  Response Evaluation Criteria In Solid Tumors, RECIST (adapted from 
Version 1.1) ........................................................................................................................ 105 
APPENDIX C. Quality of Life (QoL) Assessment............................................................. 106 

 
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APPENDIX D.  Responsibilities of the Protocol Steering Committee Chair (Protocol 
Chair) and Coordinating Center ..................................................................................... 111 
APPENDIX E.  Asymptomatic decline in LVEF: Algorithm for Continuation and 
Discontinuation of HER2-Targeted Study Medication ................................................. 112 
APPENDIX F.  Criteria for New York Heart Association Functional Classification .... 113 
APPENDIX G.  Nomogram for the Determination of Body Surface Area ..................... 114 
APPENDIX H.  ARETTA study advert ............................................................................. 115 
 
 
 
 
 

 
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LIST OF FIGURES  
Figure 1-1 Spectrum of breast cancer subtypes across populations…………………………32 
Figure 4-1 Study Schema Part 1: Neoadjuvant Treatment…………………………………..46 
Figure 4-2 Study Schema Part 2: Adjuvant Treatment………………………………………47 
 
 
LIST OF TABLES 
  
Table 3-1 
Objectives and related endpoints ......................................................................... 40 
Table 6-1 
Dose and treatment schedule ............................................................................... 52 
Table 6-2 
Recommendations for dose modification for docetaxel or FEC by event ........... 57 
Table 6-3 
Recommendations for dose modification by the appearance of the adverse drug 
reaction……. ....................................................................................................... 60 
Table 7-1 
Visit evaluation schedule (Neo-Adjuvant) (Part 1). Protocol Section 7.2 ........... 64 
Table 7-2 
Visit evaluation schedule (Part 2) (Adjuvant Therapy) for Complete/Partial 
Responders/SD (operable) Protocol Section 7.2……………………………..…68 
Table 7-3 
Visit evaluation schedule- End of treatment visit and follow up……………….70 
Table 8-1 
Reporting Conventions for Left Ventricular Systolic Dysfunction/Heart 
Failure………………………………………………………………………..….82 

 
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List of abbreviations 
AC 
AE 
AI 
AJCC  
Adriamycin/cyclophosphamide 
Adverse Event 
Aromatase inhibitor 
American Joint Committee on Cancer 
ALT 
ANC 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
Absolute neutrophil count 
AST 
ATC 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
Anthracycline 
BHGI 
BRCA1 
BUN 
CAF (FAC) 
CBC 
CCR 
CCSR 
CDP/CIS-DDP 
CI 
CISH 
CKD EPI 
Breast Health Global Initiative 
Breast cancer gene 1 
Blood urea nitrogen 
Cyclophosphamide, doxorubicin, 5-fluorouracil 
Complete Blood Count 
Core clinical report 
Core clinical study report 
Cis-diamminedichloroplatinum (Cisplatin) 
Confidence interval 
Chromogenic in situ hybridization 
Chronic Kidney Disease Epidemiology Collaboration 
CMF 
C1D1 
Cyclophosphamide, methotrexate, 5-fluorouracil 
Cycle 1, day 1 
CPM 
CRF 
Cyclophosphamide 
Case Report/Record Form; the term CRF can be applied to either EDC or 
paper hard copy 
CSP 
Clinical study protocol 
CSR 
CSR addendum  
Clinical study report 
An addendum to clinical study report (CSR) that captures all the additional 
information that is not included in the CSR  
CTC 
Common Toxicity Criteria  
CTCAE 
CTPF 
CYP 
Common Terminology Criteria for Adverse Events v 4.0 
Clinical trial pregnancy form 
Cytochrome  
DAR  
Dosage administration record 
DBC 
DF 
DHFR 
Differential blood count 
Disease-free 
Dihydrofolate reductase 
 

 
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DOR 
DQF 
DS&E 
DTX/DOC 
D5W 
Duration of response 
Data query form 
Drug safety and epidemiology 
Docetaxel (Taxotere) 
Dextrose 5% in water solution  
EC 
Epirubicin 
ECG 
ECHO 
ECOG PS 
Electrocardiogram 
Echocardiography 
Eastern Cooperative Oncology Group performance status 
EOT 
EORTC 
QLQ-30 
End of Treatment 
European Organization for Research and Treatment of Cancer 
EORTC quality of life questionnaire 
E&U+CR 
ER 
Electrolytes, urea and creatinine 
Estrogen receptor 
FAS 
FCSR 
FDA 
FEC 
FISH 
F/U 
GCP 
H 
HLF  
HER2 
HIV 
HPF 
HR+ 
Full analysis set 
Final clinical study report 
Food and Drug administration 
5-Fluorouracil, Epirubucin and Cyclophosphamide  
Fluorescence in situ hybridization 
Follow up period 
Good clinical practice 
(Herceptin) trastuzumab 
Healthy Life for all Foundation  
Human epidermal growth factor receptor 2 
Human immunodeficiency virus 
High power field (in microscopy) 
Hormone receptors positive 
i.v. or IV 
Intravenous  
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
IHC 
Independent Ethics Committee 
Immunohistochemistry 
IRB 
Institutional Review Board 
IUCD 
Intrauterine contraceptive device 
LABC 
LET 
LFT 
LHRH 
LLN 
LN 
LPLV 
Locally advanced breast cancer 
Letrozole 
Liver function tests 
Luteinizing hormone-releasing hormone 
Lower limit of normal 
Lymph node 
Last patient last visit 
LVEF 
Left ventricular ejection fraction 

 
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Protocol No. CABC123D4567 
 
 
 
MedDRA 
Medical dictionary for regulatory activities 
MTS 
NAFDAC 
NCAIDs 
NCCN 
 
NCI 
Metastasis 
National Agency for Food and Drug Administration and Control 
Non-steroidal anti-inflammatory drugs 
National Comprehensive Cancer Network (An alliance of 26 cancer centers 
in the USA) 
National Cancer Institute 
NIBMR 
NS                     
ORR 
Novartis Institute for Biomedical Research Inc 
Normal saline solution 
Objective response rate 
OS 
pCR 
piCR 
PD 
Overall survival 
Pathologic complete response 
Pathologic incomplete response 
Progressive disease 
PI 
Principal investigator 
PFS 
Progression-free survival 
p.o. 
per os/by mouth/orally 
PHI 
PK 
PLT 
PPS 
Pt(s) 
Protected Health Information 
Pharmacokinetics 
Platelet 
Per-protocol set 
Patient(s) 
PgR 
PRF 
QoL 
Progesterone receptor 
Patient registration form 
Quality of life 
 
 
REB 
RECIST 
Research Ethics Board 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
SAE  
Serious adverse event 
s.c. or SC 
Sub-cutaneous 
SD 
SEC 
SGOT 
SGPT 
SIADH 
SOC 
SOP 
Stable disease 
Specific safety event categories 
Serum glutamic-oxaloacetic transaminase 
Serum glutamic pyruvate transaminase 
Syndrome of inappropriate anti-diuretic hormone  
Standard of care 
Standard operating procedure                                                                              

 
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SUSAR 
TAM 
TTP 
UCMC  
UC CGH 
ULN 
Suspected unexpected serious adverse reactions 
Tamoxifen 
Time to progression 
University of Chicago Medical Center  
University of Chicago Center for Global Health 
Upper limit of the normal range 
USS 
WBC 
Ultrasound scanning 
White blood count 
 
Glossary of terms 
Term 
Definition 
Assessment 
A procedure used to generate data required by the study 
Cycles 
Number and timing or recommended repetitions of therapy are 
usually expressed as number of days (e.g. q28 days) 
Complete Response (CR) 
Defined by RECIST criteria disappearance of all lesions 
Dose intensity 
Computed as the ratio of total dose received and actual duration. 
The relative dose intensity computed as the ratio of dose intensity 
and planned dose received/planned duration 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of 
the procedures described in the protocol) 
Human epidermal growth 
factor receptor (HER2) 
positive tumor 
Determined by at least one HER2 test (IHC, FISH, CISH) 
according to the FDA USA and manufacturer (DAKO Inc) and 
ASCO-CAP HER2 Test 2007 Guideline and 2013-2014 
Recommendations. www.asco.org/guidelines/her2 
Hormone receptor (HR) 
positive tumor 
Determined by IHC test of Estrogen Receptor (ER) and 
Progesterone Receptor (PgR) statuses according to the FDA USA 
and manufacturer (DAKO Inc) and ASCO-CAP ER/PgR 
Guidelines http://www.instituteforquality.org/asco-cap-guideline-
recommendations-immunohistochemical-testing-estrogen-and-
progesterone-receptors 
Investigational treatment 
Drug whose properties are being tested in the study as well as 
their associated placebo and active treatment controls (when 
applicable). This also includes approved drugs used outside of 
their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used according 
to approved indication/dosage 

 
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Objective Response Rate 
(ORR) 
The proportion of patients with an overall response of CR or PR, 
where tumor response is based on change in tumor diameter on 
USS after 4 cycles of three-weekly docetaxel in combination with 
HER-2 targeted therapy 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Palliative treatment 
Palliative treatment focuses on improving the quality of life of 
patients with serious illnesses. It helps not only to reduce pain in 
patient’s body or treatment side effects, but also in mind and 
spirit. Palliative care may be combined with curative treatment. 
Palliative care team includes palliative care doctors, nurses, and 
social workers, spiritual advisors, dietitians, occupational 
therapists, pharmacists, physical therapists, respiratory therapists, 
and volunteers 
Patient Number (Patient No.) 
Subject Number (Subject 
No.) 
A unique identifying number assigned to each 
patient/subject/healthy volunteer who enrolls in the study 
Partial Response (PR) 
≥ 30% decrease in the longest diameter of target lesions, with the 
baseline measurements taken as the reference  
Partial Response inoperable 
(PRi)  
Disease that meets criteria for partial response following 
ultrasound assessment after 4 courses of docetaxel but still 
surgically assessed as inoperable based on residual tumour size 
Partial Response operable 
(PRo) 
Disease that meets criteria for PR and is surgically assessed as 
operable based on residual tumour size 
Pathologic Complete 
Response (pCR) 
Histo-pathological examination of surgical specimen describes no 
gross or microscopic disease 
Pathological incomplete 
response (piCR) 
If there is residual or microscopic disease on histo-pathological 
examination of surgical specimen 
Performance status 
Measure of cancer patients’ general well being and activities of 
daily life to determine whether they can receive chemotherapy, 
whether dose adjustment is necessary, and as a measure for the 
required intensity of palliative care. It is also used as a measure of 
quality of life. 0 = normal activity, asymptomatic; 1 = 
symptomatic, fully ambulatory; 2 = symptomatic, in bed < 50% 
of time; 3 = symptomatic, in bed > 50% of time; 4 = 100% 
bedridden 
Pharmacokinetics (PK) 
The process by which a drug is absorbed, distributed, 
metabolized, and eliminated by the body 

 
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Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
Progression Free Survival 
(PFS) 
Defined as time from first dose of study drug treatment to 
progression or death due to any cause, as assessed by 
investigators 
State of menopause 
Considered post-menopausal and not having child bearing 
potential women if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have 
had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before entering 
the study. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow 
up hormone level assessment is she considered not of child 
bearing potential 
Response Rate (RR) 
Proportion of pts with change (shrinkage of at least 30%) in 
tumor diameter detected by breast ultrasonography 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Safety assessment 
The measures used to assess the toxicity level e.g. blood tests, 
ECHO 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit 
or when study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. 
In specific examples, it is important to judge investigational 
treatment component relationship relative to a study treatment 
combination; study treatment in this case refers to the 
investigational and non-investigational treatments in combination 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment 
for any reason; may or may not also be the point/time of 
premature patient withdrawal 
Systemic toxicity 
Adverse effects caused by a substance that affects the body in a 
general rather than local manner 

 
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Variable 
Item or field used in the data analysis; derived directly or 
indirectly from data collected using specified assessments at 
specified time points 
Vital signs 
Defined by measuring the heart rate, blood pressure and 
temperature 
Protocol summary 
  
Protocol number 
IRB 18-1178 
CABC123D4567 
Title 
Assessing REsponse to neoadjuvant Taxotere and TrAstuzumab in 
Nigerian women with HER2-positive breast cancer (ARETTA) 
Clinical phase 
II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
This investigator-initiated study was co-developed with the Ibadan 
multidisciplinary breast cancer group to examine pathologic complete 
response rate to neoadjuvant chemotherapy in combination with 
HER2 blockage therapy among Nigerian women with HER2-positive 
breast cancer. Our objective is to examine what proportion of patients 
will achieve complete pathological response with docetaxel + 
subcutaneous Herceptin, potentially supplemented with FEC, and be 
spared toxicity of additional chemotherapy.  
Primary objective and 
key secondary objective 
To test the efficacy and toxicity of three-weekly docetaxel 
chemotherapy and HER2 blockage with SC Herceptin (TscH) in 
Nigerian women with early stage HER2-positive breast cancer. The 
primary endpoint is complete pathologic response (pcR) after four 
cycles (12 weeks) of T + scH.  Responding patients with stable 
disease or partial response after TscH X 4 will receive neo-adjuvant 
non-cross resistant treatment with FEC +scH X 3.  All patients who 
achieve pCR will receive Herceptin SC post surgery to complete one 
year of treatment. A key secondary objective is to assess invasive 
disease-free survival (iDFS) at one year from enrollment.   
Additional secondary 
objectives 
To determine the pattern of response and mechanism of resistance to 
three-weekly TH based on genomic biomarkers including hormone 
receptors (ER and PgR) . To determine the pharmacokinetics of 
Herceptin SC.  To assess the quality of life (QoL) of the patients 
during and after treatment. To determine the cardiac toxicity 
associated with TscH with or without FEC +scH in Nigerian patients 
with breast cancer. 

 
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Study design 
This is a one-stage phase II study with a single arm design. The 
primary endpoint is rate of complete pathologic response (pCR).    All 
patients will receive 4 cycles of T+ scH in the neo-adjuvant setting. If 
there is clinical complete response on ultrasound examination, surgery 
will be done. Those with  clinical stable disease or partial response 
and operable disease or progressive disease will receive FEC+scHP 
for an additional 3 doses in the neoadjuvant setting. After surgery, all 
patients who achieve pCR will receive one year of Herceptin SC to 
complete 18 cycles. Patients with pathological incomplete response 
may have additional chemotherapy at the discretion of the managing 
physician. However, patients who are inoperable or have progressive 
disease after evaluation by ultrasound following 4 cycles of T+ scH 
with our without FECwill go off study treatment..  All enrolled 
patients will be followed for iDFS and overall survival.  
Adjuvant treatment will include hormonal therapy for hormone 
receptor positive disease.  Radiation therapy will be administered per 
standard of care. All patients will have active follow up every three 
months and have routine blood tests and physical examination for the 
first two years after all treatment is completed, then every six months 
for 3 years, and then annually through year 10. CT scan and bone scan 
will be done as clinically indicated to evaluate recurrence. Toxicity 
and QoL will be assessed.  
Study population 
The study will be carried out among histologically confirmed HER2-
positive breast cancer patients in Nigeria who are 
chemotherapy/hormonal treatment naïve  
Inclusion criteria 
Histologically confirmed carcinoma of the breast, AJCC stages IIA-
IIIC. Females 18-70 years, with consent for the study.  See Section 5.1 
for complete list.   
Exclusion criteria 
Pregnancy, HER2-negative disease, patients with distant metastasis 
(brain or visceral disease).  See Section 5.2 for complete list.   
Investigational and 
reference therapy 
Docetaxel, Trastuzumab (Herceptin SC)  [TH] are the investigational 
treatments while 5-Flurouracil, Epirubicin, Cyclophosphamide, 
Tamoxifen/Letrozole, LHRH agonist (Zoladex), RT are adjunct 
standard therapy 
Efficacy assessments 
Complete pathologic response (pCR), breast USS response, invasive 
disease-free survival (iDFS), overall survival (OS) 
Safety assessments 
Systemic toxicity according to Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0, ECHO, vital signs, CBC, LFT, 
E&U+ CR  
Other assessments 
QoL using validated questionnaires. Genomic analysis of residual 
tumor and serum biomarkers including cfDNA.  

 
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Statistical analysis 
All patients who signed consent and initiated neoadjuvant therapy will 
be included in the analysis. Demographics and baseline features will 
be presented using descriptive statistics. Based on current review of 
the literature in other populations, for this study we expect an 
inefficient treatment regimen of T+scH to elicit 20% or fewer pCR (p0 
= 0.20) and a successful treatment regimen to have at least 40% pCR 
at surgery (p1 = 0.40).  The patients with stable disease or partial 
response who attain pCR after additional FEC X 3 will be counted as 
successes, whereas those who are declared inoperable or have PD will 
be considered failures.  A one-sided binomial test will be performed to 
test the null hypothesis of a 20% pCR rate vs. a 40% alternative.  
Secondary analyes will compare pCR rates by hormone receptor 
status, lymph node status, and breast cancer subtype using Fisher’s 
exact test.   iDFS will be defined as the time from enrollment to first 
occurrence of any of the following events:  recurrence of ipsilateral 
invasive breast tumor, recurrence of ipsilateral locoregional invasive 
disease, distant recurrence, contralateral invasive breast cancer, or 
death from any cause.  iDFS and OS will be estimated by the Kaplan-
Meier method; prognostic factors will be identified using Cox 
regression.  The frequency of toxicity by type and grade will be 
summarized. Mixed effects regression models will be fit to analyze 
QoL measures over time. 
Key words 
Breast cancer, Docetaxel, Herceptin,  neoadjuvant treatment, response, 
Nigeria 

 
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1 Introduction 
1.1 Breast cancer overview 
Breast cancer accounts for 30% of globally diagnosed cancers and 16% of cancer related 
deaths. The incidence of breast cancer is higher in high-income countries when compared to 
low and middle-income countries; however the mortality rate is similar. This is due to the 
availability of better treatment in the high-income countries (WHO, 2009). In Nigeria, breast 
cancer is the most common female malignancy with a majority of cases presenting late with 
advanced disease - either locally advanced breast cancer or metastatic disease (Parkin et al, 
2006. 
Breast cancer is a heterogeneous disease with different cancer molecular subtypes and 
phenotypes (Perou et al, 2000) each of which requires a different treatment regimen and has 
different clinical outcomes (Andre et al, 2006). The most common subtypes have been 
defined by immunohistochemical assays of tumor specimens and have been classified by 
hormone receptors (HRs) positive or negative and human epidermal growth factor receptor 2 
(HER2) positive or negative statuses.  More recent work has begun to elucidate the genomic 
abnormalities in breast cancer subtypes and to correlate these subtypes with response to neo-
adjuvant chemotherapy (Kim et al, 2010; Huber et al, 2009; Caudle et al, 2012). Patients with 
molecularly-defined luminal A breast cancer (largely HER2-negative and hormone receptors-
positive (HER2−/HRs+) appear to have considerably better prognosis compared to all other 
groups while those with HER2+ subtypes show good response to trastuzumab. 
   
The use of molecularly targeted therapy has dramatically impacted breast cancer death rates in 
the US but global disparities in breast cancer outcomes continue to widen. In their most recent 
analysis, DeSantis et al noted the remarkable strides in breast cancer screening and treatment 
with a decrease in breast cancer mortality by 36% from 1989 to 2012; representing 249,000 
breast cancer deaths averted in US women. Examples of treatment breakthroughs include 
HER2-targeted therapies, which benefit all women with HER2-positive tumors (DeSantis et 
al, 2015). 
 
1.2 Breast cancer burden in Nigeria and Sub-Saharan Africa 
Research on the breast cancer burden in Africa has been rather limited due to incomplete data 
collection and lack of population-based registries. Nonetheless, data from the Ibadan Cancer 
Registry, one of the sites reporting for GLOBOCAN, suggest that the incidence of breast 
cancer has been on the rise (GLOBOCAN, 2014; Ferlay et al, 2015; Anyanwu S, 2008). This 
could be attributed to increased life expectancy, improved infectious disease control as well as 
changes in lifestyle, diet, and physical activity level. The peak incidence age of breast cancer 
in West Africa (Nigeria) is at least a decade earlier compared to Caucasians (Adebamowo et 
al, 2000). This may be due to more aggressive histologies, which are common among younger 
age groups especially in black populations. The mean age of women with breast cancer 
reported from Ibadan is 48 years (Ihekwaba et al, 1992; Forae et al, 2014). Most breast cancer 
patients present with advanced disease and more than 80% of the Nigerian breast cancer 
patients present with locally advanced disease: stage III-IV, large tumor size, diffuse tumor, 

 
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multifocal, fungating, of high grade, with high number of LN involvement, MTS and necrosis 
(Forae et al, 2014). The reason for this late presentation is multifactorial in nature ranging 
from delayed diagnosis and religious belief to ill-informed perceptions about breast cancer 
(Odusanya et al, 2001; Pruitt et al, 2014). Socioeconomic problems cause many patients to 
seek cheaper herbal and spiritual treatment options, and fear of mastectomy often leads to late 
presentations (Ayaji et al, 2002; Busolo & Woodgate, 2014).  
Our study in Nigeria and Senegal (West Africa) reported that the proportions of ER-positive, 
PgR-positive, and HER2-positive tumors were 24%, 20%, and 17%, respectively (Huo et al, 
2009). Others have reported even higher proportions for the expression of ER (54%), PgR 
(50%), and HER2 (31%) in sub-Saharan breast cancer cases (Nwafor & Keshinro, 2015) 
while 20-30% of breast cancers are HER2-positive  (Agboola et al., 2012). 
 
 
Figure 1.1. Spectrum of breast cancer subtypes across populations (Olopade et al, 2008; Huo 
et al, 2009) 
 
Research over the past decade has revealed that the ratios of different molecular subtypes of 
breast cancer differ across populations (Figure 1.1).  Results from the Carolina Breast Cancer 
Study (CBCS) showed that 39 percent of premenopausal African American women diagnosed 
with breast cancer had basal-like disease, compared with 14 percent of postmenopausal 
African American women and 16 percent of non-African American women of any age (Carey 
et al, 2006).  A study from the California Cancer Registry also concluded that young African 
American women have a higher incidence of triple-negative breast cancer (TNBC) and also 
identified a smaller but significantly increased prevalence in Hispanic women (Bauer et al, 
2007). Regardless of the stage at diagnosis, women with TNBC showed poorer survival than 
those with other breast cancers. Non-Hispanic black women had the poorest survival of any 
comparable group with a 5-year relative survival of 14%, compared to 36% for non-Hispanic 
white women and 37% for Hispanic women.   
 

 
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1.3 Treatment options for breast cancer 
Chemotherapy can be considered for patients with a tumor size > 1 cm or any size with high 
risk features such as high histological grade, HER2-positive, ER-negative, lympho-vascular 
invasion, node positive, ER-/PR-/HER2- triple negative disease and young age at onset 
(Mauri et al 2005; Mayer et al, 2015; Partridge et al, 2014; Gnant et al, 2015; Kaufmann et al, 
2012). Chemotherapy also improves relapse-free interval when combined with endocrine 
therapy (in those indicated) especially in young premenopausal women (Taylor W, 2010). 
Chemotherapy is commonly combined with surgery and radiotherapy. Although HER2 
positive breast cancer is an aggressive form of the disease with poor prognosis, the use of 
targeted therapies in the form of  HER blockage has greatly improved the prognosis of this 
disease (Soon et al. 2008). This is the current recommendation by most treatment guidelines.   
 
1.4 Neoadjuvant chemotherapy 
The primary focus of neoadjuvant chemotherapy is to downsize tumors for mastectomy and 
therefore it is now the standard of care for selected patients in countries at all levels of 
resources (Lodge et al, 2011). Neoadjuvant chemotherapy can also be considered in high-risk 
patients such as young age or advanced disease where assessment of disease response to 
chemotherapy can be evaluated to determine mechanisms of resistance. Although neoadjuvant 
therapy does not appear to change relapse-free or overall survival rates it provides a means of 
in vivo chemo-sensitivity testing and diminishes the tumor size in most patients, which in turn 
increases the probability of successful breast conserving surgery in patients whose tumors are 
inoperable initially (Anderson et al, 2011).  Randomized clinical trials of chemotherapy 
demonstrate similar long-term outcomes when patients are given the same treatment 
preoperatively compared to postoperatively (Rastogi et al. 2008). 
 
Guidelines for the treatment of locally advanced breast cancer (LABC), with particular 
reference to resource-poor countries, have been published (El Saghir et al, 2011). The Breast 
Health Global Initiative (BHGI) summit in 2007 (http://portal.bhgi.org/Pages/Default.aspx) 
focused on the management and implementation of primary systemic therapy in the form of 
neoadjuvant chemotherapy in locally advanced breast cancer and two important points were 
highlighted (BHGI). Firstly, all trials demonstrating the efficacy of neoadjuvant chemotherapy 
in breast cancer have been conducted in developed countries. Secondly, there is a paucity of 
literature on the impact of neoadjuvant chemotherapy for LABC in developing countries such 
as Nigeria and, although scientific advances drive management guidelines, the 
implementation is limited by local resources and expertise. 
 
Although newer agents are being studied in resource-rich nations, neoadjuvant chemotherapy 
for LABC remains predominantly anthracycline-based, particularly in resource-poor nations.  
In spite of high response rates to anthracycline-based regimes, only a small fraction of 
patients achieve pathologic complete response (pCR); more than 60% of patients with LABC 
continue to die of metastatic breast cancer; and disease-free survival (DFS) rates remain 
modest at only about 30% at 5 years (Arowolo et al., 2013). Clearly, further refinement of 
treatment strategies and introduction of more effective and less toxic chemotherapeutic agents 
are warranted. It is conceivable that a less toxic regimen given for longer duration might lead 

 
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to more complete pathologic responses and improved quality of life as has been demonstrated 
in patients with hormone receptor positive tumors treated with prolonged duration of 
hormonal therapy. The identification of effective agents that can be used alone or in 
combination with other agents is uniformly accepted as an appropriate drug development 
strategy in breast cancer.   
 
In the first breast cancer clinical trial ever conducted in Nigeria, we tested single agent 
capecitabine in chemotherapy naïve patients with LABC. The study was designed to 
demonstrate feasibility of a phase II trial involving an oral chemotherapeutic agent such as 
capecitabine in a resource-poor nation like Nigeria. A total of 16 patients were recruited from 
August 2007 to April 2010. After the first 3 cycles of therapy, pCR were seen in 5 of 16 
patients (31%; 95% CI 11% - 59%).  Of the remaining 11 patients, 8 had no response (NR) or 
stable disease (SD), and 3 had progressive disease (PD). OCR at the end of 8 cycles was 44% 
(95% CI 20% - 70%). Clinical response and radiologic response by ultrasonomammography 
were highly concordant (Spearman correlation 0.70). The most common adverse effect was 
Grade 1 handfoot syndrome, which was seen in 75% of patients. Despite several limitations, 
we carried out this phase II feasibility study of neoadjuvant capecitabine for locally advanced 
breast cancer in Nigeria but the study terminated early due to poor accrual.  Nearly 90% of 
patients were screen failures because they already had metastatic disease (Arowolo et al, 
2013).   As a nation, Nigeria will heavily invest in its health infrastructure including the 
needed infrastructure for effective cancer control for early detection and treatment of common 
cancers. This study is designed to test the feasibility of establishing a robust platform for 
multi-institutional biomarker driven oncology clinical trials as a way to improve quality of 
cancer care in Nigeria. Data from this clinical trial and subsequent phase III study should 
inform cancer control policies in Nigeria. 
 
1.5 Introduction to investigational treatment(s) and other study treatment(s) 
 
1.5.1 Docetaxel (TXT) 
Docetaxel (Taxotere, TXT) is a semisynthetic member of the taxoid class of antineoplastic 
agents. It is effective in the treatment of patients with advanced (locally advanced or 
metastatic) breast cancer. Reported objective response rates for docetaxel 100 mg/m2 ranged 
from 54% to 69% and 53% to 82% as first-line monotherapy or combination therapy, 
respectively. Objective response rates of 23% to 65% and 30% to 81% have been reported for 
docetaxel as second-line monotherapy or combination therapy (Figgit and Wiseman 2000).  
The antitumor activity of docetaxel is based on binding to tubulin and stabilization of non-
functional microtubule bundles, thereby blocking normal mitotic spindle development and 
subsequent cell division (Ringel, 1991). A dose of 100 mg/m2 is below the critical threshold 
for nonlinear pharmacokinetics (about 250 mg/m2 ). Docetaxel elimination is mediated by 
hepatic metabolism, followed by biliary excretion of its metabolites. Only a minor fraction is 
excreted unchanged in urine (< 15%). Of note, docetaxel is predominantly metabolized in the 
liver by cytochrome P450 (CYP) isoenzyme CYP3A4 and, to a lesser extent, by CYP3A5. 
The pharmacokinetics of docetaxel may also be altered in vivo as a result of interactions with 
compounds that are substrates, inducers, or inhibitors of CYP3A4, CYP3A5 and glycoprotein 

 
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(Baker et al 2009).The toxicity of docetaxel includes myelosuppression, arthralgia and 
myalgia. Neurotoxicity is a dose limiting toxicity and can manifest as peripheral neuropathy. 
These toxicities do not lead to stoppage of treatment, except if severe (Seidman AD et al, 
1998). 
 
1.5.2 5-Fluorouracil, Epirubicin, Cyclophosphamide (FEC) 
The combination of 5-Fluorouracil, Epirubicin, Cyclophosphamide (FEC) is one of the 
chemotherapy regimens approved for the treatment of breast cancer. It is approved as an 
adjuvant treatment following treatment with taxanes. The NCCN guideline also approves FEC 
regimen in combination with trastuzumab and pertuzumab for patients with HER2-positive 
breast cancer in both neoadjuvant and adjuvant settings (NCCN for breast cancer 2016). A 21-
day schedule (fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 
mg/m2) given for 3 doses is recommended following administration of a taxane with 
trastuzumab/pertuzumab (Buzdar et al, 2013: NCCN, 2016). The main toxicity associated 
with this regimen is neutropenia, fatigue and cardiotoxicity though not life threatening. 
 
1.5.3. Herceptin  (Trastuzumab) (H) 
Trastuzumab (Herceptin), a humanized monoclonal antibody against the extracellular domain 
of HER2, has been shown to benefit patients with HER2 positive metastatic breast cancer 
when administered weekly or every three weeks, alone or in combination with chemotherapy. 
The pharmacokinetics of trastuzumab is characterized by low systemic clearance, low volume 
of distribution and a very long half-life (28 days). The elimination pathways have not yet been 
defined and the clinical relevance of trastuzumab kinetic variability is unknown. No drug-
drug interactions have been reported. Dosage regimens of trastuzumab are similar in the 
adjuvant setting (postoperative) and in metastatic disease (Levêque et al, 2008). Trastuzumab 
is not associated with the adverse events that typically occur with chemotherapy (alopecia, 
myelosuppression, and severe nausea and vomiting) with the exception of hypersensitivity, 
which has been reported mainly and occasionally with the first infusion, furthermore  
cardiotoxicity (principally congestive heart failure) is the most important adverse effect of 
trastuzumab. Cardiotoxicity has been reported in 1.4% of women who received the drug as a 
single agent for metastatic disease. This adverse effect is higher if combined with 
anthracyclines than with taxanes (Piccart-Gebhart et al, 2005). Refer to the trastuzumab 
Package Insert for additional information.  
 
The usual route of administration for trastuzumab is through intravenous infusion. However, 
there is the recently EU-approved subcutaneous formulation of trastuzumab - Herceptin SC 
(Hourcade-Potelleret et al, 2014; Roche, 2015), which will be tested in this study. The 
subcutaneous formulation of trastuzumab has been reported to have a pharmacokinetic profile 
and efficacy non-inferior to the intravenous administration, with a similar safety profile and 
has been reported to be preferred by patients due to its convenience (Ismael et al. 2012, Pivot 
et al. 2013). A fixed subcutaneous dose of 600mg given every three weeks for 18 cycles given 
concurently or sequentially with chemotherapy has been reported to be safe and tolerable 
(Gligorov et al. 2017). In the aforementioned studies, indigenous black populations in Africa 

 
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were not included, yet they are the ones most likely to benefit from highly effective cancer 
medicines. This is a Phase II feasibility study to evaluate the efficacy and toxicity of four 
cycles every 3 weeks of docetaxel + trastuzumab (TH) in previously untreated women with 
non-metastatic breast cancer. 
 
1.5.5 Tamoxifen (TAM), letrozole (LET) and Luteinizing Hormone Releasing Hormone 
(LHRH) agonist.  
Tamoxifen is an anti-estrogen used for treatment of hormone positive breast cancer and the 
treatment of anovulatory infertility. It is an estrogen receptor antagonist (selective estrogen 
receptor modulator).  
Letrozole is an aromatase inhibitor (AI) indicated in the first line treatment of hormone 
positive breast cancer in post-menopausal women. Both drugs have been FDA approved and 
are in use for the treatment of indicated conditions. Refer to drug information package insert 
for further information. 
Luteinizing hormone-releasing hormone (LHRH) agonist is used for endocrine 
manipulation to medically suppress the function of the ovaries in premenopausal patients with 
advanced breast cancer. LHRH agonist has direct antitumor effects leading to decrease in the 
circulating estrogen concentrations to postmenopausal levels and is an alternative to surgical 
oophorectomy. Recent findings by two randomized, phase 3 trials, the tamoxifen and 
Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT), involving 
premenopausal women with hormone-receptor–positive breast cancer, showed that ovarian 
suppression by oophorectomy (surgical or radiation) or LHRH agonist plus TAM or AI is 
considered as the new effective standard treatment (Francis et al, 2015; Pagani et al, 2014). 
Recent studies including Gynecologic Oncology Group Protocol-0199 (GOG-0199) results 
indicate that risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from 
ovarian/tubal and breast cancers not only among BRCA1/2 mutation carriers but has potential 
benefits among high-risk noncarriers. In addition, women who had a bilateral oophorectomy 
and who used hormonal therapy had nearly a threefold lower risk of incident coronary heart 
disease than women who had not used hormonal therapy after oophorectomy or those who 
never used hormonal therapy (Francis et al, 2015; Sherman et al, 2014).  Our longterm goal is 
to optimize therapy for the predominantly young women who develop aggressive breast 
cancer in Nigeria and develop national guidelines for optimal management of these patients. 
2 Rationale 
2.1 Study rationale and purpose 
 
Racial/ethnic disparities in breast cancer mortality continue to widen and biomarker intensive 
clinical trials rarely interrogate breast cancer in underserved populations of African ancestry. 
Through genome, exome, and RNA sequencing, we recently examined the molecular features 
of breast cancers using 194 patients from Nigeria and 1,037 patients from The Cancer Genome 
Atlas (TCGA). Relative to Black and White cohorts in TCGA, we saw substantial genomic 

 
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differences and Nigerian tumors are characterized by increased homologous recombination 
deficiency signature, pervasive TP53 mutations and greater structural variation — indicating 
aggressive biology. This dataset provided novel insights into potential molecular mechanisms 
underlying outcomes disparities and lays a foundation for deployment of precision therapeutics 
in underserved populations (Pitt et al 2018). 
Nigeria is long overdue for implementation of this clinical trial as there is no standard of care 
for HER2 targeted therapy in Nigeria.  In collaboration with Roche Global and the 
Investigative team of Nigerian Oncologists, the study will determine the efficacy and toxicity 
of 4 cycles of three-weekly neo-adjuvant docetaxel chemotherapy in conjunction with 
Herceptin SC followed by one year of Herceptin SC in Nigerian women with HER2-positive 
breast cancer. Of note, no one can afford HER2 targeted therapy in Nigeria or even standard 
chemotherapy without access to health insurance.   
 
The study considers three weekly docetaxel as recommended backbone to be combined with 
Herceptin SC with manageable toxicity rate.  This combination has been shown to be 
efficacious with manageable toxicities in other populations. One of the objectives for this 
biomarker intensive phase II feasibility study is to establish a platform for clinical trials in 
Nigeria and identify genomic biomarkers of response and toxicity to protocol driven and 
optimal HER2 targeted therapy in Nigerian women. Nigerian patients receive sub-optimal 
therapy even when they can afford the treatments.  Three-weekly taxane has been reported to 
be well tolerated by elderly patients with breast cancer and one of our objectives is to use this 
clinical trial to improve management of chemotherapy toxicities by training treating 
oncologists and nurses about optimal care of patients undergoing treatment for cancer 
(Beuselinck et al., 2010).   
 
Without optimal chemotherapy, breast cancer mortality in the Nigerian population will remain 
high. Ensuring the development of cancer research that meets the needs of people who live in 
low resource settings is integral to alleviating the cancer burden. There is a view that a focus 
on phase II and III cancer clinical trials in sub-Saharan Africa can give African researchers the 
opportunity to “learn by doing”, to foster sustainable clinical research capacity through 
international collaboration between African partners, the developed countries and regional 
collaboration between African research institutes (RAND 2015). Research collaborations 
between African and non-African partners hold the potential to have a significant impact on 
the development of clinical research capacity in sub-Saharan Africa.  This study is a 
collaboration between the University of Chicago and multiple centers in Nigeria. 
 
Among the study population, there are no data on the response rate, toxicity and quality of life 
during treatment with any cancer therapy and none for docetaxel or HER2 targeted therapies. 
Docetaxel can be used in elderly patients and is well tolerated in patients with mild cardiac 
pathology in which the commonly used doxorubicin-based combination may be 
contraindicated. Docetaxel has been successfully combined with Herceptin IV (trastuzumab) 
in patients with HER2-positive breast cancer without potentiating the cardiotoxic effect of 

 
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Protocol No. CABC123D4567 
 
Herceptin (Burris III, 2004). In this study, FEC will be given to patients with operable stable 
disease or partial response (in an attempt to induce pCR), as well as those with progressive 
disease or inoperable stable disease after four cycles of TscH.  However, patients with pCR 
after TH can be spared the cardiotoxicity associated with doxorubicin-based chemotherapy.  
With this schedule, we believe we can identify a subset of patients with excellent response to 
TscH who will then complete one year of Herceptin SC. Patients will be evaluated for toxicity 
and clinical improvements before each cycle, but a breast ultrasound (USS) to assess and 
document response using RECIST criteria will be performed every 6 weeks during Taxetere + 
Herceptin SC, and every 6 weeks during FEC and at 4th week after last dose of FEC for those 
indicated. 
 
2.2 Rationale for choice of drug and schedule  
2.2.1 Docetaxel (TXT) and Trastuzumab  
There is no standard of care for Nigerian patients with HER2 positive breast cancer because 
the Nigerian Health System has not been able to provide access to essential cancer medicines 
for the population. While HER2 blockade is standard of care in developed countries, this 
study will aim to establish the efficacy of Docetaxel in combination with HER2 targeted 
therapy in Nigerian patients. 
 
Docetaxel is an acceptable alternative regimen for patients with poor response to CMF 
(Cyclophosphamide, Methotrexate, 5-Fluorouracil) and Adriamycin and Cyclophosphamide 
(AC) chemotherapy.  In a randomized open-label phase III study to compare the 
pharmacokinetics, efficacy and safety of subcutaneous (SC) Herceptin (trastuzumab) with 
intravenous (IV) Herceptin (trastuzumab) administered in women with HER2-positive early 
breast cancer, the study demonstrated non-inferiority of pharmacokinetics and efficacy for 
Herceptin SC versus Herceptin IV (Ismail et al., 2012). Overall, the safety profiles of the 
Herceptin SC and IV formulations were reported as comparable and consistent with the 
known safety profile of Herceptin. Therefore, Herceptin 600 mg three-weekly dose 
administered subcutaneously in approximately 5 minutes provides a valid treatment 
alternative to the three-weekly intravenous Herceptin regimen (Roche 2012). Subcutaneous 
Herceptin is in routine use in Europe and marketed in Nigeria, and therefore is a more 
convenient way to administer the drug. In an  international, randomised PrefHer study to 
assess patients’ preference for either subcutaneous or intravenous trastuzumab, patient 
preference and safety results from PrefHer, combined with the known non-inferior efficacy 
and pharmacokinetic and safety profile data, suggest that a fixed dose of 600 mg trastuzumab 
administered subcutaneously every 3 weeks is a validated, well tolerated treatment option for 
HER2-positive breast cancer, and is the preferred treatment by patients  (Pivot et al., 2013). 
 
Dual HER2 blockade has been tested to improve overall outcomes in HER2 postive breast 
cancer but this has not been accepted as standard of care in every country as the results are 
mixed.  The added toxicity of dual blockade with potential added financial toxicity makes it 
hard to justify dual blockade as the first clinical trial to be conducted in a low resource setting 
Commented [KT-H1]: This seems to contradict the 
synopsis, which says patients with PD or inoperable will 
come off study treatment. 
 
Commented [AN2R1]: Section on Synopsis corrected to 
conform to this 

 
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like Nigeria.  Furthermore,  there is new evidence that patients who achieve pCR after THP 
can be spared the added toxicities associated with doxorubicin based chemotherapy. Hence, 
this study will consider a backbone of Taxotere chemotherapy X 4 cycles + Herceptin SC in 
the neoadjuvant setting to identify the genomic biomarkers of response that would be carried 
to a phase III study to determine the most efficient and cost effective combination 
neoadjuvant treatment for the majority of HER2 positive patients in Nigeria, where there is no 
population based screening and the majority of patients present with clinically palpable 
masses. 
 
In summary, this phase II feasibility study will test the efficacy of Taxetere + Herceptin SC X 
4 cycles in the neoadjuvant setting and one year of Herceptin SC as adjuvant therapy for 
HER2 positive breast cancer among Nigerian women.  For responsders who do not have 
complete clinical response after 4 cyclers of Taxetere, they will receive an additional 3 cycles 
of neoadjuvant non-cross resistant FEC + Herceptin SC. This study will be used to test an 
emerging platform for future biomarker based multi institutional oncology clinical trials in 
Nigeria and across Sub-Saharan Africa.   
3. Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 

 
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Table 3-1 Objectives and related endpoints 
Objectives 
Endpoints and Analyses 
Analysis 
Primary and key secondary 
 
Refer to Section 9.4 
To determine the efficacy of docetaxel + 
Herceptin SC every three weeks for four cycles 
with or without FEC + Herceptin SC for three 
cycles (with Tamoxifen/Letrozole added to 
ER/PR Positive patients) in Nigerian women 
with HER2-positive breast cancer 
 
To determine the toxicity of every three-weeks 
docetaxel + SC Herceptin with or without FEC 
+ Herceptin SC for three cycles (with 
Tamoxifen/Letrozole added to ER/PR Positive 
patients) in Nigerian women with HER2-
positive breast cancer 
 
1. Percentage of participants achieving pathological complete 
response (pCR) at surgery is the primary end point. 
[Time Frame: Approximately 4 – 6 months from commencement of 
chemotherapy. (Surgery will be  performed within 2 weeks after 
Cycle 4 of T+scH for those with complete clinical response or after 
additional 3 cycles of FEC for those with stable disease or partial 
clinical response to T+scH.) ]  
2. Percentage of participants achieving pCR by hormone receptor 
status [Time Frame: Approximately 4 – 6 months from 
commencement of chemotherapy. (Surgery will be  performed 
within 2 weeks after Cycle 4 of T+scH for those with complete 
clinical response or after additional 3 cycles of FEC for those with 
stable disease or partial clinical response to T+scH.)] 
3. Percentage of participants achieving pCR by lymph node status 
[Time Frame: Approximately 4 – 6 months from commencement of 
chemotherapy. (Surgery will be  performed within 2 weeks after 
Cycle 4 of T+scH for those with complete clinical response or after 
additional 3 cycles of FEC for those with stable disease or partial 
clinical response to T+scH.) ] 
 

 
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Objectives 
Endpoints and Analyses 
Analysis 
4. Percentage of participants achieving pCR by breast cancer 
subtype [Time Frame: Approximately 4 – 6 months from 
commencement of chemotherapy. (Surgery will be  performed 
within 2 weeks after Cycle 4 of T+scH for those with complete 
clinical response or after additional 3 cycles of FEC for those with 
stable disease or partial clinical response to T+scH.)] 
Note: Pathological complete response in the breast is defined as the 
absence of invasive cells at microscopic examination of the primary 
tumor and lymph nodes at surgery. Any remaining in-situ lesions 
are  permissible. Participants with invalid/missing pCR assessments 
will be defined as non-responders. 
5. Percentage of participants experiencing grades 3 and 4 
haematological, gastro-intestinal, neurological and cardiovascular 
toxicities. Time Frame: at any point during serial assessment from 
commencement of chemotherapy and Herceptin SC till 10 years  or 
withdrawal or death. 
Clinical and laboratory adverse events (AEs) will be reported 
according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 
5.0. In addition, cardiovascular side effects will be reported 
according to prespecified criteria (NCI-CTCAE and New York 
Heart Association [NYHA]). 
Left ventricular ejection fraction (LVEF) will be assessed using 
echocardiogram (ECHO) scans. Cardiac reassessment throughout 
the study will be performed using the same technique as at baseline. 
 

 
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Objectives 
Endpoints and Analyses 
Analysis 
Secondary 
 
Refer to Section 9.5.2 
To evaluate other response-related endpoints: 
duration of response (DOR), clinical response, 
progressive disease during neoadjuvant 
treatment, breast-conserving surgery, invasive 
disease-free survival 
1. Percentage of participants achieving clinical response (CR and 
PR) during neo-adjuvant period by breast ultrasound  
[Time Frame: Approximately 4 – 6 months from 
commencement of chemotherapy. (Surgery will be  performed 
within 2 weeks after Cycle 4 of T+scH for those with complete 
clinical response or after additional 3 cycles of FEC for those 
with stable disease or partial clinical response to T+scH.)] 
2. Percentage of participants with progressive disease during neo-
adjuvant treatment period [Time Frame: Baseline up to Cycle 4 
(assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery)  
3. NB: Tumor assessments based upon the Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria - version 1.0. The 
clinical response at each cycle up to the last assessment prior to 
surgery will be derived for: i) the primary breast lesion; (ii) 
across secondary breast lesions, (iii) across all breast lesions (iv) 
across axillary nodes (v) across supraclavicular nodes and (vi) 
across all nodes (vii) across all lesions (overall) using the 
following algorithm: CR: if measurement of '0' is noted at a 
given cycle as compared to baseline measurement which is >0 at 
screening; PR: if measurement is at least 30% decreased 
compared to baseline levels. (Reference= baseline size or sum 
of sizes). Clinical responders are participants who have 
achieved CR or PR during the neo-adjuvant treatment. Primary 
breast tumor clinical response is based on primary breast tumor 
assessment. Overall response is derived based on the sum total 
of breast tumors and all nodes examined. PD: if lesion is at least 
 

 
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Objectives 
Endpoints and Analyses 
Analysis 
20% increased from measurements at baseline. Percentage of 
participants achieving breast conserving surgery for whom 
mastectomy was planned [Time Frame: Approximately 4 – 6 
months from commencement of chemotherapy. (Surgery will be 
performed within 2 weeks after Cycle 4 of T+scH for those with 
complete clinical response or after additional 3 cycles of FEC 
for those with stable disease or partial clinical response to 
T+scH.)]Breast Conserving Surgery (BCS)  defined as 
quadrantectomy, lumpectomy, no surgery,  axillary surgical 
resection or other method of avoiding mastectomy. 
 
4. Invasive Disease Free Survival  (iDFS ) [Time Frame: from first 
dose of study drug treatment up to a maximum of 10 years. 
iDFS defined as the time from enrollment to the first 
documentation of recurrence of ipsilateral invasive breast tumor, 
recurrence of ipsilateral locoregional invasive disease, distant 
recurrence, contralateral invasive breast cancer or death due to 
any cause, as assessed by investigators. iDFS will be determined 
using Kaplan-Meier estimates. 
5. DOR, defined as time from first response to disease progression 
or death. 
6.  Overall survival (OS) is defined as time from enrollment to 
death from any cause.   
 
  

 
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Protocol No. CABC123D4567 
 
Objectives 
Endpoints and Analyses 
Analysis 
To determine the cardiac toxicity associated 
with TscH with or without FEC +scH in breast 
cancer patients 
 
To determine the pharmacokinetic profile of 
Herceptin SC given in combination with 
Docetaxel  
 
 
To determine the pharmacokinetic profile of 
Herceptin SC given in combination with FEC 
following poor response to TH 
 
To evaluate the quality of life (QoL) of 
patients on every three-weeks docetaxel (+ 
FEC) with Herceptin over time  
 
 
 
 
 
To explore mechanisms of resistance to HER2 
targeted therapy in Nigerian women  
The percentage of participants with Heart failure (NYHA Class III 
or IV or as confirmed by a cardiologist) and a decrease in LVEF of 
at least 10 EF points from baseline and to below 50%. 
 
Blood concentrations of Herceptin SC at multiple time points using  
the peak exposure Cmax  and the extent of exposure AUC 0-21d from 
day 0 to day 21 will be determined.  
 
 
Time-to-peak drug plasma concentration Tmax, drug concentration at 
the end of the dosage interval Ctrough.  
 
 
The various domains of QoL over time and the changes from 
baseline using the validated (by the European Organization for 
Research and Treatment of Cancer (EORTC)) QoL instrument 
(global and breast module). Analysis will be conducted to 
investigate the changes in HRQL over time. 
 
 
Genomic analysis of serial blood/serum specimens and evaluation 
of tumor biopsy specimens for genomic biomarkers of primary 
resistance to chemotherapy.  Tumor subtypes/tumor biology will be 
correlated with patient’s characteristics, response to treatment and 
iDFS.  
 

 
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4. Study design  
4.1 Overview 
This is a one-stage phase II study with a single arm design. It will be conducted in women 
with HER2-positive breast cancer with stages IIA to IIIC (defined by AJCC 2009 
classification) of all hormonal statuses. All patients will receive 4 cycles of docetaxel + 
Herceptin SC.  Breast ultrasound will be done after every 2 cycles (every 6 weeks) during 
neoadjuvant chemotherapy. Those with complete clinical response following breast 
ultrasound assessment after 4 cycles of docetaxel + Herceptin SC will undergo surgery.  At 
surgery, those with pCR will not have further chemotherapy and they will receive one year of 
Herceptin SC to complete 18 cycles. Those with partial response or stable disease (operable) 
will be switched to have FEC+ Herceptin SC for additional 3 cycles in the neoadjuvant setting 
before surgery and continue to complete 18 cycles of Herceptin SC after surgery within one 
year.  Patients with stable disease (inoperable) after salvage FEC + Herceptin SC or 
progressing patients before salvage FEC + Herceptin SC will go off study treatment and be 
followed for survival end point.  Adjuvant treatment will include hormonal therapy for 
hormone receptor positive disease.  Radiation therapy will be administered per standard of 
care. 
The primary Endpoint is pCR in the one-stage phase II design.    All patients will have active 
follow up every three months and have routine blood tests and physical examination for the 
first two years and every  6-12 months for 10 years. CT scan and bone scan will be done as 
clinically indicated to evaluate recurrence. (Figures 4-1, 4-2)  
 
The response evaluation will be adapted from RECIST criteria (Response Evaluation Criteria 
In Solid Tumors, version 1.1) using breast ultrasound as follows: 
1. 
Complete (Clinical) Response (CR): disappearance of breast lesion and lymph 
node, confirmed (after 4 cycles of TH or after 3 cycles of FEC + H). (Surgery 
should take place approximately 4 weeks after last dose  of chemotherapy.)  
2. 
Partial Response (PR): ≥30% decrease in the longest diameters of target breast 
/lymph node lesions, with the baseline measurements taken as the reference, 
confirmed at 16th week. 
3. 
Partial Response inoperable (PRi): Disease that meets criteria for partial response 
following ultrasound assessment after 4 courses of TH and 3 additional courses of 
FEC + H but still surgically assessed as inoperable based on residual tumour size. 
4. 
Partial Response operable (PRo): Disease that meets criteria for PR and is 
surgically assessed as operable based on residual tumour size. 
5. 
Stable Disease (SD): neither PR nor PD criteria are met (may be operable [SDo] 
or inoperable [SDi]). 
6. 
Progressive Disease (PD) ≥ 20% increase in the longest diameters of target 
lesions, with the longest diameters recorded when treatment started taken as the 

 
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reference, appearance of new lesions, or unequivocal progression of non-target 
lesions. 
7. 
Pathologic Complete Response (pCR): If histo-pathological examination of 
surgical specimen (breast and lymph nodes) does not describe any gross or 
microscopic disease.  Presence of in situ disease is permissible. 
Each patient will be assigned one of the following response categories: 1) complete 
pathologic response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because of other 
cause, or 8) unknown (not assessable, insufficient data).  Note:  categories 2-4 are ultrasound 
findings for patients who do not have pCR or were deemed inoperable.  Patients with a 
complete clinical response who are found not to have a pCR will be categorized as partial 
responders.  
All premenopausal patients will receive LHRH agonist for two years for contraception and 
fertility preservation. Hormone-receptor positive patients will receive hormonal therapy with 
tamoxifen or letrozole after surgery, radiotherapy and LHRH agonist according to the 
expression of hormone receptors ER and PgR (see glossary and section 10.3) and according to 
the state of primary menopause (see glossary) at the onset of the study. 
 
 
 
 
 
 

 
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FIGURE SHOULD READ <=14 pCR RESPONSES, NOT <14  
4.2 Definition of end of study 
End of study Last Patient Last Visit (LPLV) will be upon completion of 10 years of follow up 
of last patient recruited into the study and collection of survival information.  
Follow up visits will be carried out for all patients every 3 months for two years and thereafter 
every 6 months for the next 3 years and yearly for last 5 years (10 years total). During this 
period, patients will be monitored for duration of response/relapse (locoregional and distant) 
using clinical examination and blood tests as needed. 
The first study report – Core Clinical Study Report (CCSR) will be done after all enrolled 
patients have either completed surgery or been deemed inoperable. Second report (Interim 
Clinical Study Report (ICSR) will be done after 5 years of follow up while the third  report 
(Final Clinical Study Report, FCSR) will be done after 10 years of follow up. 
 
4.3 Early study termination 
The study can be terminated at any time for any reason by the investigators. Should this be 
necessary, study participants will be seen as soon as possible and the same assessments as for 
prematurely withdrawn patients will be conducted. The investigators will inform appropriate 
IRBs of the early termination of the trial. 
 
5. Patient population 
This study will be carried out among indigenous black women of all tribal groups in Nigeria. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are enrolled and receive treatment in the study. 
Commented [KT-H3]: ** should read patients with 
progressive disease, inoperable after Docetaxel will go off 
study.  Non-responders could have SD and get FEC, 
right?               
Commented [AN4R3]: Those patients in ** should 
receive FEC. The statement will be deleted.  
<= 4 to  be effected 

 
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5.1 Inclusion criteria 
Patients eligible for inclusion in this study should meet all of the following criteria: 
Written informed consent must be obtained prior to any screening procedures 
1. 
Women ages of 18 to 70 years old 
2. 
Biopsy-accessible  breast tumor of significant size for core needle 
biopsy/ultrasound measurable (≥ 2cm) 
3. 
Patients with histologically confirmed carcinoma of the female breast with 3+ 
positive HER2 status by IHC 
4. 
Clinical stages IIA –IIIC (AJCC 2009)  
5. 
Chemotherapy-naïve patients (for this malignancy) 
6. 
Performance status: ECOG performance status 0−1 (Appendix A) 
7. 
Non-pregnant and not nursing. Women of childbearing potential must take the 
pregnancy test and must commit to receive LHRH agonist Zoladex (goserelin) for 
two years starting from the commencement of the study medications 
8. 
Required Initial Laboratory Data. Adequate hematologic, renal and hepatic 
function, as defined by each of the following:  
1. 
Granulocyte ≥ 1,500/μL  
2. 
Platelet count ≥ 100,000/μL  
3. 
Absolute neutrophil count (ANC) ≥ l500/μL 
4. 
Hemoglobin ≥ 10g/dL 
5. 
Bilirubin ≤ 1.5 x upper limit of normal 
6. 
SGOT and SGPT < 2.5 x upper limit of normal  
7. 
Creatinine within institutional normal limits or glomerular filtration rate ≥ 
30 mL/min/1.73 m2 by CKD EPI equation (see http://mdrd.com/ for 
calculator) 
9. 
ECHO: Baseline left ventricular ejection fraction of  ≥ 55% 
 
 
5.2 Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
 
1. 
Pregnant or lactating women. Women of childbearing potential not using a 
reliable and appropriate contraceptive method. Postmenopausal women must have 
been amenorrheic for at least 12 months to be considered of non-childbearing 
potential.  Patients of childbearing potential will agree to continue the use of 
Commented [KT-H5]: Advertisement says 18-75 
Commented [AN6R5]: 70 is the upper limit. Advert will 
be corrected 
Commented [KT-H7]: Not quite consistent with Section 
6.1 
Commented [AN8R7]: FISH or CISH will be included 
here 

 
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acceptable form of contraception for 24 months from the date of last Herceptin 
administration. 
2. 
Patients with distant metastasis (brain and/or visceral metastasis) 
3. 
Serious, uncontrolled, concurrent infection(s). 
4. 
Treatment for other carcinomas within the last 5 years, except non-melanoma skin 
cancer and treated cervical carcinoma in-situ (CCIS)  
5. 
Participation in any investigational drug study within 4 weeks preceding the start 
of study treatment  
6. 
Other serious uncontrolled medical conditions that the investigator feels might 
compromise study participation including but not limited to chronic or active 
infection, HIV-positive patient, uncontrolled hypertension, symptomatic 
congestive heart failure, unstable angina pectoris, uncontrolled Diabetes mellitus, 
or psychiatric illness/social situations that would limit compliance with study 
requirements. 
7. 
Patients with HER2-negative disease 
 
5.3 Recruitment process 
 
As the first investigator initiated biomarker based clinical trial in Nigeria, we have spent the 
past year developing a robust recruitment plan as detailed below: 
 
1. Patient base: We have established a screening log at each site.  In the past 6 months, we 
have refined our screening process and 35 potential patients were identified. Enrollment will 
not be competitive at each site because there is no ongoing study at any of the sites in Nigeria. 
 
2. Extensive outreach efforts: We are also planning extensive outreach efforts to include 
a) Media coverage at protocol’s launch. We will partner with the Nigerian Federal Ministry of 
Health, Committee of Chief Medical Directors, Breast Cancer Advocacy Groups and 
community members to develop publicity around the launch so that Nigerian citizens are 
aware of the availability of the clinical trial in four sites in Nigeria. The trial will also be 
posted at the websites of all the participating institutions.  
b) Information on availability of the trial will be sent to colleagues at nearby institutions using 
emails, text messages, and relevant professional group social media to direct eligible 
participants for the study. 
c) Flyers and pamphlets containing information on the trial will be prepared and distributed to 
clinicians and health workers at meetings to provide information on the trial. The flyers will 
also be distributed to the public (sample of advertisement –appendix H).  
d) The trial will also be advertised on mass media such as radio and television and 
newspapers.  
3. We have established multidisciplinary breast cancer Management Tumor Board at UCH 
Ibadan with plans to establish Tumor Boardsat the other collaborating Institutions where 

 
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eligible patients will be screened. At LUTH there is a breast cancer clinic where all the 
clinicians see patients jointly. Recruitment will be facilitated at this center. 
 
4. Lastly, within our translational research program, we are developing a robust recruitment 
and retention program to remove barriers to participation in clinical trials among Nigeria 
breast cancer patients.  
6. Treatment  
6.1 Study treatment 
For this study, “Study treatment” refers to all combinations of antineoplastic drugs given 
during the course of the trial. All dosages prescribed and dispensed to the patient and all dose 
changes during the study must be recorded.  
The investigator or responsible site personnel will instruct the patient to take the study drugs 
as per protocol (promote compliance). Drug accountability must be performed on a regular 
basis. The site personnel will ensure that the appropriate dose of each study drug 
(chemotherapy and anti HER 2 agents) is administered at each visit and will provide the 
patient with the correct amount of any oral medications. 
We plan to treat patients with docetaxel + Herceptin SC three-weekly for a total of 12 weeks. 
Ultrasonography for response assessment will be done every 6 weeks and patients achieving 
complete clinical response after 4 cycles of docetaxel + Herceptin SC will undergo surgery.  
Each study site has a team of surgeons included in the study team. These surgeons will be 
participating in all aspects of the surgery related to the study protocol. Partial responders or 
patients with stable disease will be given 3 additional cycles of non-cross resistant FEC + 
Herceptin SC.  If there is evidence of disease progression or inoperable stable disease, patients 
will be taken off study treatment.  
 
1. 
The HER2 status will be detected in core biopsy for initial assignment and in resected 
tumors to re-assess HER2 status for treatment evaluation. Cases with HER2 IHC score 
3+ and cases with score 2+ that are confirmed by FISH or CISH for gene amplification 
will be considered HER2+. 
2. 
Patients will undergo surgery within 4- 6 weeks of last dose of chemotherapy regimen. 
Surgical tumor specimen will undergo routine institutional histo-pathological 
examinations. It will be used for confirmation of complete response in this study, i.e. 
whether clinical complete response corresponds to pathological complete response. 
ER/PR and HER2 statuses will be re-evaluated on any residual tumor. Residual tumor 
samples will be sent for genomic analysis to evaluate molecular markers of response. 
3. 
Radiation therapy will be given after chemotherapy and surgery according to institutional 
practice. As a general guideline, radiation treatment will be started 6-8 weeks after 
completion of definitive surgery and chemotherapy. Patients undergoing breast 
conservation therapy will be treated to the intact breast with tangential fields at 180-200 
cGy/fraction to a total dose of 5000-6600 cGy, including any boost. It is recognized that 
use of post mastectomy and regional nodal radiation is variable. Recommended 
Commented [KT-H9]: table says 4-6 weeks 
Commented [AN10R9]: This will be adjusted to read 4-6 
weeks 

 
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guidelines are to treat the post-mastectomy chest wall and/or nodal regions in patients 
with 4 or more positive nodes in the axilla and in patients with tumor of 5 cm or more in 
size to 4500-5500cGy at 180-200 cGy/fraction. As there is no radiation question in this 
protocol, there will be no dosimetry or portal field review. 
4. 
Adjuvant hormone therapy is recommended for 5-10 years for all ER+ or PgR+ patients 
after the completion of surgery and chemotherapy (ER+/PgR+ defined as ≥1% of stained 
nuclei/hpf). Hormone receptors status will be determined in initial core biopsy for 
assignment of targeted therapy with TAM or Aromatase Inhibitor of choice and it will be 
re-assessed in resected tumors. 
5. 
Tamoxifen (20 mg orally once daily) or an aromatase inhibitor letrozole 2.5mg orally 
once daily (for documented postmenopausal women only) will be started within  
12 weeks of completion of chemotherapy. This allows for the variable period needed for 
surgery to be completed. All premenopausal patients will receive LHRH agonist Zoladex 
(goserelin) 10.8mg (subcute) every 3 months for 2 years from the onset of study 
treatment. 
Quality of life (QoL) assessment using EORTC QoL instrument (English or Yoruba language 
versions) will be administered for all participants before each chemotherapy session 
(Appendix C). 
6.2 Dosing guidelines  
Docetaxel will be given at 75 mg/m2, increasing to 100 mg/m2 from cycle 2 onwards if the 
75mg starting dose was well tolerated (by i.v. infusion and diluted in NS or D5W) and given 
every three weeks for four cycles. Patients with CCR will have surgery within 4 weeks of last 
dose of docetaxel + Herceptin. Patients  with partial response or stable disease will continue 
with 3 doses of FEC (three cycles of intravenous FEC (fluorouracil 600 mg/m2, epirubicin 90 
mg/m2, and cyclophosphamide 600 mg/m2- diluted in NS or D5W) + Herceptin every 3 weeks 
before surgery.  
All patients will receive anti-HER-2 blockade Herceptin. Herceptin therapy at 600 mg subcute 
(fixed dose irrespective of patients’ weight/body surface area) on day 1 of each cycle and 
thereafter every three weeks. A total of 18 doses will be given (one year). Herceptin dosing is 
not interrupted during surgery.  
The injection site should be alternated between the left and right thigh and should be 
administered at a steady rate over 3 - 5 minutes using a hand-held syringe. New injections 
should be given at least 1 inch/2.5 cm from the old site in healthy skin and never into areas 
where the skin is red, bruised, tender, or hard. During the treatment course with Herceptin SC, 
other medications for SC administration should preferably be injected at different sites. 
For all patients docetaxel will be administered after 30-60 minutes of trastuzumab 
administration.  
Oral tamoxifen 20mg or Arimidex Img or letrozole 2.5mg or Exemesatane 25 my (with 
Zoladex as indicated) will be given daily to complete 5-10 years of adjuvant hormonal 
treatment.  All premenopausal patients will receive SC LHRH agonist goseriline (Zoladex) 
10.8mg on day 1 of chemotherapy and every 3 months after chemotherapy for 2 years. 
 

 
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6.3 Ultrasound evaluation of response 
Ultrasonography of the breast  for evaluation of response shall be done at baseline and every 6 
weeks during neoadjuvant treatment (as well as post FEC if FEC is administered) by study 
radiologists at each site. Radiologist will report the results from ultrasonography as part of 
routine clinical care. Central review will be conducted by the Radiology Subcommitee of the 
clinical trial group.  
 
6.4 Dosing regimen 
 
Table 6-1 
Dose and treatment schedule  
Study treatment 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or Regimen 
 
 
 
 
Docetaxel 
Intravenous infusion (1 hr) 75 mg/m2, then 
100 mg/m2 from 
cycle 2 onwards 
if tolerated  
Day 1, 21 ---- (3-weekly) 4 
doses  
Epirubicin 
 
5 Fluorouracil 
Intravenous infusion (1 hr)  
 
Intravenous 
90mg/m2 
 
600mg/m2 
 3-weekly cycle, 3 doses  
 
3-weekly cycle, 3 doses  
Cyclophosphamide 
Trastuzumab 
(Herceptin) 
 
Intravenous 
Subcutaneous injection (2-
5 mins) 
 
 
600mg/m2 
600mg  
 
 
3-weekly cycle, 3 doses 
Day 1 (21 day cycle) 18 
doses 
 
*Tamoxifen  
*Letrozole 
*LHRH agonist 
goserelin (Zoladex) 
Oral tablets 
Oral tablets 
Subcutaneous injection 
20 mg 
2.5 mg 
10.8mg 
Daily (continuous) after 
surgery for 10 years 
Every 3 months for 2  years 
*Tamoxifen/Letrozole/LHRH agonist only for HR+ pts; LHRH agonist goserelin (Zoladex) 
only for pre-menopausal pts 
 
6.5 Treatment duration 
The planned treatment duration for study and supportive drugs are as follows: 
1. Docetaxel 4 cycles with Herceptin SC (12 weeks) as neoadjuvant therapy before 
surgery. Docetaxel should be administered after trastuzumab. An observation period of 
60 minutes is recommended after the first dose of trastuzumab injection, thereafter an 
observation period of 30-60 minutes after subsequent injections before docetaxel.  

 
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2. FEC: 3 cycles + scH of 21-day cycles (9 weeks) for partial responders or stable 
disease patients to TscH starting after assessment of reponse at week 16. (This allows 
3 weeks for the effect of the last dose of TscH to manifest before response evaluation). 
3. Trastuzumab (Herceptin SC): 18 cycles every three weeks (52 weeks) for each patient 
starting at the first day of treatment with docetaxel. The injection site should be 
alternated between the left and right thigh.  
4. Missed doses: If a dose of Herceptin SC is missed, it is recommended to administer 
the next 600 mg dose as soon as possible. The interval between subsequent Herceptin 
SC injections should not be less than three weeks. If the dose of docetaxel or FEC is 
missed, next dose can be administered within two weeks and patient will continue in 
the study. In cases of missed interval of more than two weeks, patients can receive 
next dose. 
5. Tamoxifen:  20mg daily for 10 years after surgery and chemotherapy/LHRH or 
Letrozole: 2.5 mg daily for 10 years after surgery/chemotherapy as an alternative to 
tamoxifen 
6. LHRH agonist (goserelin) 3.4 mg or 10.8mg every 3 months for 2 years starting from 
the commencement of the study medications 
 
 6.6 Pretreatment considerations: 
Docetaxel  
1. Hydration: Patients should maintain adequate oral hydration (2 to 3 L/day) 
2. Oral dexamethazone 8mg twice daily for 3 days starting 1 day prior to docetaxel 
administration 
3. 
i.v. ondansetron 8mg, i.v. dexamethaxone 20mg, i.v. diphenhydramine 50mg, i.v. 
ranitidine 50mg 
4. 
Infection prophylaxis: primary prophylaxis for GCSF is indicated for all patients 
using Docetaxel .  
 
FEC   
1. Hydration: Patients should maintain adequate oral hydration (2 to 3 L/day) 
2. Hydration: Patients should maintain adequate oral hydration (2 to 3 L/day) 
3. 
i.v. ondansetron 8mg, i.v. dexamethaxone 20mg, i.v. diphenhydramine 50mg, iv 
ranitidine 50mg. 
4. Infection prophylaxis: Primary prophylaxis for GCSF is not indicated. 
Trastuzumab 
1. 
i.v. diphenhydramine 50mg with i.v. dexamethasone 8mg bolus (after docetaxel and 
FEC chemotherapy since diphenhydramine with dexamethasone will be part of  
premedication for docetaxel, and dexamethasone will be part of FEC chemotherapy) 

 
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6.7 Guidelines for continuation of treatment 
All enrolled and responding patients will be treated with TH regimen for a total of 12 weeks 
before surgery. If there is evidence of stable disease (SD) or partial response  after 12 weeks, 
such patients will be placed on FEC regimen for 3 cycles with Herceptin before reassessment. 
Patients showing clear progression at 12 weeks will be taken off study treatment and managed 
per treating physician.  Among those receiving FEC, if after completion of FEC the patient 
has progressed or is deemed inoperable, they will be taken off study treatment and managed 
per treating physician. 
  
6.8 Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. These changes must be 
recorded on the Dosage Administration Record and Treatments CRF (TX). The following 
guidelines will be applied:  
 
During neoadjuvant treatment, only two dose delays of up to 2 cycles each will be allowed. In 
addition, a patient must discontinue treatment with the study medications if after resumimg at 
a lower dose treatment, the toxicity recurs with the same or worse severity (Table 6.2).  For 
adjuvant Herceptin, patients should not miss more than 3 months of adjuvant Herceptin. 
If a patient requires a dose interruption for more than 2 consecutive cycles during the 
neoadjuvant phase, this patient will be discontinued from the study treatment. Patients who 
discontinue the study treatment will still be followed up as described in Tables 7.1-7.3. 
Toxicity due to docetaxel or FEC may be managed by symptomatic treatment, dose 
interruptions and adjustment of docetaxel /FEC dose. Doses of medications omitted for 
toxicity are not replaced or restored; instead the patient should resume the planned treatment 
cycles. The omitted doses will be noted as treatment interruptions. Patients who miss their 
treatment doses for more than 2 consecutive weeks will be classified under treatment 
interruptions and will not be analyzed as per protocol treatment. 
Dose modification for Docetaxel  
1.  Myelotoxicity: if the ANC ≤1500 cells/mm3 or platelets ≤100,000/mm3 on day 1 of 
each cycle, therapy will be delayed until counts recover. 
2. In case the treatment had to be postponed for 1 week due to toxicity, the dosage of 
docetaxel will be reduced to 75 mg/m2 if the patient was on 100mg/m2 or to 60mg/m2 
if the patient was on 75mg/m2. 
3. Dose adjustment for diarrhea: withhold docetaxel for grade 2 or worse diarrhea and 
restart at a lower dose (75 mg/m2 if the patient was on 100mg/m2 or to 60mg/m2 if the 
patient was on 75mg/m2) after complete resolution.   
4. Patients who develop grades 3 or 4 neuropathy for a week or longer will have their 
doses reduced to 75 mg/m2 if the patient was on 100mg/m2 or to 60mg/m2 if the 

 
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patient was on 75mg/m2.  Patients who develop ≥ grade 3 neuropathy while on 60mg/ 
m2 should have docetaxel treatment discontinued entirely (See Table 6-3).   
5. Docetaxel infusions could be slowed down or interrupted for minor symptoms such 
as flushing or local cutaneous reactions and resumed once symptoms abate. Similar 
with FEC infusions. 
Note: If there is a change in body weight of at least 10%, the dosage will be recalculated.  
 
Dose modification for FEC 
1. Myelotoxicity: treatment with FEC will be delayed until the absolute neutrophil count 
is greater than 1500/mm3 and platelet count is greater than 100,000/mm3  
2. If a patient develops severe neutropenia (<500/mm3) for a week or longer, or febrile 
neutropenia during the prior course, then the FEC doses will be reduced by 12.5% for 
subsequent courses. FEC doses will be decreased by 12.5% in patients whose platelet 
count nadir is <25,000/mm3 for longer than five days. 
 
Note: If there is a change in body weight of at least 10%, the dosage will be recalculated.  
 
Dose modifications for Herceptin SC (trastuzumab)  
No reductions in the dose of Herceptin SC (trastuzumab) will be made during this clinical trial 
unless due to symptomatic cardiac dysfunction. Patients may continue Herceptin SC therapy 
during periods of reversible, chemotherapy-induced myelosuppression, but they should be 
monitored carefully for complications of neutropenia during this time. The specific 
instructions to reduce or hold the dose of chemotherapy should be followed. Trastuzumab will 
be permanently discontinued if severe or life-threatening (based on CTCAE grading) 
administration reactions occur.  
Monitor LVEF clinically every 3 weeks at every visit. 
Infusion Reactions: The infusion rate will be decreased for subjects experiencing mild or 
moderate infusion reactions according to CTCAE grading. If a subject experiences dyspnea or 
clinically significant hypotension the infusion will be stopped. Herceptin will be permanently 
discontinued if severe or life-threatening infusion reactions (based on CTCAE grading) occur.  
Herceptin injection can be slowed down if patient is feeling uncomfortable and continued 
slowly when the patient is fine. 
 
Cardiomyopathy: We will assess for symptoms before each cycle and evaluate cardiac 
toxicity by Echocardiography every 12 weeks during the neoadjuvant treatment and every 3 
months during adjuvant Herceptin. Treatment with trastuzumab will be stopped for a 
minimum of 3 weeks (one cycle) for any of the following:  
• LVEF is below 50% and ≥ 15% points decrease from baseline 
Commented [KT-H11]: Doesn't agree with Table 6.3 
Commented [AN12R11]: This is specific to the the two 
conditions referred to based on the clinical symptoms and 
duration of the toxicty. The table states general rule. This can 
be inserted in the Table 
Commented [KT-H13]: does not agree with Appendix E 
Commented [AN14R13]: This section will be corrected to 
read 10% in order to make it applicable to those who will 
receive FEC which is also cardiotoxic.  

 
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If LVEF returns to 50% or higher treatment can be resumed. If LVEF decrease persists or has 
declined further, or if clinically significant CHF has developed, treatment with Herceptin will 
be stopped. 
If after a repeat assessment within approximately 3-7 weeks (2 cycles), the LVEF has not 
improved, or has declined further, trastuzumab should be discontinued, unless the benefits for 
the individual patient are deemed to outweigh the risks (see appendix E).  

 
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Table 6-2. 
Recommendations for dose modification for docetaxel or FEC by event 
Toxicity 
Dose modification* 
   Worst toxicity (CTCAE v5)  
During a cycle of therapy 
   No toxicity 
Maintain dose level 
Investigations (Hematologic) 
Neutropenia (ANC) 
   Grade 1 (ANC < LLN - 1500/mm3) 
Maintain dose level 
   Grade 2 (ANC < 1500 - 1000/mm3) 
Maintain dose level (see Table 6-3) 
   Grade 3 (ANC < 1000 - 500/mm3) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level  (Table 6-3)  
   Grade 4 (ANC < 500/mm3) 
Omit dose until resolved to ≤ Grade 2, then  2 dose levels 
Thrombocytopenia 
   Grade 1 (PLT < LLN - 75,000/mm3) 
Maintain dose level 
   Grade 2 (PLT < 75,000 - 50,000/mm3) 
Maintain dose level 
   Grade 3 (PLT < 50,000 - 25,000/mm3) 
(Lower limit PLT+ 30,000/mm3) Omit dose until resolved to ≤ Grade 1, then  
If resolved in ≤ 7 days, maintain dose level 
If resolved in > 7 days, ↓ 1 dose level  
   Grade 4 (PLT < 25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Febrile neutropenia  
   (ANC < 1.0 x 109/L, fever ≥ 38.5°C) 
Omit dose until resolved, then  1 dose level 
Investigations (Renal) 
Serum creatinine 
   Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
   Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose until resolved to ≤ Grade 1 or baseline, then maintain dose level 
   Grade 3 (> 3.0 - 6.0 x ULN)  
Omit dose and discontinue patient from study drug treatment  

 
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Toxicity 
Dose modification* 
   Worst toxicity (CTCAE v5)  
During a cycle of therapy 
   Grade 4 (> 6.0 x ULN) 
Omit dose and discontinue patient from study drug treatment 
Investigations (Hepatic)* 
Bilirubin 
   Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
   Grade 2 (> 1.5 - 3.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level  
If resolved in > 7 days, then ↓ 1 dose level 
   Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then ↓ 1 dose level  
If resolved in > 7 days, then discontinue patient from study drug treatment 
   Grade 4 (> 10.0 x ULN) 
Omit dose and discontinue patient from study drug treatment 
AST or ALT 
   Grade 1 (> ULN - 2.5 x ULN) 
Maintain dose level 
   Grade 2 (> 2.5 - 5.0 x ULN) 
Maintain dose level 
   Grade 3 (> 5.0 - 20.0 x ULN) 
Omit dose until resolved to ≤ Grade 1 (or ≤ Grade 2 if liver metastases present), then: 
If resolved in ≤ 7 days, maintain dose level  
If resolved in > 7 days, ↓ 1 dose level 
   Grade 4 (> 20.0 x ULN) 
Omit dose and discontinue patient from study drug treatment 
AST or ALT and Bilirubin 
AST or ALT Grade 3 and ≥ Grade 2 blood 
bilirubin  
 
Omit dose and discontinue patient from study drug treatment. 
Diarrhea** 
 

 
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Toxicity 
Dose modification* 
   Worst toxicity (CTCAE v5)  
During a cycle of therapy 
   Grade 1  
   Grade 2  
 
 
   Grade 3 
   Grade 4 
Maintain dose level, but initiate anti-diarrhea treatment 
Omit dose until resolved to ≤ grade 1, then maintain dose level.  
If diarrhea returns to ≥ grade 2, then omit dose until resolved to ≤ grade 1, then ↓ 1 dose 
level 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level 
Omit dose and discontinue patient from study drug treatment 
*All dose modifications will be based on the worst preceding toxicity. 
** Antidiarrhea medication is recommended at the first sign of abdominal cramping, loose stool or overt diarrhea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6-3. 
Recommendations for dose modification by the appearance of the adverse drug reaction 

 
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Adverse drug 
reaction 
Grade 2 
Grade 3 
Grade 4 
1st appearance 
Interrupt treatment until resolved 
to grade 0-1, then continue at 1 
dose level* lower than the original 
docetaxel or FEC dose where 
possible  
Interrupt treatment until resolved 
to grade 0-1, then continue at 1 
dose level* lower than original 
docetaxel or FEC dose, with 
prophylaxis where possible 
Interrupt treatment, if investigator 
considers it to be in the best interest of 
the patient, continue at 2 dose levels 
lower docetaxel or FEC dose, once 
toxicity has resolved to grade 0-1 
2nd appearance of 
the same toxicity 
Interrupt treatment until resolved 
to grade 0-1, then continue at 2 
dose levels** lower than the 
original docetaxel or FEC dose 
Interrupt treatment until resolved 
to grade 0-1, then continue at 2 
dose levels** lower than original 
docetaxel or FEC dose 
 
3rd appearance of 
the same toxicity Discontinue study treatment 
Discontinue study treatment 
 
*1 dose level:  Docetaxel  = 75mg/m2 if on 100mg/m2 or 60mg/m2 if on 75mg/m2  
                         FEC = decrease by 10% from normal dose 
**2 dose level: Docetaxel  = 60mg/m2 if on 100mg/m2 or discontinuation if on 75mg/m2 
                         FEC=  decrease by 15% from normal dose  
 
  

 
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6.9 Disease progression during study 
Patients will be taken off study treatment at the time of clinical progression.  
Toxicity will be classified (Table 6-3) according to the NCI CTCAE Version 5.  
 
6.10 Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant abnormal laboratory value must be followed up at least once a week 
(or more frequently if required by institutional practices, or if clinically indicated) for 4 
weeks, and subsequently at approximately 4-week intervals, until resolution or stabilization of 
the event, whichever comes first. Appropriate clinical experts such as ophthalmologist, 
endocrinologist, dermatologist, psychiatrist etc. will be consulted as deemed necessary. All 
patients must be followed up for adverse events and serious adverse events for 30 days after 
receiving the last dose of any study agent. 
 
6.11 Anticipated risks and safety concerns of the study treatments 
The study medications have previously been in clinical use with good safety profile. In the 
proposed study, these medications are given in routine dose regimens and known toxicities are 
anticipated. These include: myelosupression, mucositis, diarrhea and vomiting, neuropathy 
and cardiotoxicity. 
The following measures will be adopted to ensure safety of the participants: 
1. Patients will be given 3 phone numbers (study nurse, PI and clinic emergency) to 
contact in case of complaints. 
2. Clinical reviews before chemotherapy will be carried out since the patients will be 
seen three-weekly for chemotherapy. 
3.  Phone calls by the study nurse will be conducted regularly to check for complaints 
during the follow up period. 
4. Appropriate clinical management would be given to patients with complaints. 
 
6.12 Concomitant medications 
Medications required to treat AEs, to manage cancer symptoms, concurrent diseases and 
supportive care agents such as packed red blood cell agents, pain medications, anti-emetics, 
short courses of steroids, topical treatments for stomatitis, anti-diarrheal and focal 
radiotherapy for palliation (not including the primary site of interest) are allowed. 
Biphosphonate therapy for prevention of bone metastasis is allowed.  
If biphosphonate therapy is initiated after commencement of protocol therapy, the reason will 
be clearly stated. 
 
6.13 Prohibited concomitant therapy 
Hormonal contraceptive agents are not indicated while on study medications. 

 
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Docetaxel therapy  
Concomitant use of aminoglycosides should be avoided during treatment with docetaxel. 
FEC  
Medications with strong risk of cardiotoxicity should be administered with caution. 
Trastuzumab (Herceptin SC) therapy 
Medications that carry strong risk of cardiotoxicity should be administered with caution. If 
possible, physicians should avoid anthracycline-based therapy for up to 7 months after 
stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be 
monitored carefully. 
 
6.14 Patient numbering 
 
6.14.1 Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.) assigned when the 
patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout her entire participation in the trial. The Subject No. consists of the Center Number 
(Center No.) as assigned by HLF office to the investigation site with a sequential Subject  
(patient) number suffixed to it, so that each subject is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available. 
 
6.14.2 Treatment assignment  
N/A 
 
6.14.3 Treatment blinding 
This is an open label study. 
 
6.15 Study drug preparation and dispensation 
Study drugs are given intravenously or subcutaneously as described above and will be 
administered to the patients by study site authorized personnel only. All dosages prescribed to 
the patient and all dose changes during the study must be recorded on the Dosage 
Administration Record and Treatments CRF (TX). 
 
6.16 Drug supply and storage 
Study drugs will be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study medication will be stored 
according to the instructions specified on the drug labels and in the Investigators’ Brochure .  

 
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6.17 Study drug accountability and compliance  
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study medication in a drug accountability log. Drug accountability will be noted by the 
field monitor during site visits and at the completion of the study. At the time of study close-
out and, if appropriate during the course of the study, the investigator will return all used and 
unused study drugs, packaging, drug labels, and a copy of the completed drug accountability 
log to the Study PI or Study Monitor.  
 
7. Study flow and visits schedule 
Tables 7-1, 7-2, and 7-3 lists all of the assessments; the visits indicated with an “X” when 
they are performed. Table 7-1 refers to the neoadjuvant phase of the study, Table 7-2 to the 
surgery and adjuvant phase, and Table 7-3 to the post-treatment follow-up phase. All data 
obtained from these assessments must be supported by record in the patient’s source 
documentation and entered into the REDCap database.  The CRF on which data from each 
assessment is to be entered is indicated in parenthesis.   
For all visits, there is a ± 3 days window on assessments to take into account scheduling over 
public or religious holidays if not explicitly specified otherwise.   
Laboratory assessments that were completed within 3 days prior to Cycle 1 Day 1 (C1D1) do 
not need to be repeated. For efficacy assessments, there is a ±7 day window (refer to Section 
7.2.1). Screening USS, chest x-ray and pre-treatment tumor biopsy will be completed within 
14 days before first dose of study drug administration. 
All data obtained from these assessments will be supported by the record in the patient’s 
source documentation. No CRF will be used as a source document. 
 
 7.1 Screening 
The approved Informed Consent Form (ICF) will be signed and dated before any screening 
procedures are performed (procedures that are part of the clinical routine during the initial 
diagnostic work-up of the patient may be performed before signing the ICF). A copy of the 
ICF will be given to the patient or to the person signing the form. The date when the study 
informed consent was signed will be registered in the medical record of the patient and on the 
IC CRF in REDCap by investigator or designee. 
Patient’s eligibility will be evaluated by study inclusion and exclusion criteria and safety 
assessments.  
 
7.1.1 Details of assessment 
For details of assessments, refer to Table 7-1 . All screening assessments will be completed 
within 14 days prior to the first dose. 

 
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Table 7-1 
Visit evaluation schedule (Neo-Adjuvant).  
Assessment 
Screening 
Part 1 and 2: 
3-Weekly 
visit 
Sequential visit number 
 NV11  NV2 
NV3 
NV4 
NV5 
NV6 
NV7 
NV8 
NV9 
 
 
 
Calendar visit day 
 
1 
22 
43 
64 
85 
106 
127 
148 
 
 
 
 
 
+/- 3 days 
Obtain informed consent (IC) 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical history and epidemiological 
data/Prior meds (CH) 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics (D) 
X 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of cancer (DX) 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (IE) 
X 
 
 
 
 
 
 
 
 
 
 
 
Current medical conditions/medications 
(BE) 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance status (BE) 
X 
 
 
 
 
 
 
 
 
 
 
 
Height (BE) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (BE) 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (BE) 
X 
 
 
 
 
 
 
 
 
 
 
 
EKG (BE) 
X 
 
  
 
 
 
 
 
 
 
 
 
Physical examination (PE) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Weight (PE) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

 
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Assessment 
Screening 
Part 1 and 2: 
3-Weekly 
visit 
Sequential visit number 
 NV11  NV2 
NV3 
NV4 
NV5 
NV6 
NV7 
NV8 
NV9 
 
 
 
Calendar visit day 
 
1 
22 
43 
64 
85 
106 
127 
148 
 
 
 
 
 
+/- 3 days 
Vital signs (PE) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology (H) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical Chemistry (CC) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Imaging 
 
 
 
 
 
 
 
 
 
 
 
 
   Breast Ultrasound (IM) 
X 
 
 
X 
 
X2 
 
X2 
X3 
 
 
 
   Chest x-ray (IM) 
X 
 
 
 
 
 
 
 
 
 
 
 
   Ultrasound (abdomen/pelvis) (IM) 
X 
 
 
 
 
 
 
 
 
 
 
 
Bone scan (BCT) 
X 
                                               As clinically indicated 
CT scan of brain (BCT) 
As clinically indicated 
CT scan of chest, abdomen, pelvis 
(BCT) 
As clinically indicated 
ECHO every 6 weeks while on 
neoadjuvant therapy (ECHO) 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
Adverse events (AE) 
Continuous assessment 
Blood for “Omics biomarkers” (BM) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Biomarkers (ER, PgR, HER-2) (BM) 
X 
 
 
 
 
X 
 
 
 
 
 
 
Commented [SB15]: (6 weeks, not 12, per the protocol) 
Commented [AN16R15]: Closer monitoring (6weekly) 
advised while patients are on chemotherapy as well as 
Herceptin. For cost considerations we thought 12 weekly 
could be done. However, this will only make ECHO to be 
done at beginning and end of Docetaxel which may be late to 
discover toxicity. Six  weekly allows ECHO to be done 
midway of  Docetaxel chemotherapy for early detection of 
signs of toxicity.  While only on Herceptin to complete 18 
doses, it will be 12 weekly. Then every 6 months till 2 yrs 
after therapy. Relevant sections can be adjusted. 

 
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Assessment 
Screening 
Part 1 and 2: 
3-Weekly 
visit 
Sequential visit number 
 NV11  NV2 
NV3 
NV4 
NV5 
NV6 
NV7 
NV8 
NV9 
 
 
 
Calendar visit day 
 
1 
22 
43 
64 
85 
106 
127 
148 
 
 
 
 
 
+/- 3 days 
Docetaxel IV every three weeks (TX) 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Herceptin SC (TX) 
 
X 
X 
X 
X 
X2 
X2 
X2  
 
 
 
 
FEC (as indicated) (TX) 
 
 
 
 
 
X2 
X2 
X2 
 
 
 
 
LHRH agonist every 3 months for 2 yrs  
(premenopausal pts) (LHRH) 
 
X 
 
 
 
X 
 
 
 
 
 
 
QoL  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Herceptin PK (PK)                                         As required 
Antidrug Antibodies (AA)                             As required 
Event Form (EV)                                           As required 
Withdrawal Form (WD)                                As required 
 
1 All screening procedures must be done within 14 days of first dose of study therapy. 
 
2 Patients with USS CR (operable) will have surgery within 4 weeks of last dose of Docetaxel+Herceptin. Patients with USS PR/SD (operable) will get salvage therapy with FEC+H for 3 
cycles. Patients with inoperable SD  will also get salvage therapy with FEC +H for 3 cycles, but will be considered non-responders for statistical analysis purposes. Patients showing clear 
progression will be taken off study treatment and managed per treating physician. 
 
3 Patients with USS PR/SD (operable) will have surgery within 4 weeks of last dose of FEC+H. Patients with SD (inoperable) or PD during/after FEC treatment will be taken off study 
treatment, managed per treating physician and scheduled for End of Treatment visit, but will have continued follow-up unless the patient withdraws from the study. 

 
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Table 7-2: Visit evaluation schedule (Surgery and Adjuvant Therapy)  
Assessment 
Surgery 
Adjuvant 3-weekly visits for SC Herceptin 
 
 
 
 
 
Sequential visit number 
 
AV1 
AV2 
AV3 
AV4 
AV5 
AV6 
AV7 
AV8 
AV9 
AV10 AV11 AV121 
AV131 AV141 
Calendar Visit Day 
 
 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 
211 
232 
253 
274 
Vital signs (PE) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology (H) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry (CC) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Surgery/Pathology (SP) 
(Tumor pathologic response 
evaluation based on 
histopathology of resected 
tumor) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of fresh tumor 
and FFPE (at baseline and 
after surgery) (SP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiotherapy (Estimated 4-
6 weeks after surgery) (RT) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ECHO every 3 months 
while on adjuvant Herceptin 
(ECHO) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 

 
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Herceptin SC every 3 wks 
to complete 18 doses (TX) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LHRH agonist every 3 
months for 2 yrs 
( premenopausal pts) 
(LHRH) 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
QOL every 3 months 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Adverse events (AE) 
Continuous monitoring 
 
 
 
 
Bone scan (BCT) 
As clinically indicated 
 
 
 
 
 
CT scan of brain (BCT) 
 
As clinically  indicated 
 
 
 
 
CT scan of chest, abdomen, 
pelvis (BCT) 
 
As clinically indicated 
 
 
 
 
Daily TAM or LET for  
HR+ patients (TAM/LET)                 X ----------------------------------------------------------------------------------------------------------------------X 
Herceptin PK (PK)                                          As required 
Antidrug Antibodies (AA)                              As required 
Event Form (EV)                                            As required 
Withdrawal Form (WD)                                 As required 
 
1Omit if patient received neoadjuvant FEC+Herceptin SC 
 

 
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Table 7-3 
Visit evaluation schedule- End of treatment visit and follow up 
Follow-up Period (10 Years Total) 
Assessment 
Safety Follow-up 
Survival Follow-up 
60 Days 
Years 1-2 
Years 3-5 
Years 6-10 
EOT: End of 
Study 
Treatment 
(+/- 3 days) 
FV1: 30 Days 
post EoT 
(+/- 3 days) 
FV2-FV9: 
Every 3 
months1 
 
FV10-
FV15: 
Every 6 
months 
FV16-FV20: Every 12 
months 
End of Treatment (EOT)                          
X 
 
 
 
 
 
Physical Examination (PE) 
X 
X 
 X 
  
 X 
 X 
Vital Signs (PE) 
X 
X 
 X 
  
 X 
 X 
Laboratory Assessments 
Hematology (H) 
X 
X 
X  
  
 X 
 X 
  
Clinical Chemistry (CC) 
X 
X 
X  
  
 X 
 X 
  
Blood for "Omics biomarkers" (BM) 
X 
X 
X  
  
 X 
 X 
  
ECHO (ECHO) 
X 
  
X (FV3, 5, 7, 
9, only)  
X 
X 
  
Imaging 
Bone scan (BCT) 
As clinically indicated 
CT scan of brain (BCT) 
As clinically indicated 
CT scan of chest, abdomen, pelvis 
(BCT) 
As clinically indicated 
Adverse Events (AE) 
X 
X 
  
  
  
  

 
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QoL (QOL) 
  
X 
  
X 
  
X 
  
Daily TAM/LET for HR+ patients after 
surgeryfor 10 years (TAM/LET) 
X ----------------------------------------------------------------------------------------------------------X 
Survival Follow-up (SFU) 
  
  
X1 
  
X 
  
X 
LHRH agonist every 3 months for 2 
yrs2 (premenopausal patients) (LHRH) 
 
 
X 
 
 
 
 
Event Form (EV)                                            As required 
Withdrawal Form (WD)                                 As required 
1.First Survival contact is at Month 3 post EoT 
2Two years from start of treatment 

 
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7.1.1.1 General Guidelines 
Prior to registration and any study-specific evaluations being performed, all patients 
must have given written informed consent for the study and must have completed the 
pre-treatment evaluations.  Patients must meet all of the eligibility requirements listed 
in Section 3.  
Eligible patients will be registered on study centrally by HLF staff.  
Following registration, patients should begin protocol treatment within 7 business 
days.  Issues that would cause treatment delays should be discussed with the Lead 
Principal Investigator.  If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study will be canceled.  The study 
coordinator/CRA should be notified of cancellations as soon as possible. 
7.1.1.2  Registration Process 
When a potential patient has been identified, enrolling site must notify HLF staff by 
calling 234-805-660-2274. Reservations for potential subjects will only be held for 
subjects who have signed consent for that particular study. 
 
The following information will be included: 
• Study title 
• Name of study site where patient is being treated 
• Name of treating physician 
• Name of site PI 
• Patient’s initials  
• Patient’s date of birth 
• Patient’s height in centimeters, weight in kilograms and ECOG performance 
status 
• Proposed treatment start date 
• Date of signed consent 
• Eligibility criteria met (no, yes) 
 
A confirmation of registration will be issued by HLF staff after eligibility is confirmed.   
 
7.1.2 HLF Data Submission 
 
Data reporting will be performed utilizing the REDCap electronic data capture system.  The 
University of Chicago staff will provide applicable user registration information.  
 
Each screened (consented) patient is to be entered into REDCap within 48 hours of patient 
registration. In addition to direct data entry, you may be required to provide supporting 
source documentation. Source records are original documents, data, and records (e.g., 
medical records, raw data collection forms, pharmacy dispensing records, recorded data 
from automated instruments, laboratory data) that are relevant to the clinical trial. Each site 

 
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will prepare and maintain adequate and accurate source documents. These documents are 
designed to record all observations and other pertinent data for each subject enrolled in this 
clinical trial. Source records must be adequate to reconstruct all data transcribed onto the 
case report forms.  
 
All required data must be recorded in the REDCap database at the completion of each cycle.  
AEs (including SAEs) are to be entered in real time. SAEs are to be sent via email 
(preferred) or fax to the University of Chicago (PhaseIICRA@medicine.bsd.uchicago.edu 
and qaccto@bsd.uchicago.edu; Fax: 773-702-4889) within 24 hours of HLF’s knowledge of 
the event.  
Forms will be submitted by sites to the HLF Data Management Center (DMC) in compliance 
with the Data Submission schedule below for entry into REDCap. There are two options for 
submitting forms. 
• 
The forms may be faxed to the DMC at (234)-2-234-2-8101371. Copies must be 100% 
of the original form size 
• 
The forms may be mailed/faxed to the HLF: 
Healthy Life For All Foundation (HLF) Office 
P.O. Box 30175 Secretariat, Ibadan, Oyo State, Nigeria 
Tel/Fax: 234-8056602274 
E-mail Dayo Adepoju: dayoadepoju@yahoo.com 
Data Submission Schedule 
Form 
Submission schedule 
On-Study Forms-Pathology and 
biopsy reports 
Within one week of registration/screening 
Tissue Block with Pathology 
Reports 
 
Submit with paraffin block to HLF LAB and a copy to the 
HLF DMC. 
Visit forms (Neo-adjuvant and 
Adjuvant Form)  
Submit once at the end of each protocol specific 
chemotherapy for each patient within 48 hours 
Adverse Events Form 
Submit for each patient on same day of detection.  
Quality of Life Assessment Form 
Submit at the end of each clinic visit for study drug 
administration for all patients within 48 hours. Thereafter 
every 3 months during follow up visits.  
 Follow-up Forms 
On completion or discontinuation of protocol therapy, submit 
every 3 months for 2 years, then every 6 months until year 5, 
then annually until year 10. In addition, submit at any 
significant clinical event (EV form). 
 
Commented [KT-H17]: I thought we were using tablets, 
then uploading into REDCap 
Commented [AN18R17]: REdCap will be used. This 
section  was not updated because decision on REDCap 
deployment has been evolving. Now that we are sure, it will 
be corrected. 

 
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7.1.3 Patient demographics and other baseline characteristics 
Data to be collected will include general patient demographics, relevant medical history and 
details of prior treatments, current medical conditions, concomitant medications, prior 
therapies, diagnosis, extent of tumor and tumor histopathology including hormonal and HER2 
statuses. 
 
7.2 Treatment period 
During the treatment period, the patient must follow the Investigators instructions with 
regards to contraception, concomitant medications, and dosing regimen (see Section 6.1).  
For details of the frequency of the visits and assessments during the treatment period, refer to 
Tables 7-1 & 7-2. 
 
7.3 End of treatment visit including study completion and premature withdrawal 
Patients who discontinue study treatment will be scheduled for an End of Treatment (EOT) 
visit as soon as possible and within 14 days after the decision to discontinue has been made, at 
which time all of the assessments listed for the EOT visit will be performed.  An EOT CRF 
page will be completed. The date and primary reason for stopping the study treatment will be 
recorded. At a minimum, all patients who discontinue study treatment, including those who 
refuse to return for a final visit, will be contacted for safety evaluations during the 30 days 
following the last dose of study treatment.  
Patient who discontinue study treatment will also return for 30-day safety F/U (see Section 
7.5.1), and survival F/U assessments at the visits according toTable 7-3 and will not be 
considered withdrawn from the study. If patient refuses to return for these visits or is unable 
to do so, every effort will be made to contact this patient or a knowledgeable informant by 
telephone to obtain the F/U information. 
If a patient discontinues study treatment, but continues study assessments in the F/U period, 
the patient remains on a study until completion of the protocol criteria for ending study 
assessments.   
 
7.4 Criteria for premature patient withdrawal 
Patient may voluntarily withdraw from the study or be dropped from the study at the 
discretion of the investigator at any time. A Withdrawal (WD) form should be completed.  
Patient may be withdrawn from the study if any of the following occur: 
• Any life threatening adverse event (Section 8.2) 
• Patient withdrawal of consent 
• Lost to follow-up 
• Disease progression 
• Initiation of a different cancer therapy. 
 
Commented [KT-H19]: conflicts with 6.8 
Commented [AN20R19]: I think severe adverse events 
referred to in 6.8 could be life threatening. Or Which 
statement contradicts?  

 
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7.4.1 Replacement policy 
Patients will not be replaced on the study. However, if a subject is considered as non-
evaluable for the neoadjuvant treatment response assessment, enrollment of a new subject as a 
replacement will be considered to meet the required number of evaluable subjects for 
statistical validity. Enrollment of new subjects may be considered until the required number of 
evaluable subjects on neoadjuvant regimen is achieved.  
 
7.5 Follow up period 
Patient lost to follow up will be recorded as such on the CRF. For patient who is lost to 
follow-up, the investigator will show “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, home visits if 
feasible, etc.  
 
7.5.1 30 - day safety follow up period 
All patients will have safety evaluations at 30 days after the last dose of study treatment. 
Information related to AEs (including concomitant medication taken for ongoing AEs) and 
ongoing anti-neoplastic treatments will be collected at 30 days after the last dose of study 
drug. All AEs suspected to be related to study treatment should be followed up weekly, or as 
clinically indicated, until resolution or stabilization. 
 
7.5.2 Survival follow up period 
All patients enrolled in the study will be followed for survival every 3 months by clinic 
appointments or by phone call for 2 years and thereafter every 6 months for next 3 years, and 
yearly for 5 years (10 years total), or until lost to follow-up or withdrawal of consent, 
whichever occurs first.  
 
7.6 Assessment types 
 
7.6.1 Efficacy assessments 
Tumor response will be evaluated locally by the investigator based on the adapted RECIST 
criteria (see Appendix B). The largest breast tumor lesion with the largest involved axillary 
lymph node will be assessed at baseline by ultrasound technique. The following assessments 
are required at screening/baseline (within 14 days of the start of treatment): 
1. 
Breast ultrasound, abdomen and pelvis ultrasound 
2. 
If bone metastases are suspected, localized or skeletal survey by plain x-ray 
imaging will be acquired for all skeletal lesions suspected clinically  
Subsequent tumor evaluations will be performed per the schedule outlined in Table 7-1 or as 
clinically indicated. If the last prior tumor evaluation was within 28 days of EOT or objective 
evidence of progressive disease has already been documented, the tumor evaluation does not 
need to be repeated at EOT. 

 
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Tumor evaluations after the screening assessment will include evaluation of all sites of 
disease identified at baseline, using the same technique that was used at screening. If there 
was no evidence of disease in a body region at baseline, this region does not need to be 
imaged at subsequent assessments, unless there is clinical concern for a new lesion in that 
body region. 
 
7.6.2 Safety and tolerability assessments 
Safety will be monitored by assessing the procedures listed below as well as collecting of the 
adverse events at every visit. All safety assessments will be performed pre-dose unless 
specified otherwise. 
 
Physical examination 
A complete physical examination that evaluates all major organ systems will be performed at 
a time of screening/baseline. Subsequent physical exams will be done if indicated and may be 
limited to focusing on sites of disease to evaluate clinical signs and symptoms. 
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
CRFs. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the patient’s CRF. 
Physical exams to be performed are outlined in Tables 7-1, 7-2 & 7-3. 
 
Vital signs 
Vital signs (heart rate, blood pressure and temperature) will be obtained in the sitting position, 
or as appropriate prior to any blood collection. 
Vital signs will be performed as outlined in Tables 7-1, 7-2 & 7-3. 
 
Height and weight 
Height in centimeters (cm) and body weight (approximated to 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured.   
Height and weight to be performed as outlined in Tables 7-1, 7-2 & 7-3. 
 
Performance status 
The ECOG Performance Status will be assessed at screening (recorded on BE form) and 
regularly throughout the whole study period (recorded on PE form) irrespective of the time of 
dosing (refer to Appendix A). 
 
Laboratory evaluations 
Study sites will use local laboratories for the analysis of all safety lab samples collected at the 
time points as indicated in Tables 7-1, 7-2 & 7-3. More frequent assessments may be 

 
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performed if clinically indicated, or at the investigator’s discretion, and these will be recorded 
on the Event Form (EV).  
An abnormal laboratory value that is clinically relevant (e.g., requires an interruption or delay 
in study treatment, or leads to clinical symptoms, or requires therapeutic intervention) must be 
documented in the Adverse Event CRF. If any abnormal laboratory value constitutes an AE, it 
must be recorded on the Adverse Event CRF. 
 
Hematology 
The following will be assessed: 
Complete blood count (CBC) and differential blood count (DBC) including white blood count 
(WBC), neutrophil count (including bands), lymphocyte, monocyte, eosinophil, and basophil 
counts, hemoglobin, and platelet. 
 
Clinical chemistry 
The following will be assessed: 
Sodium, potassium, chloride, bicarbonate, urea or BUN, creatinine, AST (SGOT), ALT 
(SGPT) and total bilirubin. If a total bilirubin elevation of ≥ Grade 2 occurs, direct and 
indirect bilirubin will be measured. Clinical chemistry collections will be performed as 
outlined in Tables 7-1, 7-2 & 7-3. 
 
Urinalysis 
A macroscopic urinalysis (dipstick or other equivalent method according to local practice), 
including leukocytes, protein, glucose and blood will be performed. 
Abnormal findings will be followed up with a microscopic evaluation and/or additional 
assessments as clinically indicated. 
Urine collection will be performed as outlined in Table 7-1. 
 
Pregnancy and fertility assessments  
When effective contraception is required, the pregnancy testing is recommended at screening 
and/or pre-dose and at the end of the trial. At screening (or baseline), urine pregnancy test 
should be performed, while at the end of trial the urinary pregnancy tests are sufficient. 
 
Echocardiogram (ECHO) 
Echocardiogram will be performed at the time of screening and/or baseline, then every 6 
weeks and continue every 3 months while patient is on Herceptin alone. Thereafter ECHO 
should be performed every 6 months for the first 2 years after Herceptin treatment. 
ECHO will be performed by a qualified physician and documented on the ECHO CRF page. 
Each ECHO result will be labeled with the study number, patient initials (per regulations 
permit), patient ID number and date. These records will be kept in the source documents at the 
study site. Clinically significant abnormalities existing at the time of the patient signing the 

 
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informed consent will be reported on the Medical History CRF page. Clinically significant 
findings will be discussed with the Steering Committee Chairman and Internal Monitor Breast 
Cancer Group prior to enrolling the patient in the study. New or worsened clinically 
significant findings occurring after signing the informed consent will be recorded on the 
Adverse Events CRF page. 
 
7.7 Patient reported outcomes  
 
7.7.1 The EORTC Quality of Life questionnaire 
Questionnaires of The EORTC general quality of life QLQ-C30 version 3.0 and Breast 
Cancer Module QLQ-BR23 English Language and Yoruba Language versions will be used in 
the study (Appendix C). 
It is composed of scales that assess physical functioning, role functioning as well as 
emotional, cognitive, social and global health statuses assessment. There are also scales to 
assess various symptoms. The breast cancer module has items to assess outcomes peculiar to 
breast cancer and treatment such as body image, sexual functioning and future perspective. 
The questionnaires will be completed by the patient/or with the assistance of the study nurse 
while waiting to receive their chemotherapy. The study nurses and the investigators will be 
available for questions about the study and completion of the forms.   
8. Safety monitoring and reporting 
8.1 Adverse events 
8.1.1 Definitions 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.  
Abnormal laboratory values or test results occurring after informed consent has been signed 
constitute adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant, require therapy (e.g., hematologic abnormality that requires transfusion 
or hematological stem cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent will be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent will be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring will be 
continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) will be described using a diagnosis whenever 
possible, rather than individual underlying signs and symptoms. When a clear diagnosis 
cannot be identified, each sign or symptom will be reported as a separate Adverse Event.  
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 

 
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If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through a Death 
Form. 
The occurrence of adverse events will be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are voluntarily reported by patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments.  
Each adverse event will be evaluated to determine: 
1. 
Severity grade (CTCAE Grade 1-4) 
2. 
Duration (start and end dates) and association with study therapy (not related, 
unlikely, possible, probable, definite) 
3. 
Action taken with respect to study treatment: none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable. 
4. 
Whether medication or therapy was given: no concomitant medication/non-drug 
therapy, concomitant medication/non-drug therapy. 
5. 
Outcome: not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown.  
6. 
Whether it is serious or not. AE or SAE is defined in Section 8.2.1. 
 
All adverse events will be treated appropriately. Any concomitant medication or non-drug 
therapy given to the patient will be recorded on the Adverse Event CRF.  
Once an adverse event is detected, it will be followed up until its resolution or until it is 
judged to be permanent, and assessment will be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
Safety reports and actions taken will be made by the study site Co-PI to study PI and HLF 
simultaneously. The study PI will inform the Steering Committee Chairman. 
Progression of malignancy (including fatal outcome) will be documented using the 
appropriate method (for example, according to the adapted RECIST criteria for solid tumors). 
Adverse events separate from the progression of malignancy (for example, deep vein 
thrombosis at the time of progression or hemoptysis concurrent with finding of disease 
progression) will be reported according to standard guidelines developed for such events with 
proper attribution regarding relatedness to the drug. 
 
8.2 Serious adverse event 
8.2.1 Definition 
Serious adverse event (SAE) is defined as one of the following: 
1. 
It is fatal or immediately life-threatening 

 
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2. 
Results in persistent or significant disability/incapacity 
3. 
Constitutes a congenital anomaly/birth defect 
4. 
It is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
5. 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
Note that hospitalization for the following reasons should not be reported as SAE: 
1. 
Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, e.g. treatment for disease progression  
2. 
Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the informed 
consent 
3. 
Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission lasting greater than 24 hours or involves an event not fulfilling any of the 
definitions of a SAE listed above is not a SAE. 
 
8.2.2 Reporting 
All events meeting SAE definitions above require reporting regardless of attribution.   SAEs 
will be followed until resolution or until clinically relevant improvement or stabilization. SAE 
collection ends 30 days after the last dose of study agent(s).  
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
the study treatment must be reported as described in section 8.5.  
Any SAE experienced after this 30 day SAE follow-up period will only be reported if the 
investigator suspects a causal relationship to the study treatment.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as a 
follow-up to the original episode as described in Section 8.5.  
Any event meeting SAE criteria and occurring at a different time interval or otherwise 
considered to be completely unrelated to a previously reported one will be reported as a new 
event. 
Information about all SAEs is collected and recorded on the Adverse Event Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough 
report. The investigator must assess and record the relationship of each SAE to each specific 
part of the study treatment.  

 
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Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the Nigerian National Agency for Food and Drug Administration (NAFDAC) by the Country-
PI, Dr Ntekim as follows: 
Life threatening SUSARs or death: within 7 calendar days after first knowledge by the 
sponsor. Detailed report will follow within additional 8 calendar days. 
All other SUSARs that are not fatal or life threatening: Within 15 calendar days after first 
knowledge by medical PI 
Follow up information will be actively sought and submitted as it becomes available. 
 
8.3 Pregnancies 
Pregnancy is not encouraged during the study period. Barrier method of contraception or 
intrauterine contraceptive devices (IUCDs) must be taken by every patient at risk of 
pregnancy. Every patient will be educated on importance and obligation to use contraception 
during the study treatment and 7 months after discontinuation of Herceptin study treatment. 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment or 
within 7 months from last dose of Herceptin during follow-up period must be reported to the 
investigator/treating physician.  Site staff are responsible for reporting the pregnancy to HLF 
within 72 hours of learning of this event. HLF will report the pregnacy to the Lead PI and 
University of Chicago PCCC and Cancer Center staff as described in section 8.5. 
The pregnancy will be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy follow-up will be recorded in the study database and will include an assessment of 
the possible relationship to the study treatment and pregnancy outcome. Any SAE 
experienced during pregnancy will be reported as described as described in Section 8.5.   
 
8.4  
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported using 
the Serious Event Reporting Form and/or MedWatch Form discussed below must also 
be reported in routine study data submissions.   
All adverse events (except grade 1 and 2 laboratory abnormalities that do not require an 
intervention), regardless of causal relationship, are to be recorded in the case report form and 
source documentation. The Investigator must determine the intensity of any adverse events 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0 and their causal relationship.  
8.4.1 Reporting of Study-Specific Adverse Events and Serious Adverse Events 
Heart failure 

 
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Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) 
should be reported as an SAE. If the diagnosis is heart failure it should be reported as such 
and not as individual signs and symptoms thereof. In the eCRF, signs and symptoms should 
be recorded. Heart failure should be graded according to NCI-CTCAE v 4.0 for "heart failure" 
(Grade 2, 3, 4 or 5) and in addition the New York Heart Association (NYHA) classification 
(Appendix F). ‘Left ventricular systolic dysfunction’ should not be used to describe 
symptomatic dysfunction as per NCI –CTCAE v.5.0. Heart failure occurring during the study 
and up to 10 years after last administration of study medications must be reported irrespective 
of causal relationship and followed until one of the following occurs: resolution or 
improvement to baseline status, no further improvement can be expected, or death. 
 
Asymptomatic Left Ventricular Systolic Dysfunction 
Asymptomatic declines in LVEF should not be reported as AEs since LVEF data are collected 
separately in the eCRF. Exceptions to this rule are as follows: 
• An asymptomatic decline in LVEF ≥10 percentage-points from baseline to an LVEF 
< 50% must be reported as an adverse event with the term of ‘ejection fraction decreased’ as 
per NCI-CTCAE v5.0 and, in addition, a comment in the AE comments field should confirm 
that this was asymptomatic. 
• An asymptomatic decline in LVEF requiring treatment or leading to discontinuation of 
trastuzumab must also be reported. 
Please note that this AE should also be captured as a non-serious event of special interest on 
the SAE form. 
Table 8.1 summarizes the reporting conventions for left ventricular systolic dysfunction. 
Table 8.1: Reporting Conventions for Left Ventricular Systolic Dysfunction/Heart 
Failure 
Observation 
How to Report 
Term to be 
Reported 
Grading 
Asymptomatic 
decline in LVEF < 
10%-points from 
baseline or to an 
LVEF≥ 50% 
No additional 
reporting required, 
LVEF results to be 
reported on eCRF 
N/A 
N/A 
Asymptomatic 
decline in LVEF ≥ 
AE (eCRF AE e-
ejection fraction 
NCI CTCAE for 
“ejection fraction 

 
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10%-points from 
baseline to an LVEF 
< 50% 
form) 
decreased (a) 
decreased” 
Asymptomatic 
decline in LVEF 
requiring treatment 
or leading to 
discontinuation of 
study drug 
AE (eCRF AE e-
form) and complete 
SAE form and 
indicate as AE of 
special interest 
ejection fraction 
decreased (a) 
NCI CTCAE for 
“ejection fraction 
decreased” 
Heart failure 
(symptomatic left 
ventricular systolic 
dysfunction) 
AE (eCRF AE e-
form) and SAE 
(SAE form) 
“Heart failure” 
NCI CTCAE for 
"heart failure" and 
NYHA Class 
Any symptomatic Left Ventricular Systolic Dysfunction event must be reported as “heart 
failure” 
a Report the status “asymptomatic” and the LVEF value in the comments field as appropriate 
Please refer to the algorithm to assist the decision as to whether to initiate (after completion of 
anti-HER2 therapy), continue or discontinue anti-HER2 study medication based on LVEF 
assessment in asymptomatic patients (see Appendix E). 
8.5  
Serious Adverse Event Reporting to the Coordinating Center 
Use the UC CCC protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
All serious adverse events (as defined in section 8.2.1) and pregnancy (as described in section 
8.3) occurring on this study require expedited reporting to the Lead PI and University of 
Chicago Comprehensive Cancer Center (UC CCC).     
Responsible site staff must report the event to HLF within 24 hours of site knowledge of the 
event.  HLF will be responsible for reporting the event to the Lead PI and UC CCC as 
described below within 24 hours of receiving the report from the site.   
Reports must be sent by HLF to the following:  
PhaseIICRA@medicine.bsd.uchicago.edu Fax: 773-702-4889 AND  
qaccto@bsd.uchicago.edu 
 
All serious adverse events should also be reported to the local IRB of record according to their 
policies and procedures.  
  
8.6 
Serious and Unexpected Adverse Event reporting by the Coordinating Center 
 
HLF staff will notify sites of all significant safety updates occurring during the study. 

 
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8.7 Warnings and precautions 
No evidence available at the time of the development of this study protocol indicated that 
special warnings or precautions are required, other than those noted in this protocol and in the 
individual drug information leaflets provided by the manufacturers. Additional safety 
information collected throughout the study period will be included in the patient informed 
consent form and will be discussed with the patient during the study as needed. 
9. Statistical methods and data analysis 
The data from all participating centers in this protocol will be combined.  The primary 
analysis of study data will be conducted at the time when all patients have completed surgery, 
or discontinued treatment. These data will be summarized in the primary Clinical Study 
Report (CSR). The final analysis of study data will be conducted at the end of the study. All 
available data from all patients will be analyzed and reported. 
 
9.1 Analysis sets 
9.1.1 Full Analysis Set (FAS) 
The FAS will include all patients who received at least one dose of docetaxel with Herceptin 
as well as appropriate hormonal agents with the exception that patients who miss their 
treatment doses for more than 2 consecutive weeks will be classified as non-evaluable and 
will not be included in the FAS. 
Patients who were screened but never started treatment will be listed.  
Unless otherwise specified, the FAS will be the default analysis set used for all efficacy 
analyses, including the primary analysis. 
 
9.1.2 Safety Set 
The Safety Set (SS) will include all patients who received at least one dose of docetaxel and 
have at least one valid post-baseline safety assessment. The statement in AE CRF that a 
patient has no AE constitutes a valid safety assessment.  The SS will be used for all toxicity 
analyses. 
 
9.2 Patient demographics and other baseline characteristics 
Demographics and other baseline data will be summarized descriptively in tables and charts in 
the FAS and SS.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
recorded. 
 

 
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9.3 Treatment (study treatment, concomitant therapies, compliance) 
The actual dose and duration in days of TscH plus FEC + scH treatment as well as the dose 
intensity (computed as the ratio of total dose received to actual duration) will be listed and 
summarized for all patients. In other words, if patient misses some doses or received lower 
doses than planned, the actual dose and duration will be different from those that were 
planned. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized for all patients.  
 
9.4 Primary objective 
The primary objective of this trial is to evaluate the efficacy of every three-weekly docetaxel 
+ Herceptin SC for four cycles, possibly supplemented by FEC. Patients achieving complete 
clinical response after docetaxel + Herceptin SC will go to surgery while patients with stable 
disease or partial response will receive 3 additional cycles of FEC + Herceptin before surgery. 
Inoperable, as well as progressing patients after 4 cycles of T+scH  followed by 3 cycles of 
FEC will be taken off study treatment.  Pathological complete response is defined as the 
absence of invasive and in-situ neoplastic cells at microscopic examination of the primary 
tumor and lymph nodes at surgery. Any remaining in-situ lesions are permissible.   
 
9.5 Primary Outcome Measure 
The primary statistic used to evaluate the efficacy of the study regimen is the overall 
pathologic complete response rate (pCR), defined as the proportion of patients with a pCR as 
defined in section 9.4 above. Patients who achieve pCR with the addition of FEC + scH will 
be included in the primary end point analysis and counted as successes, whereas those who 
are declared inoperable or who have progressed will be counted as failures. 
 
Statistical hypothesis, model, and method of analysis 
The primary efficacy analysis will be performed using the FAS.  A one-stage design will be 
used. Let p0 be the response proportion (pCR rate) that, if true, clearly implies that the 
treatment does not warrant further study and let p1 be the response proportion that, if true, 
would imply that the treatment has sufficient efficacy to warrant further trials. The statistical 
analysis of a single-arm phase II trial tests the null hypothesis H0 : pCR ≤ p0 against the 
alternative hypothesis H1 : pCR ≥ p1. We choose a design given a predetermined level of 
power (1 - β), significance level (α), and sample size (N). We decide in favor of the 
hypothesis corresponding to p0 or p1 based on the success rate observed by using an 
appropriate cut-off (R) between p0 × N and p1 × N. If R or fewer responses occur in the N 
patients, the drug is rejected. 
 
For this study we expect an inefficient treatment to elicit 20% or fewer positive responses (p0 
= 0.20) and a successful treatment regimen to have at least 40% positive responses (p1 = 
0.40). This is based on a reported pCR of 46.8% and 56.3% for stages III and II Brazilian 

 
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breast cancer patients treated with neoadjuvant trastuzumab and chemotherapy (Buzatto et al., 
2017). To achieve 90% power at a one-sided α=0.05, we will need to evaluate 47 patients, and 
if 14 or fewer responses are observed the treatment regimen will be rejected, whereas 15 or 
more would warrant further study of the treatment, potentially in a phase III trial. To allow for 
a 10% non-evaluable rate, we will enroll up to N=53 patients.  
 
Interim safety analysis will occur after 20 patients have gone to surgery.  An interim report 
will be generated for review by the DSMB to ensure that there are no logistical or safety 
issues to warrant stopping the protocol, e.g. an unacceptable rate of non-compliance with 
study protocol or adverse events.   
 
In addition to the above hypothesis testing, the pathological complete response rate will be 
estimated and 90% confidence interval given. 
 
9.6 Handling the missing values; censoring and discontinuations 
In the primary CSR the continuing events (e.g. adverse events, concomitant therapies, etc.) 
will be summarized and recorded using the cut-off date as the date of completion with an 
indication within listings that the event is continuing. 
For the patient who discontinued the study with ongoing events, the discontinuation date will 
be used as the completion date of the event with the appropriate censoring as described below. 
The reason for discontinuation from the study will be summarized and listed, along with dates 
of first and last study treatment, duration of exposure to study treatment and the date of 
discontinuation for each patient. 
Other missing data will be noted as missing on appropriate tables/listings. 
Patients who have disease progression and continue receiving non-study treatment after 
progression will qualify for progressive disease at the time of progression and will be counted 
as PD in ORR and other efficacy calculations. 
 
9.7 Secondary objectives 
All secondary efficacy assessments (DOR, iDFS) will be analyzed according to the 
investigator’s assessment as contained in the CRFs. All secondary efficacy analyses will be 
performed based on the FAS, unless otherwise specified. 
No adjustment for multiple testing will be made. 
 
9.8 Secondary efficacy objectives  
9.8.1 Invasive disease-free survival (iDFS) 
 
iDFS will be defined as the time from enrollment (initiation of treatment) to the first 
documentation of recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral 
locoregional invasive disease, distant recurrence, contralateral invasive breast cancer or death 

 
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from any cause. A patient who has not recurred or died at the date of the analysis will be 
censored at the time of the last follow up  evaluation. Follow up will be by simple clinical 
evaluation and blood tests every 3 months with use of ultrasound (abdomen/pelvis), chest 
xray, CT scan or bone scan as indicated to evaluate symptoms. By default, if disease 
recurrence or death is documented after one single missing follow up evaluation, the actual 
event date of disease recurrence/death will be used for the iDFS event date. If disease 
recurrence or death is documented after two or more missing clinical evaluations, the iDFS 
time for these patients will be censored at the date of the last adequate clinical evaluation. 
iDFS will be estimated using the Kaplan-Meier method (Kaplan and Meier, 1958)) and 
appropriate summary statistics. Cox regression models will be fit to evaluate the impact of 
baseline variables on iDFS (Cox, 1972). 
 
9.8.2 Subgroup analysis 
The proportions of pCR and partial responses in subgroups of patients according to 
demographic and tumour characteristics, namely age (< 50, ≥ 50 years), stage of disease, 
histological type (invasive ductal, lobular, others) and ER, PrR statuses will be compared in 
univariate analyses and tested for statistical significance using x2 or Fisher’s exact test at alpha 
level of 0.05. 
 
9.9 Safety objectives 
9.9.1 Analysis set and grouping for the analysis 
For all safety analyses, the safety set (SS) will be used. All listings and tables will be 
presented for all patients with or without full THP treatment. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from the day of patient’s informed consent to the day before first 
dose of study medication 
2. On-treatment period: from the day of first dose of study medication to 30 days after last 
dose of study medication 
3. Post-treatment period: starting at the day 30+1 after last dose of Herceptin. 
 
9.9.2 Adverse events (AEs) 
Summary tables for AEs include only AEs that started or worsened during the on-treatment 
period, e.g. the treatment-emergent AEs. However, all safety data (including those from the 
pre- and post-treatment periods) will be listed, and data collected during the pre-treatment and 
post-treatment period are to be flagged. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, by the severity (based on CTCAE 
grades version 5), type of AE, and relation to study treatment.  
Death reportable as SAE and non-fatal SAEs will be recorded for each patient and tabulated 
by the type of AE. 

 
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Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events that are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). 
For each specified SEC, number and percentage of patients with at least one event as part of 
the SEC will be reported. 
 
9.9.3 Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.) the study’s reporting team will grade laboratory data accordingly. For 
laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values not 
graded as 1 or higher. Grade 5 will not be used. 
For some tests (e.g. white blood cell differentials) the lower limits of normal ranges used in 
CTCAE definition have to be replaced by clinically meaningful limits expressed in absolute 
counts. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classification based on laboratory normal ranges.  
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
1. Frequency table for newly occurring on-treatment grades 3 or 4 (see below for details); 
2. Frequency table of low/normal/high/(or low and high) grades if for the given laboratory 
test the CTCAE grades were not defined;  
3. Baseline concentration of Herceptin will be stated. The average and range of serum 
concentrations (µg/mL) pre-dose at cycles 2, 5 and 8 of Herceptin will be stated. In 
addition, the overall serum Herceptin exposure assessed by AUC at cycles 5 and 8 will 
be summarized as well as Cmax at cycles 5 and 8. 
 
 
9.9.4 Other safety data 
Other safety data collected will be listed and summarized using descriptive statistics as 
appropriate. Notable values may be flagged. Notable/abnormal values for safety data will be 
used for shift tables. 
ECHO 
1. Shift table of baseline to worst on-treatment results for overall assessments; 
2. List ECHO evaluations for all patients with at least one abnormality. 
 
Additional analyses for secondary objectives  
Other secondary binary outcomes, such as clinical response rates, progressions during 
neoadjuvant therapy, etc. will be reported along with confidence intervals. Duration of 
response will be analyzed using the Kaplan-Meier method. 
 

 
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9.10 Patient-reported outcomes  
The EORTC QLQ-C30 questionnaire along with breast module (BR23) will be used to collect 
patient QoL data. The raw QoL data will be scored according to the EORTC scoring manual 
(Fayers, 2001). The global health status/global QoL domain sub-scale score is identified as 
the primary QoL variable of interest. Physical functioning, social functioning, emotional 
functioning, nausea and vomiting, diarrhea, fatigue, and appetite loss sub-scale scores are 
identified as secondary QoL variables of interest. The symptom scales will be presented only 
for the treatment period. 
All results will be presented for two patient groups. For on-treatment QoL, results will be 
presented for all patients, and patients switching to FEC. For follow-up QoL after treatment 
period, results will be presented for patients completing 4 doses of docetaxel and those 
completing 3 cycles of FEC, respectively.  
Descriptive statistics (N, mean/proportion median, SD, Q1, Q3) will be used to summarize the 
individual items and scores using sub-scale scores of QoL data at each scheduled assessment 
time point. Patients will be included if they completed at least one questionnaire item. 
Additionally, deviations from screening in the domain scores at the time of each assessment 
will be summarized. Patients with an evaluable screening score and at least one evaluable post 
baseline score during the treatment period will be included in the analysis of changes from 
baseline using paired t-tests (assessments after disease progression will be excluded). 
Additionally, the baseline and follow-up values will be plotted longitudinally over time and 
analyzed using mixed effects regression modeling. 
The compliance to the schedule of administration of validated EORTC QLQ-C30+BR23 will 
be summarized by patient group for each visit. Furthermore, data on the number of patients 
filling out the PRO/QoL data and the number of patients with the missing PRO/QoL 
assessments will be summarized by patient group for each visit. 
The statistical analysis will comprise the estimation of the treatment effects in terms of 
changes in the primary and secondary QoL variables of interest during the treatment period 
and at the end of follow-up. 
10 Biospecimens management and biomarker analysis 
10.1 Biospecimens 
 
All study subjects will provide written informed consent to allow their data and biospecimen 
materials to be used in proposed trial and for future translational research. The consent form 
will specifically state that samples will be shared with other ongoing and future studies by 
Nigerian researches and by the University of Chicago investigators on breast cancer in 
Nigerian women. The ongoing studies are: “Identifying Genetic Alterations in Breast 
Cancer Samples from Nigerian Women” (GABCNW, UCMC IRB#12-2173), with the 
West African Breast Cancer Study (WABCS, collaborative study with NIBR) and The 
Nigerian Breast Cancer Study “Genetics of Breast Cancer in Blacks” (NBCS, GBCB, 
UCMC IRB#13304B). As is customary, all patients will be consented such that any sample 

 
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type taken and the resulting nucleic acid and genetic and genomic data will be available for 
sharing with commercial entities for research only and open to additional research studies 
later. The study protocol will be approved by the Institutional Review Boards/Independent 
Ethics Committees/Research Ethics Boards (IRB/IEC/REB) of the study sites including 
University Of Ibadan College of Medicine, the Lagos State University Teaching Hospital, and 
the Roche’s legal department and the University of Chicago.  
 
Samples acquisition, processing and shipping procedures will be performed in timely manner 
and in compliance with the partner Protocol “Identifying Genetic Alterations in Breast Cancer 
Samples from Nigerian Women” (GABCNW, UCMC IRB#12-2173) and according to NCI 
standards. Biospecimens from patients participating in the proposed will concurrently be 
eligible for the GABCNW genomic study. GABCNW protocol describes the details of sample 
management and biomarker analysis and is available upon request. The proposed ARETTA 
Protocol will share data and biospecimen material with this and another on-going case-control 
study “The Nigerian Breast Cancer Study” (NBCS, UCMC IRB#13304B) conducted in 
Ibadan, Nigeria. Subjects will therefore sign only one consent for this study to enable the 
samples to be shared with the above studies and future collaborative research between 
Nigerian investigators and UC CGH. 
 
Biospecimen material includes FFPE tissue samples,  frozen tissue and blood samples and 
will be collected at various time points as indicated in the trial scheme (Tables 7.1-7.3). 
Sampling will be performed by each investigation center and sufficient biopsies and residual 
tissues will be taken as part of patient’s diagnostic evaluation and for further biomarker 
analyses. Fixed tissues will be prepared from cases with an adequate tumor volume. Each 
laboratory involved in the analysis of samples will be responsible for entering appropriate 
assay results.  
 
10.2 Pathology consideration 
 
As standard of care, a diagnostic pretreatment biopsy core and residual tumor tissue will be 
evaluated by a local pathologist according to local histopathologic standards. This includes a 
hematoxylin and eosin (H&E) stain and IHC assessment for ER, PgR, and HER2 according to 
FDA-cleared/approved protocols and ASCO/CAP recommendations. The assessment of 
additional markers such as Ki67 and others is not excluded. Histologic confirmation of 
disease will be the responsibility of each investigation site independently. Central review will 
be performed if necessary. A copy of the pathology reports confirming diagnosis is to be sent 
to the Coordinating Center HLF and Sponsor UC CGH. 
 
10.3 Biomarkers, correlative and special studies 
 
IHC markers based on community standards and according to the cleared/approved tests at 
each site’s participating pathology laboratory will be collected from a participant’s diagnostic 
breast core biopsy and residual tissues as part of the standard of care. These markers include 
but not restricted by the expression of tumor ER, PgR, and HER2. ER, PgR and HER2 IHC 

 
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procedures and antibodies will be used as described in UCMC Protocols IRB#12-2173 and 
IRB#13304B. For each marker, the original scoring parameters, e.g. intensity staining and 
percentage of cells stained positive will be recorded. The scoring system recommended by 
ASCO CAP will be applied, e.g., tumor is HRs+ if >1% nuclei stained. The cut off point 
described in UCMC Protocols IRB#12-2173 and IRB#13304B, e.g., tumor is HR+ if ≥ 10% 
cell nuclei are immunoreactive, will also be recorded. Tumor is HER2+ if weak to moderate 
(2+) complete membrane staining in > 10% of the tumor cells; or strong complete membrane 
staining (3+) observed in > 10% of the tumor cells. HER2 status will be complemented by 
HER2 FISH or CISH assays when appropriate. FISH/CISH testing is required for HER2 IHC 
2+ cases as indicated by FDA and ASCO-CAP guidelines. See sections “Glossary of Terms 
and MOP. FISH/CISH assays will be performed at the UC CGH Sponsor site. Latest ASCO-
CAP recommendations on HRs and HER2 statuses will also be explored as described in 
sections “Glossary of Terms” and MOP. 
 
Tissue obtained during trial will be used to define molecular subtypes in core biopsy and in 
resected tumors to re-assess HRs/HER2 status for treatment evaluation and for assignment of  
adjuvant targeted therapy (tamoxifen). Tissue collected under this study will also be used by 
the University of Chicago investigators to generate further biomarkers and molecular data on 
next-generation technology platforms for ongoing (IRB12-2173 and 13304B) and future 
studies on breast cancer in Nigerian women. These molecular characteristics 
(biomarkers/pathways) will be used for better stratifying tumor type and to correlate with 
pathologic, imaging, or response to treatment measures. During the course of the trial, 
standard and exploratory biomarkers will be tested for their ability to predict tumor response 
to specific classes of investigational targeted therapeutics.  
11   STUDY MANAGEMENT AND REGULATORY AFFAIRS 
11.1 Multicenter Guidelines 
 
The specific responsibilities of the Principal Investigator and the Coordinating Center are 
presented in Appendix D.  Clinical studies coordinated by The University of Chicago must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements 
The Study Lead PI/Coordinating Center is responsible for distributing all official protocols, 
amendments, and IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required.   
11.2  Institutional Review Board (IRB) Approval and Consent 
 
Unless otherwise specified, each participating institution must obtain its own IRB approval. It 
is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 

 
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In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and 
to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations and local or 
state regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the 
study, the patient will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 
11.3 Required Documentation 
Before the study can be initiated at any site, the following documentation must be provided to 
the Cancer Clinical Trials Office (CCTO) at the University of Chicago Comprehensive 
Cancer Center. 
 
• A copy of the official IRB approval letter for the protocol and informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-investigators who 
will be involved in the study. 
• Investigational drug accountability standard operating procedures 
• Additionally, before the study can be initiated at any site, the required executed 
research contract/subcontract must be on file. 
 
11.4  Data and Safety Monitoring  
This is a phase II feasibility and capacity building study.  While the Nigerian sites’ PIs are 
well equipped to treat cancer patients, none has served as PI on a cancer treatment trial.  The 
University of Chicago as Sponsor will perform close monitoring of each site.  We plan to start 
initial enrollment in Ibadan followed by LASUTH and LUTH and OAUTH. We plan to start 
accrual slowly but we should be able to recruit 2 patients per month at each site (4- 8 eligible 
patients get on study) for up to 24 months to demonstrate complete accrual. Thus, the sample 
size of 53 patients will be obtained in approximately 24 months or less if all sites come on 
board immediately as this is a capacity building study.  The 1st site will be Ibadan and we will 
get the patients through the 1st 12 weeks before other centers open.   We anticipate bringing in 
additional centers every 12 weeks.  Interim analysis will occur after 20 patients have gone to 
surgery primarily to evaluate the response rate and SAE rate. The follow-up period will be the 
time on treatment up until surgery. At the time of interim analysis, study conduct and data 
collection, patient treatment adherence, and adverse events in aggregate will be assessed.  
 
The most worrisome cardiac event is heart failure. After the first 20 patients have been 
enrolled and completed all chemotherapy till surgery, the DSMB will perform a planned 

 
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review of heart failure data. If a 6% or higher incidence of heart failure NYHA Classes III to 
IV or definite or probable cardiac death is observed (i.e., an absolute difference of more than 
3% from the expected 3% rate of heart failure on trastuzumab plus standard of care 
chemotherapy) the DSMB can recommend amending or stopping the trial.  
 
Stopping of accrual will occur if it is determined that either   a) infrastructure has not 
developed well enough to support this study, b) patient treatment adherence is insufficient to 
obtain a realistic estimate of efficacy, c) adverse events are unexpectedly more frequent than 
noted with previous clinical experience using docetaxel with or without FEC. 
 
HLF staff will be responsible for monitoring each site according to local regulations.   
Prior to subject recruitment, and unless otherwise specified, a participating site will undergo a 
Site Initiation Teleconference to be conducted by the designated HLF staff  and/or University of 
Chicago research team. The site’s principal investigator and his or her study staff must attend 
the site initiation meeting.  
Monitoring will be conducted to verify the following: 
• Adherence to the protocol 
• Completeness and accuracy of study data and samples collected 
• Compliance with regulations  
• Submission of required source documents  
 
Participating sites will also undergo a site close-out teleconference upon completion, 
termination or cancellation of a study to ensure fulfillment of study obligations during the 
conduct of the study, and to ensure that the site Investigator is aware of his/her ongoing 
responsibilities. 
This protocol will undergo weekly review at the University of Chicago’s multi-institutional 
data and safety monitoring teleconference as per procedures specified by the UC CCC NCI-
approved Data and Safety Monitoring Plan. The conference will review: 
• Enrollment rate relative to expectations, characteristics of participants 
• Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• Adherence to protocol (protocol deviations) 
• Completeness, validity and integrity of study data 
• Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form and sent via 
email to HLF.  HLF will be responsible for reporting to Sponsor at 
PhaseIICRA@medicine.bsd.uchicago.edu within 2 business days of receipt from site. 
Deviations that are considered major because they impact subject safety or alter the 
risk/benefit ratio, compromise the integrity of the study data, and/or affect subjects’ 
willingness to participate in the study must be reported to HLF within 7 days. All major 
protocol deviations should also be reported to the local IRB of record according to their 
policies and procedures. 

 
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11.5 Data Safety Monitoring Board 
 
A Data Safety and Monitoring Board (DSMB) - an external seven-member board to enhance 
the safety of study subjects and scientific integrity of the study will be constituted. The 
conduct and data generated from the study will be monitored as defined in 11.4. The DSMB 
will meet annually during the trial at a time determined by members. The board will review 
the protocol for any major concerns prior to implementation. During the trial, the DSMB 
should review cumulative study data to evaluate safety, study conduct, and scientific validity 
of the trial. The committee will check to ensure the safety of the study participants and 
consistency of the data generated at each of the four study sites. Consideration of adverse 
events rates including individual events of particular concern (e.g. SUSARs) will also be 
done. The committee will also monitor rates of recruitment, ineligibility, noncompliance, 
protocol violations and dropouts, overall and by study site with completeness and timeliness 
of data.  Midway into the study, the board will issue an interim monitoring report (IMR) of 
the trial making recommendations on continuation of the study as designed, continuation of 
the study with minor or major modifications of protocol/informed consent, early study 
termination or temporary suspension of enrollment and/or study intervention until some 
uncertainty is resolved. They can also recommend extension of the study treatment period for 
participants. 
 
11.6 Auditing 
 
Audits provide assurance that trials are conducted and study data are collected, documented 
and reported in compliance with the protocol. Further, quality assurance audits ensure that 
study data are collected, documented and reported in compliance with Good Clinical Practices 
(GCP) Guidelines and regulatory requirements.  
The audit will review subjects enrolled in accordance with audit procedures specified in the 
UC CCC Data and Safety Monitoring plan.  
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during 
its conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform HLF that such a request has been 
made.  HLF will notify the sponsor and University of Chicago staff.  
11.7 Amendments to the Protocol 
 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to 
the University of Chicago IRB for review and approval. A list of the proposed modifications 
or amendments to the protocol and/or an explanation of the need of these modifications will 
be submitted, along with a revised protocol incorporating the modifications. Only the Study 
Lead PI can authorize any modifications, amendments, or termination of the protocol. Once 
a protocol amendment has been approved by the University of Chicago IRB, the 
Regulatory Manager will send the amended protocol and consent form (if applicable) to 

 
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HLF electronically. HLF will distribute the amended protocol to all sites.  Upon receipt of 
the packet the affiliate institution is expected to do the following: 
• The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
 
• The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  
The version dates can be found on the footer of every page of the protocol and 
consent form.  The amendment number can be found on the University of Chicago 
IRB amendment approval letter that is sent with the protocol/amendment mailing.  
 
• The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to HLF staff as soon as it is 
received.  
11.8 Annual IRB Renewals, Continuing Review and Final Reports 
 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the participating institutions’ IRBs at least once a year for the duration of the study. The 
annual IRB renewal approvals for participating institutions should be forwarded promptly to 
HLF staff. If the institution’s IRB requires a new version of the consent form with the 
annual renewal, the consent form should be included with the renewal letter. 
11.9 Record Retention 
 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator.  In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region.  In all other cases, study documents 
should be kept on file until three years after the completion and final study report of this 
investigational study. 
 
11.10 Obligations of Study Site Investigators 
 

 
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The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  He/she must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
The Study Site Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered into the CRFs. Periodically, monitoring 
visits or audits will be conducted and he/she must provide access to original records to permit 
verification of proper entry of data.  
 
11.11 Study finance and sponsorship 
 
UC CGH is taking the responsibility to secure funding for the clinical trial and associated 
translational research. Funding will be primarily from the Breast Cancer Research Foundation 
(BCRF) and the NIH if we are able to obtain funding for correlative studies.  Roche Global 
will supply study drugs.   
Costs charged to patient: all routine clinical care, surgery and radiotherapy. Patients who 
might not be able to fully cover the expenses for these aspects of their treatment may receive 
some assistance depending on the availability of clinical trial funds. Recommendations for 
such assistance will be given by the medical social worker of the study site and by the Study 
site PI.  
The cost of the collection and shipment of research samples and biomarker/global molecular 
pathways analysis using emerging technologies and instrumentation for high throughout 
genome analysis will be funded by existing research grants from Novartis Institute for 
Biomedical Research (NIBR).  
Participating sites/institutions are responsible for other local costs associated with specimen 
collection, processing, and shipment.  
 
11.12 Steering Committee 
 
A Steering Committee appointed by the collaborating institutions will monitor trial progress 
and conduct and advice on scientific credibility of trial at each investigational site/institution 
and as a whole. The Steering Committee will have a total of five (5) members and will be 
chaired by study PI, study sponsor University of Chicago CGH.  
The Steering Committee will meet face-to-face or via teleconference on a schedule to be 
determined. The Steering Committee regularly reviews the overall trial accrual and may 
request information about a trial’s performance to detect barriers or issues. The Steering 
Committee will identify additional specific communication activities to meet the needs of the 
proposed protocol and to provide the overall supervision of the trial. The Steering Committee 

 
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ultimately carries the responsibility for deciding whether a trial needs to be stopped on 
grounds of safety or efficacy. 
 
11.13 Coordinating Center and Sponsor 
 
This study will use the infrastructure of Healthy Life for All Foundation (HLF, 
http://www.hlfonline.org) to coordinate and connect all study-sites together. HLF in Nigeria 
will provide additional support for this study by handling all logistical activities related to this 
trial in Nigeria.  
HLF is responsible for the following activities for all sites: 
a. Patient registration/check for eligibility 
b. Data entry 
c. Monitoring: HLF will be responsible for monitoring each site according to 
local regulations 
d. Training: HLF will be responsible for arranging a site initiation visit (SIV) and 
training each site on all aspects of the protocol including data entry, SAE 
reporting, etc. 
e. SAE/SUSAR Reporting: HLF will be responsible for reporting SAEs and 
SUSARs according to local regulations. Additionally, they will report SUSARs 
to UC via the US CRA. 
f. Auditing Sites, if necessary 
 
In addition, HLF will submit all IRB related documents to the site IRB(s) and forward to the 
UC CGH as requested.  
 
The UC CGH sponsor, in collaboration with NIBR/Roche and in collaboration with HLF, will 
oversee this multicenter-controlled clinical trial. These Centers are helping with identifying 
breast cancer burden in Nigerian women, in designing, implementation, and oversight of the 
study protocol and procedures, including the collection, management, reporting, and 
interpretation of study findings. UC CGH will provide meeting and workshops organization, 
training and regulatory guidance. In addition, UC CGH will perform those core lab analyses 
that would not be available at the study sites and conduct translational part of the study. 
The University of Chicago Personalized Cancer Care Consortium (PCCC) will provide 
infrastructure for overall monitoring and oversight of the trial.   
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al. Subcutaneous versus intravenous administration of (neo) adjuvant trastuzumab in patients 
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multicentre, randomised trial. Lancet Oncol 2012; 13(9):869-878. 
 
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APPENDICES 
 
APPENDIX A. ECOG Performance Status 
 
Grade 
ECOG* 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
*As published in Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX B.  Response Evaluation Criteria In Solid Tumors, RECIST (adapted from 
Version 1.1) 
 
Baseline documentation on “target” lesion  
Two measurable lesions per breast made up of primary lesion in the breasts and one axillary 
lymph node will be identified as target lesions and recorded and measured as baseline. 
Target lesion will be selected on the basis of its size (lesion with the longest diameter) and its 
suitability for accurate repeated measurements (by breast ultrasonography). 
The longest diameter (LD) for all target lesions will be reported as the baseline LD. The 
baseline LD will be used as reference to characterize the objective tumor response. 
All other lesions (or sites of disease) will be identified as non-target lesions and will also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each will be noted throughout follow-up. 
 
Response Criteria Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions 
Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline LD 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest LD since the treatment started 
Progressive Disease (PD): At least a 20% increase in the LD of target lesions, taking as 
reference the smallest LD recorded since the treatment started or the appearance of one or 
more new lesions 
Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions. 
IStable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Ultrasound measurements: 
 
The measurement of breast tumour size will be in 3 -dimensions, measured in 2 planes. 
In the longitudinal plane, widest Longitudinal dimension is measured (LS). In the Transverse 
plane, widest transverse dimension (TS) and anteroposterior dimension (AP) / height is 
measured. 
 

 
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APPENDIX C. Quality of Life (QoL) Assessment 
 

 
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APPENDIX D.  Responsibilities of the Protocol Steering Committee Chair (Protocol 
Chair) and Coordinating Center 
 
 Responsibility of the Protocol Chair 
 
1. The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments. The protocol will not be 
rewritten or modified by anyone other than the Protocol Chair. There will be only one 
version of the protocol, and each participating institution will use that document. The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
2. The Protocol Chair is responsible for the overall conduct of the study at all participating 
sites and for monitoring its progress. All reporting requirements will be the responsibility 
of the Protocol Chair. 
3. The Protocol Chair will be responsible for the timely review of Adverse Events (AE) to 
assure safety of the patients. 
4. The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
    
Responsibility of HLF and the Coordinating Center 
 
1. Each participating study site will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH. The HLF will be responsible for assuring that 
each participating institution has an OHRP assurance and will maintain copies of IRB 
approvals from each participating site. 
2. Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) will be submitted. 
3. HLF is responsible for central patient registration. HLF is responsible for assuring that 
IRB approval has been obtained at each participating site prior to the first patient 
registration from that site. 
4. The Coordinating Center is responsible for the preparation of all submitted data for review 
by the Protocol Chair. 
5. The Coordinating Center will maintain documentation of AE reports. Participating 
institutions report AEs directly to HLF and submits AE data to the Coordinating Center 
via REDCap. The Coordinating Center will submit AE reports to the Protocol Chair for 
timely review. 
 
Audits may be accomplished in one of two ways: (1) source documents and research records 
for selected patients are brought from participating sites to the HLF for audit, or (2) selected 
patient records may be audited on-site at participating sites. If the NCI chooses to have an 
audit at the Coordinating Center, then the Coordinating Center is responsible for having all 
source documents, research records, all IRB approval documents, NCI Drug Accountability 
Record forms, patient registration lists, response assessments scans, x-rays, etc. available for 
the audit.The UC can send representative to examine source documents on-site. 

 
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APPENDIX E.  Asymptomatic decline in LVEF: Algorithm for Continuation and 
Discontinuation of HER2-Targeted Study Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX F.  Criteria for New York Heart Association Functional Classification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX G.  Nomogram for the Determination of Body Surface Area 
 
         Height   
 
 
 
Body surface   
 
Mass 
 
Based on the Formula from Du Bois and Du Bois, Arch intern Med, 17, 863 (1916): 0 = M0 425xL0 725+x71,84 resp log0 
=logMx0,425+logLx0,725+1,8564 (0: Body surface [in cm2], M; Body mass [in kg]: L: Body length [in cm] 
 
 
 

 
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APPENDIX H.  ARETTA study advert 
 
 
 
 
 
 
 
 
Have untreated 
Breast Cancer? 
 
If you have breast cancer that is newly diagnosed without any previous treatment, 
you may qualify for participation in a research study.  Researchers at the University 
College Hospital Ibadan, Lagos State University Teaching Hospital Ikeja, Obafemi 
Awolowo University Teaching Hospital Ile-Ife and Lagos University Teaching 
Hospital Idi-araba Lagos under the supervision and sponsorship of researchers 
from the University of Chicago USA are evaluating among Nigerian women for 
the first time, a new formulation of a drug that is known to improve the survival 
of a type of breast cancer known as HER-2 positive. 
  
Qualified participants between ages 18 to 75 years with early stage breast 
cancer are eligible for this trial. 
 
If you or someone you know would like to know more, contact: 
Dr Atara Ntekim, University College Hospital Ibadan 08023059292                                                       
Dr Abiodun Popoola, Lagos State University Teaching Hospital  Ikeja 08033021434                                   
Dr Olukayode Arowolo, Obafemi Awolowo University Teaching Hospital Ile Ife 08037171477               
Dr Anthonia Sowunmi, Lagos University Teaching Hospital Idi-araba 08037216723