Genomics Guided Targeted Post-neoadjuvant Therapy in Patients With Early Breast Cancer - a Multicenter, Open-label, Umbrella Phase-II Study - COGNITION-GUIDE
Phase: PHASE2
Conditions: Early-stage Breast Cancer
Sponsor: German Cancer Research Center

 
 
Page 1 of 69 
 
Clinical Trial Protocol 
 
Genomics guided targeted post-neoadjuvant therapy in 
patients with early breast cancer – a multicenter, open-label, 
umbrella phase-II study 
 
COGNITION-GUIDE 
 
 
Clinical Trial Code: 
DKFZ-2019-008  
EudraCT No.: 
Clinicaltrials.gov: 
2020-002606-22 
NCT05332561 
Clinical Phase: 
Phase II 
Version and date: 
Version 1.1, 12.04.2023  
Sponsor: 
German Cancer Research Center (DKFZ) 
 
Represented in law by its Scientific Director Prof. Dr. Michael 
Baumann and its Administrative Director Ursula Weyrich 
 
Im Neuenheimer Feld 280 
69120 Heidelberg, Germany 
Phone: +49-6221 / 42 - 2850/ - 2860 
Fax: +49-6221 / 42 2840 
E-Mail: michael.baumann@dkfz.de 
            u.weyrich@dkfz-heidelberg.de 
 
 
CONFIDENTIALITY & DISCLOSURE STATEMENT 
This document is for confidential information purposes only. All the information contained in this document, 
especially unpublished data, is the intelligence property of German Cancer Research Center (DKFZ) and 
only for the use of the individual or entity to whom it has been sent or to whom it has been given by an 
authorized member of the DKFZ staff. The information is being provided to you for the sole purpose of 
conducting a clinical trial sponsored by the DKFZ. 
You may disclose the contents for this document to study personnel under your supervision who need to 
know the contents for this purpose, as well as your Institutional Review Board(s) or Independent Ethics 
Committee(s), subject to the following conditions: The contents of this document may not be disclosed to 
any other person or entity without written permission of the DKFZ and may not be used for any other 
purpose than the conduct of this trial. The foregoing shall not apply to disclosure required by governmental 
regulations or laws; however, you will give prompt notice to the DKFZ of any such disclosure. 
If the reader of this document is not the intended recipient, you are hereby notified that any dissemination, 
distribution or copying of this item is strictly prohibited. If you have received this item in error, please notify 
the DKFZ by telephone, and immediately return the original and all enclosures. 

 
 
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Abbreviations 
Ab 
Antibody 
ADC 
Antibody-drug conjugate 
ADL 
Activities of Daily life 
ADR 
Adverse Drug Reaction 
AE 
Adverse Events 
AESI(s) 
Adverse Event(s) of Special Interest 
AGO 
 
German Society of Gynecological Oncology 
AKT 
AKT Serine/Threonine Kinase, Proteinkinase B 
ANC 
Absolute Neutrophil Count 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMG 
Arzneimittelgesetz, German Drug Law 
AML 
Acute Myeloid Leukemia 
AST 
Aspartate Aminotransferase 
ARR 
Administration-Related Reactions 
AUC 
BID 
Area under the Curve 
Bis in die/ twice a day 
BP 
Blood Pressure 
BC 
Breast Cancer 
BRCA 
Breast Cancer 
BUN 
Blood Urea Nitrogen 
CATCH 
Comprehensive Assessment of Clinical Features and 
Biomarkers To Identify Patients with Advanced or 
Metastatic Breast Cancer for Marker Driven Trials in 
Humans 
CBP 
Child Bearing Potential 
CDK 
Cyclin-dependent Kinase 
CI 
Coordinating Investigator 
CI (stat.) 
Confidence Interval 
CHO 
Chinese Hamster Ovary (cells) 
COGNITION 
Molecular diagnostic registry platform: Comprehensive 
assessment of clinical features, genomics and further 
molecular markers to identify patients with early breast 
cancer for enrolment on marker driven trials  
COGNITION-GUIDE 
Clinical Trial: Genomics guided targeted post-neoadjuvant 
maintenance therapy in patients with early breast cancer 
COGNITION-MOMENT 
Registry study of German Breast Group with focus on 
residual tumors and metastases: A MOMENT (Molecular 
Mechanisms of Therapy Resistant Breast Cancer) of 
Cognition. Genomic profiling is conducted in collaboration by 
NCT / DKFZ along the lines of COGNITION.  
CPK 
Creatine Phosphokinase 

 
 
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CPS-EG  
Pre-treatment clinical stage (CS), post-treatment pathologic 
stage (PS), pre-treatment estrogen receptor status E and 
grade (G) 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CT 
Computed tomograpy 
(NCI) CTCAE 
(National Cancer Institute) Common Terminology Criteria for 
Adverse Events 
CYP 
Cytochrome P450 
DCIS 
Ductal carcinoma in situ 
DCR 
Disease Control Rate 
DDFS 
Distant Disease Free Survival 
DDI 
Drug-Drug Interaction 
DFS 
Disease-Free Survival 
DILI 
Drug-induced liver injury 
DNA 
Deoxyribonucleic acid 
DKFZ 
Deutsches Krebsforschungszentrum, German Cancer 
Research Center  
DKTK  
Deutsches Konsortium für Translationale Krebsforschung, 
German Cancer Consortium 
DSGVO 
Datenschutz-Grundverordnung (Verordnung (EU) 2016/679)  
DSUR 
Development Safety Update Report 
eBC 
Early Breast Cancer  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EF 
Ejection Fraction 
EGFR 
Epidermal Growth Factor Receptor (HER1) 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EOS 
End of Study 
EOT 
End of Treatment 
ER 
Estrogen Receptor  
FACT-Cog 
Functional Assessment of Cancer Therapy-Cognitive ability 
scale 
FAP 
Full Analysis Population 
FPI 
First patient in, beginning of the clinical phase 
FSH 
Follicle stimulating hormone 
fT3 / fT4 
Free triiodothyronine / free thyroxine  
GBG 
German Breast Group 
GCP 
Good Clinical Practice 
Gamma GT 
Gamma glutamyltransferase 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 

 
 
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HbA1C 
Glycosylate Hemoglobin 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HER(2) 
Human Epidermal Growth Factor Receptor (2), (ERBB2, erb-
b2 receptor tyrosine kinase (2)) 
HIV 
Human Immunodeficiency Virus 
HR+ 
Hormone-Receptor positive 
HR (statistics) 
Hazard Ratio 
I 
Inhibitor 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICs 
Immune cell(s) 
IDFS 
IDMC 
Invasive Disease-Free Survival 
Independent Data Monitoring Committee 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IIT 
Investigator Initiated Study 
IMP 
 
Investigational medicinal product 
INF 
Interferon 
INFORM  
Individualized Therapy For Relapsed Malignancies in 
Childhood 
INR 
International normalized ratio 
ITT 
Intention-To-Treat 
IV / i.v. 
Intravenous 
LDH 
Lactate dehydrogenase 
LPLV 
Last Patient Last Visit 
ISF 
Investigator Site File 
ITT 
Intention to treat 
LVEF 
Left ventricular ejection fraction 
KKS 
Koordinierungszentrum Klinische Studien 
m 
Metastatic 
MAPK 
Mitogen-activated Protein Kinase 
MDS 
Myelodysplastic Syndrome 
MEDRA 
Medical Dictionary for Regulatory Activities 
MTB 
Molecular Tumor Board 
mTOR 
Mammalian Target of Rapamycin 
NACT 
Neoadjuvant Chemotherapy 
NCT 
National Center for Tumor Diseases 
NCT DKTK/MASTER 
Molecularly Aided Stratification for Tumor Eradication 
Research 
NSCLC 
Non-small cell lung carcinoma 
NYHA 
New York Heart Association 

 
 
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OFS 
Ovarian Function suppression  
ORR 
Overall Response Rate 
OS 
Overall Survival 
P-gp 
P-glycoprotein 
PARP 
Polyadenosine 5’Diphosphoribose [poly (ADP  
Ribose)] Polymerase 
pCR 
pathological Complete Response 
PCR 
Polymerase chain reaction 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand-1 
PFS 
Progression Free Survival 
PHQ-4 
Patient Health Questionnaire for Anxiety and Depression 
PIK3CA 
Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic 
Subunit Alpha 
PI3K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetic 
PIP 2/3 
PLT 
Phosphatidylinositol 4,5-bis/tri phosphate 
Platelet Count 
PR 
Partial Response 
PNACT 
Post-Neoadjuvant (Chemo)Standardtherapy (+/- 
Radiotherapy) 
PO / p.o. 
Per Os, oral 
PRO 
Patient Reported Outcome 
PT 
Prothrombin Time 
(a)PTT 
(activated) Partial Thromboplastin Time 
PTEN 
Phosphatase and Tensin Homolog 
PTS 
Patients 
PSQI 
Pittsburgh Sleep Quality Index 
QD 
Quaque Die/ every day 
QoL 
Quality of Life 
RBC 
Red Blood Count 
RNA 
Ribonucleic acid 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Events 
SAP 
SC 
Statistical Analysis Plan 
Steering Committee 
SC / s.c. 
Subcutaneous 
SD 
Stable Disease 
SERD 
Selective Estrogen Receptor Downregulator  
SOP 
Standard Operating Procedures 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TNBC 
Triple-Negative Breast Cancer  

 
 
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TROP-2 
Trophoblast cell surface antigen-2 
TSH 
Thyroid stimulating hormone 
UGT1A1 
UDP-Glucuronosyltransferase 1 Polypeptid A1 
ULN 
Upper Limit of Normal 
WBC 
White blood cells/ count 
WES 
Whole-Exome Sequencing 
WGS 
Whole-Genome Sequencing 
WHO 
World Health Organization 
 
 
 

 
 
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Summary 
In early breast cancer (eBC), pathological complete response (pCR) after neoadjuvant therapy 
acts as surrogate marker for metastasis and overall survival. Therapy intensification by adding an 
adjuvant therapy line (post-neoadjuvant treatment) substantially lowers the risk of relapse in high-
risk breast cancer patients with residual disease after neoadjuvant treatment (non-pCR). While 
this approach was exemplified in two phase III trials without biomarker-stratification (CREATE-X, 
KATHERINE), even higher efficiency might be achieved by individualized genomic-guided post-
neoadjuvant therapies.  
To date, prospective whole genomic and transcriptomic sequencing in the framework of precision 
oncology concepts is predominantly conducted in advanced-stage cancer, limiting the overall 
benefit mainly to prolongation of progression-free survival rather than cure.  
In contrast, the implementation of precision oncology in an early disease stage may empower 
targeted intervention based on high throughput sequencing at a time point with low tumor burden 
and limited clonal complexity, harbouring the prospect to substantially improve cure rates by 
prohibition of incurable metastasis.  
Whole-genome (WGS), whole exome (WES), gene panel and transcriptome sequencing in the 
molecular diagnostic registry platform COGNITION (neoadjuvant-treated eBC patients) revealed 
relevant diagnostic information on molecular-druggable alterations in a substantial proportion of 
patients in different molecular pathways (e.g. phosphatidylinositol 3-kinase (PI3K)/ 
serine/threonine kinase (AKT), apoptosis, DNA-repair, immune escape etc.).  
Within the seven-arm umbrella phase-II clinical trial COGNITION-GUIDE, we aim to deliver 
molecularly-tailored cancer care by implementing an additional response- and genomics-guided 
post-neoadjuvant therapy after finishing the guideline-compliant post-neoadjuvant treatment in 
high-risk breast cancer patients with residual cancer burden after neoadjuvant therapy to reduce 
the substantial risk of local and distant relapse.  
The trial evaluates not a single drug but rather a general strategy of precision oncology in the 
curative setting and provides the basis for future confirmatory biomarker-driven trials.  
Eligible patients are identified considering pCR-status and clinical stage estrogen receptor status 
grade (CPS-EG)-score following surgery after neoadjuvant therapy. Allocation to the therapy-
arms is conducted by a molecular tumor board based on in depth molecular characterization of 
tumors within the COGNITION registry program. Recruitment of adequate patient numbers in 
well-defined molecular subgroups is achieved in a multicenter approach.  
The study aims to show an overall benefit of the precision medicine approach in high-risk eBC 
patients and to allow for secondary exploratory evaluation of each study-arm.  
The primary endpoint of the study is invasive Disease-Free Survival (IDFS) after 4 years 
measured from surgery to local or distant relapse or death. The sample size of the entire trial is 
240 eligible patients.  
 
 

 
 
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Zusammenfassung 
Beim frühen, potentiell kurativ behandelbaren Brustkrebs (eBC) ist das pathologische evaluierte 
Ansprechen auf neoadjuvante Therapie (pCR Status) ein Surrogat-Parameter für Metastasierung 
und Gesamtüberleben. Die Therapie-Intensivierung in Form einer zusätzlichen adjuvanten 
Therapielinie (post-neoadjuvante Therapie) reduziert substanziell das Rezidivrisiko bei 
Patientinnen mit Hochrisiko eBC mit Resttumor nach neoadjuvanter Chemotherapie (non-pCR). 
Dies konnte in zwei randomisierten Phase III Studien ohne Biomarker-Stratifikation (CREATE-X, 
KATHERINE) gezeigt werden. Basierend auf diesen Ergebnissen ist die Hypothese der 
vorliegenden Studie, dass mit einer durch das individuelle genetische Profil geleiteten 
zielgerichteten zusätzlichen post-neoadjuvanten Therapie nach Abschluss der leitliniengerechten 
post-neoadjuvanten Therapie eine weitere Verbesserung der Wirksamkeit erreicht werden kann.  
Molekular-stratifizierte Präzisionsonkologie-Konzepte, welche die prospektive Sequenzierung 
des gesamten Genoms und des Transkriptoms umfassen, werden gegenwärtig meist bei 
fortgeschrittenen Krebserkrankungen eingesetzt, bei denen der Nutzen sich vor allem auf die 
Verlängerung des progressionsfreien Überlebens beschränkt und weniger auf die Verbesserung 
der Heilungsraten ausgerichtet ist.  
Im Gegensatz dazu eröffnet der Einsatz der Sequenzierung des gesamten Genoms und des 
Transkriptoms in einem frühen Erkrankungsstadium zu einem Zeitpunkt mit geringer Tumorlast 
und geringer genetischer Komplexität die Möglichkeit, die Heilungsrate mit zielgerichteten 
Therapien wesentlich zu steigern und das Auftreten einer Metastasierung zu verhindern. 
Innerhalb der Molekulardiagnostik Registerplattform COGNITION (eBC Patient:innen mit 
Indikation für Neoadjuvanz) hat die Hochdurchsatzsequenzierung des Genoms und des 
Transkriptoms relevante diagnostische Informationen über molekulare Angriffspunkte bei einem 
beträchtlichen Anteil der Patient:innen in verschiedenen molekularen Signalwegen aufgezeigt 
(z.B. Phosphatidylinositol 3-Kinase (PI3K)/ Serin-/Threoninkinase (AKT)-, DNA-Reparatur, 
Apoptose, Immunevasion etc.).  
Die sieben-armige COGNITION-GUIDE Phase II-Studie hat das Ziel, im Rahmen der 
Präzisionsonkologie im frühen, potentiell kurativ behandelbaren Krankheitsstadium durch eine 
zusätzliche, molekular stratifizierte post-neoadjuvante Therapie die Behandlung von 
Brustkrebspatientinnen mit hohem Rezidiv- und Metastasierungsrisiko zu verbessern.  
Die Studie prüft den Nutzen der Präzisionsonkologie mit Translation in molekular zielgerichteten 
Therapieansätzen in einem potentiell kurativen Krankheitsstadium als Grundlage für zukünftige 
konfirmatorische Biomarker-basierte randomisierte interventionelle Studien.  
Geeignete Patientinnen und Patienten werden mittels pathologischer Evaluation nach OP und 
CPS-EG-Score nach neoadjuvanter Therapie und Operation identifiziert und nach eingehender 
molekularer Charakterisierung der Tumoren im Rahmen des COGNITION-Register-Programms 
von einem molekularen Tumorboard verschiedenen Behandlungsarmen zugeteilt. Die 
Rekrutierung adäquater Fallzahlen in klar definierten molekularen Untergruppen wird in einem 
multizentrischen Ansatz erreicht.  
Die Studie prüft, ob ein Gesamtnutzen des präzisionsmedizinischen Ansatzes bei Hochrisiko-
eBC-Patient:innen erreicht werden kann und ermöglicht eine explorative Evaluation der einzelnen 
Studienarme.  
Primärer Endpunkt der Studie ist das invasive krankheitsfreie Überleben (Invasive Disease Free 
Survival, IDFS) nach 4 Jahren (von der Operation bis zum lokalen Rezidiv, Metastasierung oder 
Tod). Die Fallzahl der gesamten Studie beträgt 240 eingeschlossene Patient:innen. 
 

 
 
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Table of Contents 
ABBREVIATIONS ...................................................................................................................... 2 
RESPONSIBILITIES .................................................................................................................. 7 
SUMMARY ................................................................................................................................. 9 
ZUSAMMENFASSUNG ........................................................................................................... 10 
TABLE OF CONTENTS ........................................................................................................... 11 
LIST OF FIGURES ................................................................................................................... 14 
LIST OF TABLES .................................................................................................................... 14 
PROTOCOL SYNOPSIS .......................................................................................................... 15 
TRIAL SCHEDULE - OVERVIEW ............................................................................................ 21 
1 
INTRODUCTION ............................................................................................................... 24 
 
SCIENTIFIC BACKGROUND .............................................................................................. 24 
 
TRIAL RATIONALE/ BENEFIT- RISK ASSESSMENT ............................................................. 25 
 
REFERENCE COMMITTEE ............................................................................................... 27 
1.3.1 
Independent Data Monitoring Committee (IDMC) .................................................. 27 
1.3.2 
Steering Committee (SC) ...................................................................................... 27 
2 
TRIAL OBJECTIVES AND ENDPOINTS ........................................................................... 28 
 
PRIMARY OBJECTIVE ..................................................................................................... 28 
 
SECONDARY OBJECTIVES .............................................................................................. 28 
 
EXPLORATIVE OBJECTIVES ............................................................................................ 28 
 
PRIMARY ENDPOINT ...................................................................................................... 28 
 
SECONDARY ENDPOINTS ............................................................................................... 28 
 
EXPLORATIVE ENDPOINTS ............................................................................................. 28 
3 
TRIAL DESIGN .................................................................................................................. 29 
4 
TRIAL DURATION AND SCHEDULE................................................................................ 29 
5 
SELECTION OF PATIENTS .............................................................................................. 31 
 
NUMBER OF PATIENTS AND RECRUITMENT ...................................................................... 31 
 
GENERAL CRITERIA FOR PATIENTS’ SELECTION .............................................................. 31 
 
ARM-SPECIFIC CRITERIA FOR PATIENTS’ SELECTION ....................................................... 31 
 
GENERAL INCLUSION CRITERIA ...................................................................................... 33 
 
GENERAL EXCLUSION CRITERIA ..................................................................................... 34 
 
CRITERIA FOR WITHDRAWAL .......................................................................................... 35 
5.6.1 
Withdrawal of Patients........................................................................................... 35 
5.6.2 
Handling of Withdrawals ........................................................................................ 35 
5.6.3 
Replacement of Patients ....................................................................................... 35 
5.6.4 
Premature Closure of the Clinical Trial or a Single Center ..................................... 35 
 
PRIOR AND CONCOMITANT ILLNESSES ............................................................................ 36 
 
BACKGROUND MEDICATION ........................................................................................... 36 
 
PRIOR AND CONCOMITANT MEDICATION / NON-DRUG TREATMENT ................................... 36 
6 
INVESTIGATIONAL MEDICINAL PRODUCT/-S ............................................................... 36 
 
GENERAL INFORMATION ABOUT INVESTIGATIONAL MEDICINAL PRODUCT/-S ...................... 36 
 
THERAPEUTIC/ DIAGNOSTIC EFFECTS ............................................................................. 36 
 
KNOWN SIDE EFFECTS .................................................................................................. 36 
 
DOSAGE SCHEDULE ...................................................................................................... 37 
 
CONTRACEPTION........................................................................................................... 37 
 
OVERDOSE ................................................................................................................... 37 
 
TREATMENT ASSIGNMENT .............................................................................................. 37 
 
SUPPLIES, PACKAGING AND LABELING ............................................................................ 38 
 
ACCOUNTABILITY........................................................................................................... 38 

 
 
Page 12 of 69 
 
COMPLIANCE ............................................................................................................. 38 
7 
TRIAL METHODS ............................................................................................................. 39 
 
REGISTRATION AND ENROLLMENT .................................................................................. 39 
 
DESCRIPTION OF CLINICAL, LABORATORY AND THERAPEUTIC MEASUREMENTS ................. 39 
7.2.1 
Clinical Assessments ............................................................................................ 39 
7.2.2 
Laboratory Assessments ....................................................................................... 40 
7.2.3 
Measurement of Efficacy Parameters .................................................................... 43 
7.2.4 
Further Assessments ............................................................................................ 44 
 
DESCRIPTION OF STUDY VISITS ...................................................................................... 45 
7.3.1 
Screening .............................................................................................................. 45 
7.3.2 
Arm Allocation ....................................................................................................... 46 
7.3.3 
Baseline / Before experimental Treatment Start .................................................... 46 
7.3.4 
Trial Visits Treatment Period ................................................................................. 46 
7.3.5 
End of Treatment (EOT) Visit ................................................................................ 47 
7.3.6 
After EOT-Safety Observation ............................................................................... 47 
7.3.7 
Follow-up Period ................................................................................................... 47 
 
METHODS OF DATA AND SAMPLE COLLECTION ................................................................ 47 
7.4.1 
Data Collection and Handling ................................................................................ 47 
7.4.2 
Sample Collection and Handling ........................................................................... 48 
8 
ANCILLARY AND POST TRIAL CARE ............................................................................. 48 
9 
ASSESSMENT OF ADVERSE EVENTS ........................................................................... 48 
 
SPECIFICATION OF ADVERSE EVENTS ............................................................................. 48 
9.1.1 
Adverse Events ..................................................................................................... 48 
9.1.2 
Serious Adverse Event .......................................................................................... 49 
9.1.3 
Adverse Drug Reaction / Serious Adverse Drug Reaction ..................................... 50 
9.1.4 
Expectedness ....................................................................................................... 50 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................................ 50 
 
PERIOD OF OBSERVATION AND DOCUMENTATION ............................................................ 50 
9.2.1 
Grading of AEs ...................................................................................................... 51 
9.2.2 
Coherence between AEs and the IMP / Background Medication ........................... 51 
9.2.3 
Outcome of AEs .................................................................................................... 51 
9.2.4 
Action taken with the IMP / Background Medication .............................................. 52 
9.2.5 
Countermeasures .................................................................................................. 52 
 
REPORTING OF SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS OF SPECIAL INTEREST BY 
INVESTIGATOR ........................................................................................................................ 52 
 
REPORTING OF PREGNANCIES ....................................................................................... 52 
 
SECOND SAE ASSESSMENT .......................................................................................... 52 
 
EXPEDITED REPORTING ................................................................................................. 53 
 
EMERGENCY TREATMENT .............................................................................................. 53 
 
ADVERSE EVENTS AFTER THE REGULAR SAFETY FOLLOW UP PERIOD ................................ 53 
 
PREGNANCY ................................................................................................................. 54 
9.9.1 
Maternal exposure ................................................................................................ 54 
9.9.2 
Paternal exposure ................................................................................................. 54 
 
NEW CANCERS .......................................................................................................... 54 
 
DEATHS ..................................................................................................................... 55 
 
ADVERSE EVENTS OF SPECIAL INTEREST (AESIS) ....................................................... 55 
 
OTHER REPORTINGS .................................................................................................. 55 
 
SAFETY MONITORING OF BACKGROUND THERAPY ........................................................ 55 
10 
STATISTICAL CONSIDERATIONS ............................................................................... 56 
 
STUDY DESIGN .......................................................................................................... 56 

 
 
Page 13 of 69 
 
ANALYSIS VARIABLES ................................................................................................. 56 
10.2.1 
Primary analysis................................................................................................. 56 
10.2.2 
Secondary Analysis ........................................................................................... 56 
10.2.3 
Explorative Analysis ........................................................................................... 56 
10.2.4 
Safety Analysis .................................................................................................. 57 
 
SAMPLE SIZE CALCULATION ........................................................................................ 57 
 
ANALYSIS POPULATIONS............................................................................................. 57 
10.4.1 
Full Analysis Population ..................................................................................... 57 
10.4.2 
Per Protocol Populations .................................................................................... 58 
10.4.3 
Safety Population ............................................................................................... 58 
 
STATISTICAL METHODS .............................................................................................. 58 
10.5.1 
Demographic and other Baseline Characteristics ............................................... 58 
10.5.2 
Study Therapy, Treatment Compliance, and Follow-up ...................................... 58 
10.5.3 
Analysis of the Primary Endpoint ....................................................................... 58 
10.5.4 
Analysis of Secondary Endpoints ....................................................................... 58 
10.5.5 
Analysis of Explorative Endpoints ...................................................................... 59 
10.5.6 
Other Analyses .................................................................................................. 59 
10.5.7 
Analysis of Safety Endpoints .............................................................................. 59 
10.5.8 
Handling of Missing Data ................................................................................... 59 
 
SAFETY MONITORING ANALYSES ................................................................................. 59 
11 
DATA MANAGEMENT ................................................................................................... 60 
11.1 
DATA COLLECTION ..................................................................................................... 60 
11.2 
DATA HANDLING......................................................................................................... 60 
11.3 
STORAGE AND ARCHIVING OF DATA ............................................................................ 60 
12 
ETHICAL AND LEGAL ASPECTS ................................................................................. 61 
 
GOOD CLINICAL PRACTICE ......................................................................................... 61 
 
PATIENT INFORMATION AND INFORMED CONSENT ........................................................ 61 
 
CONFIDENTIALITY ....................................................................................................... 61 
 
RESPONSIBILITIES OF INVESTIGATOR ........................................................................... 62 
 
APPROVAL OF TRIAL PROTOCOL AND AMENDMENTS ..................................................... 62 
 
CONTINUOUS INFORMATION TO INDEPENDENT ETHICS COMMITTEE ............................... 62 
 
NOTIFICATION OF REGULATORY AUTHORITIES ............................................................. 62 
 
REGISTRATION OF THE TRIAL ...................................................................................... 62 
 
INSURANCE ................................................................................................................ 63 
 
RISK ASSESSMENT IN A PANDEMIC SITUATION............................................................... 63 
13 
QUALITY ASSURANCE ................................................................................................ 63 
 
MONITORING.............................................................................................................. 63 
 
INSPECTIONS/ AUDITS ................................................................................................ 63 
14 
AGREEMENTS .............................................................................................................. 63 
 
FINANCING OF THE TRIAL ............................................................................................ 63 
 
DECLARATION OF INTERESTS ...................................................................................... 64 
 
DISSEMINATION POLICY .............................................................................................. 64 
14.3.1 
Reports .............................................................................................................. 64 
14.3.2 
Publication ......................................................................................................... 64 
15 
SIGNATURES ................................................................................................................ 65 
16 
DECLARATION OF INVESTIGATOR ............................................................................ 66 
17 
REFERENCES ............................................................................................................... 67 
18 
APPENDIX ..................................................................................................................... 69 
 
SUB-PROTOCOLS ....................................................................................................... 69 

 
 
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List of Figures 
Figure 1. Design of molecular diagnostic registry platform COGNITION and clinical trial 
COGNITION-GUIDE................................................................................................................. 26 
Figure 2: Timeline for COGNITION-GUIDE in the context of standard therapy and COGNITION
 ................................................................................................................................................. 30 
Figure 3: Blood draw sampling scheme .................................................................................... 43 
Figure 4: Overview of PRO Measurements and Schedule ........................................................ 45 
 
 
List of Tables 
Table 1 Analyte Types Biobanking Blood Samples ................................................................... 42 
Table 2 Schedule Blood Draws ................................................................................................ 43 
Table 3: Screening ................................................................................................................... 45 
Table 4: AESIs applicable for all IMPs ...................................................................................... 55 

COGNITION-GUIDE:  
Umbrella Protocol  
EudraCT: 2020-002606-22 
Version 1.1  
Date: 12.04.2023 
 
Page 15 of 69 
Protocol Synopsis 
Title 
Genomics guided targeted post-neoadjuvant therapy in patients with 
early breast cancer – a multicenter, open-label, umbrella phase-II study 
(COGNITION-GUIDE) 
 
Trial Phase 
Phase II 
 
Sponsor 
German Cancer Research Center (DKFZ), represented in law by its scientific director  
Prof. Dr. Michael Baumann and administrative director Ursula Weyrich 
Im Neuenheimer Feld 280 
D-69120 Heidelberg 
 
Coordinating Investigator (CI) 
Prof. Dr. Andreas Schneeweiss (LKP)  
NCT Heidelberg 
Im Neuenheimer Feld 460  
D-69120 Heidelberg 
 
Co-Coordinating Investigator (Co-CI) 
Prof. Dr. Richard F. Schlenk 
NCT Trial Center 
Im Neuenheimer Feld 130/3 
D-69120 Heidelberg 
 
Scientific Program Coordinator 
Prof. Dr. Peter Lichter  
German Cancer Research Center (DKFZ) 
Im Neuenheimer Feld 580 
D-69120 Heidelberg  
 
Financing/ Status of the Sponsor  
The trial is financed by funds of National Center for Tumor Diseases / German Cancer Research 
Center Heidelberg and the Federal Ministry of Education and Research (BMBF). Study drugs 
are provided free of charge by Roche Pharma AG, Astra Zeneca and Gilead Sciences. 
 
Number of Sites 
Five oncological hospitals in Germany. 
 
Number of Patients 
240 eligible patients are enrolled in the study. 
 
 

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Indication 
Patients with early breast cancer and high-risk for relapse following neoadjuvant chemotherapy 
and surgery.  
 
Trial Population 
 
High-risk early breast cancer patients, defined as  
• 
Triple negative breast cancer (TNBC) or human epidermal growth factor receptor 2 
(HER2)+ breast cancer (BC) with residual cancer burden (non-pCR, defined as other 
than ypT0/is ypN0), or 
• 
Hormone-receptor positive (HR+)/HER2- BC with non-pCR and  
 
CPS-EG score ≥ 3, or 
 
ypN+ and a CPS-EG score ≥ 2 
after neoadjuvant therapy, surgery and standard post-neoadjuvant therapy according to current 
German guidelines.  
Patients identified within COGNITION (or COGNITION-MOMENT) as high-risk-patients and 
who are admitted to and discussed in the NCT molecular tumor board (MTB) are allocated to 
one of the different therapy-arms of COGNITION-GUIDE in case of druggable 
genetic/transcriptomic alterations meeting the respective biomarker criteria. High-risk patients 
who are marker-negative or with failure to conduct molecular profiling are allocated into the 
observational arm of COGNITION-GUIDE. 
 
General Inclusion Criteria  
General inclusion criteria are relevant for all patients at screening and at baseline. Arm-specific 
inclusion criteria are outlined in the corresponding sub-protocol and are evaluated at baseline. 
Patients meeting all of the following criteria are considered for enrollment into the trial: 
1. Provision of written informed consent 
2. Female and male patients with non-metastatic early (stage I-III) breast cancer aged ≥ 18 
years 
3. Conducted neoadjuvant chemotherapy and surgery as well as conducted standard post-
neoadjuvant treatment +/- radiotherapy (standard according to German guidelines except 
Abemaciclib and Olaparib) 
4. For patients with initially triple negative (TNBC) or HER2-positive breast cancer:  
• 
Non-pCR defined as other than ypT0/is ypN0 
5. For patients with initially hormone receptor positive and HER2-negative breast cancer: Non-
pCR and CPS-EG score  
• 
≥ 3 and ypN0, or 
• 
≥ 2 and ypN+  
6. ECOG Performance Status ≤ 1 
7. Acute effects of any prior therapy resolved to baseline severity or National Cancer Institute 
Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade ≤ 1 
except for adverse effects not constituting a safety risk by investigator judgement 
8. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential 
negative urine pregnancy test at post-operative screening and baseline as well as highly 
effective forms of contraception have to be in place thereafter 
• 
Evidence of childbearing potential is defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile  
• 
Postmenopausal or evidence of non-childbearing status is defined as:  
o Amenorrhea for 1 year or more without an alternative medical cause following 
cessation of exogenous hormonal treatments plus follicle stimulating hormone 

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(FSH) levels in the postmenopausal range in women not using hormonal 
contraception or hormonal replacement therapy 
o Chemotherapy-induced menopause 
o Surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, total 
hysterectomy or tubal ligation at least 6 weeks before IMP treatment)  
o Female patients with age ≥ 60 years 
• 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy 
9. Female patients of childbearing potential and male patients with partners of childbearing 
potential who are sexually active must agree to the use of two forms of contraception in 
combination (male condom and one highly effective method). These should be started 
immediately after signing the informed consent form and continued throughout the period of 
study treatment plus a substance-depending time period (see respective sub-protocol) for 
female patients and a substance-depending time period for male patients. Details on 
contraception and pregnancy testing for male and female patients (and if indicated their 
partners) under IMP treatment are described within the respective sub-protocol 
10. Ability of patient to understand and comply with the protocol for the duration of the study, 
including treatment and scheduled visits and examinations 
11. Adequate bone marrow, renal, and hepatic function defined by laboratory tests* 
* Arm-specific laboratory parameters and reference values to be met at baseline within 14 days prior to experimental 
study treatment are described within the respective sub-protocol. 
 
 
General Exclusion Criteria  
General exclusion criteria are relevant for all patients at screening and at baseline. Arm-specific 
exclusion criteria are outlined in the corresponding sub-protocol and are evaluated at baseline. 
Patients presenting any of the following criteria are not included in the trial: 
1. Other malignancy within the last 5 years except: adequately treated non-melanoma skin 
cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1 
grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone 
marrow involvement) curatively treated with no evidence of disease for ≥ 5 year 
2. Concurrent severe, uncontrolled systemic disease that would place patient at undue risk or 
interfere with planned treatment 
3. Concurrent or previous treatment within 30 days in another interventional clinical trial with an 
investigational anticancer therapy 
4. Persistent toxicity (≥ Grade 2 according to NCI CTCAE v5.0 caused by previous cancer 
therapy, excluding alopecia 
5. Clinical signs of active infection (> Grade 2 according NCI CTCAE v5.0) 
6. History of or newly diagnosed human immunodeficiency virus (HIV) infection and 
immunocompromised patients  
7. Active Hepatitis A virus infection 
8. Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface 
antigen (HBsAg) test. Patients with a past or resolved HBV infection, defined as having a 
negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening , 
are eligible for the study if active HBV infection is ruled out on the basis of HBV DNA viral load 
per local guidelines 
9. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at 
screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA  
10. Dementia or significant impairment of cognitive state 
11. Epilepsy requiring pharmacologic treatment 
12. Pregnancy and breast feeding 

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13. Inability to take oral medication and gastrointestinal disorders likely to interfere with 
absorption of study medication 
14. Major surgery (any invasive operative procedure in which a more extensive resection is 
performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered) 
within four weeks before screening and baseline excluding breast-tumor resection after 
neoadjuvant chemotherapy. Patients must have recovered from any effects of any major 
surgery 
15. Systemic chemotherapy or radiotherapy within four weeks or a longer period depending on 
the characteristics of the agents used 
16. Heart failure classified as New York Heart Association (NYHA) II/III/IV 
17. Severe obstructive or restrictive ventilation disorder 
18. Patients with clinically active tuberculosis  
19. Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the 
use of an investigational drug 
20. Is taking or requiring the continued use of any of the prohibited concomitant medications 
listed in the respective subprotocols at baseline 
21. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder or 
non-malignant systemic disease. Examples include, but are not limited to, uncontrolled 
ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord 
compression or, superior vena cava syndrome. 
 
 
Trial Objectives and Endpoints 
 
Primary Objective 
• 
to improve clinical outcome in early high-risk breast cancer by biomarker-guided post-
neoadjuvant therapy (systemic treatment in the adjuvant setting following neoadjuvant 
therapy, surgery and post-neoadjuvant standard therapy)  
 
Secondary Objectives  
• 
To assess Invasive Disease-free Survival (IDFS) as defined by Hudis et al*,1 four years 
after surgery in each study arm separately 
To assess  
• 
Distant Disease-free Survival (DDFS) as defined by Hudis et al**,1 four years after 
surgery 
• 
overall survival (OS) 
• 
Safety and tolerability of biomarker-guided post-neoadjuvant treatment  
in each study arm separately and overall  
• 
To evaluate feasibility of biomarker-guided post-neoadjuvant treatment 
 
Explorative Objectives 
• 
Subjective tolerability, feasibility and quality of life of biomarker-guided post-
neoadjuvant treatment evaluated by patient-reported outcomes (PROs) (see chapter 
10.2) in each study arm separately and overall 
• 
To assess the clinical value of liquid biopsies in the study context  
 
Primary Endpoint 
• 
IDFS* of patients four years after surgery overall (definition chapter 10.2) 
 

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Secondary Endpoints 
• 
OS (definition chapter 10.2) 
• 
IDFS* in each study arm separately (definition chapter 10.2) 
• 
DDFS** (definition chapter 10.2) 
• 
Safety including incidence of adverse events (definition chapter 10.2) 
 
Explorative Endpoints 
• 
Patient reported outcomes (definition chapter 10.2) 
• 
To assess the clinical value of liquid biopsies in the study context 
 
*IDFS: time from surgery to whatever comes first a) ipsilateral invasive breast tumor recurrence, b) local/regional invasive 
breast cancer recurrence, c) distant recurrence, d) death attributable to any cause incl. breast cancer, e) contralateral 
invasive breast cancer or f) Second primary non-breast invasive cancer. 
**DDFS: time from surgery to whatever comes first a) distant recurrence, b) death attributable to any cause incl. breast 
cancer or c) second primary non-breast invasive cancer. 
 
Trial Design 
Multicenter, open-label, multi-arm, umbrella phase-II study 
Patients are screened and enrolled earliest 1 month and latest 3 months after completion of 
post-neoadjuvant standard therapy (including radiotherapy, if indicated). In case of existing 
exclusion criteria estimated by the investigator as transient a rescreening can be performed 
within this time frame. The arm-allocation takes place after the interdisciplinary molecular tumor 
board of the NCT between general inclusion and start of the study-medication. Further arm-
specific in- and exclusion criteria are evaluated by the investigator before the start of 
experimental study treatment (baseline). Study treatment starts within 14 days after the 
baseline visit. The IMP treatment duration for each patient is expected to be 12 months followed 
by a substance-depending safety follow-up (observational arm: 12 months). 
Visit schedule and assessments are summarized in the trial schedule overview and the trial 
schedules for each treatment arm in the applicable sub-protocol. 
 
Investigational Medicinal Products and Dosage Overview 
 
Arm 1 
Immune 
Evasion* 
Atezolizumab (anti-PD-L1 antibody), i.v.: 
    1200 mg d1, q21d 
Arm 2 
PI3K* 
Inavolisib (PI3K inhibitor):  
    9mg, d1-d28, q28d 
Arm 3 
AKT* 
Ipatasertib (AKT inhibitor):  
    400 mg d1-d28 q28d 
Arm 4 
DNA 
Repair* 
Olaparib (PARP inhibitor): 
    300 mg bid d1-d28, q28d 
Arm 5 
TROP-2* 
Sacituzumab Govitecan (TROP-2 antibody), i.v.:  
    10mg /kg BW, d1, d8, q21d 
Arm 6 
ERBB2* 
Trastuzumab/Pertuzumab (anti-HER2 antibody), s.c.: 
    initial dose: Trastuzumab 600 mg, Pertuzumab 1200 mg, 
30 000 units hyaluronidase 
    maintainance dose: Trastuzumab 600 mg, Pertuzumab 
600 mg, 20 000 units hyaluronidase; d1, q21d 
Arm 7 
N/A* 
Observational Arm (Biomarker-negative or inability to conduct 
molecular profiling) 
 
*if hormone-receptor positive (HR+) concurrently to standard-of-care adjuvant endocrine 
therapy. For specific therapy regimen refer to corresponding sub-protocol. 

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Sample Size  
Based on historical data disease-free survival (DFS) in high risk patients with early breast 
cancers following neoadjuvant chemotherapy defined by no pathological complete response 
(for TNBC and HER2+ BC) and a high CPS-EG-score (for HR+HER2- BC) at 4 years after 
surgery is in the range of 60% to 70% 2-5. Therefore, we test the one-sided null hypothesis H0: 
IDFS (4-year) ≤70%. Assuming exponential survival, uniform accrual over 3 year and a follow-
up of 2 years after inclusion of the last patient, sample size is calculated to achieve a power of 
90% to reject the null hypothesis at a significance level of 5% given an IDFS rate of 80% at 4 
years. To show this, 215 patients have to be eligible for the statistical analysis. To account for 
up to 10% loss to follow-up, 240 patients (pts) have to be recruited in total.  
 
The following patient allocation to the respective study-arms is expected: 
 
o Arm 1 Atezolizumab (Immune Evasion) 
 
18-26% (43-62 patients (pts)) 
o Arm 2 Inavolisb (PI3K) 
 
 
 
4-9%     (10-22 pts) 
o Arm 3 Ipatasertib (AKT) 
 
 
 
8-14%   (19-34 pts) 
o Arm 4 Olaparib (PARP, DNA-Repair) 
 
15-21% (36-50 pts) 
o Arm 5 Sacituzumab Govitecan (TROP-2) 
 
18-24% (43-58 pts) 
o Arm 6 Trastuzumab / Pertuzumab (ERBBB)  
2-3%     (5-7 pts) 
o Arm 7 Observation*  
 
 
 
8-14%   (19-34 pts) 
(*Biomarker-negative or inability to conduct molecular profiling) 
 
 
Statistical Analysis.  
The primary endpoint IDFS is analyzed according to the Kaplan-Meier method and confidence 
interval (CI) estimation for IDFS is based on the cumulative hazard function using Greenwood’s 
formula for variance estimation. All secondary endpoints are analyzed in an explorative manner. 
After the overall assessment of the primary hypothesis explorative subgroup analyses in the 
different treatment arms are performed. Interim safety analyses are performed in all arms after 
24 and 36 months. 
 
Trial Duration and Dates 
Total trial duration: 
90 months 
Recruitment period: 
48months 
Minimum endpoint follow-up: 
48 months after surgery 
Duration of clinical phase: 
84 months (FPFV – LPLV) 
First patient first visit (FPFV) 
Q2/2023 
Last patient first visit (LPFV): 
Q1/2027 (FPFV + 48 months recruitment)  
Last patient last visit (LPLV): 
Q1/2030 (FPFV + 84 months clinical phase) 
Trial Report Completed: 
Q4/2030 (LPLV + 6 months) 
 
 

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Trial Schedule - Overview 
Overview of trial design, general assessments for all study arms regarding screening, baseline and follow-up period and schedule for observational arm. 
 A detailed trial schedule for each treatment arm (baseline, study treatment, end of treatment, safety follow-up) is specified in the applicable sub-protocol. 
 
 
 
Screening1 
Baseline,2 3 
Arm-Specific: 
see Sub-
Protocols 
Study Treatment (Arms 1 - 6)2 
 Treatment Cycles dependent on IMP 
(+/- 2 days) 
End of 
Treat-
ment 
Safety 
Follow-
up5, 6 
Follow-up 
Period 
Treatment Arms 1-6: See Sub-Protocols 
Baseline2, 3 
General /  
Arm 
Allocation17 
Observation (Arm 7)  
Visits every 3 months after Baseline (+/- 
7 days) 
End of 
Observation4 
  
Cycle and visit description   
Visit 1  
 Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
  
  
1 - 3 months 
after end of 
standard 
therapy3 
≤ 28 days after 
enrollment 
Month 3 
Month 6 
Month 9 
12 months after 
treatment start or 
Baseline 
FU every 3 
month for 3 
years and 
then all 6 
month until 
EOS 
  
Clinical Assessments 
  
  
  
 
  
  
  
  
Informed consent 
X 
X (IMP)5,7 
  
 
  
  
  
  
Demographics 
X 
  
 
  
  
  
  
Medical/ oncologic history 
X  
  
 
  
  
  
  
Inclusion/ Exclusion 
X1 
X8 
  
 
  
  
  
  
Signs/ symptoms 
X 
X 
  
 
  
  
  
  
Vital signs 
X 
X 
X 
X 
X 
X 
  
  
Physical examination 
X 
X 
X 
X 
X 
X 
  
 
ECOG 
X 
X 
 
 
 
X 
 
  
ECHO 
X 
  
 
  
(X)  
  
  
ECG 
X 
X 
 (X) 
(X) 
(X) 
(X) 
  
  
Enrollment 
X 
  
 
  
  
  
 
Arm allocation 
 
X18 
 
 
 
 
 

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Screening1 
Baseline 
Observation (Arm 7)  
Follow-up  
Month 3 
Month 6 
Month 9 
Observation End 
  
Laboratory Assessments 
  
  
  
 
  
  
  
  
Hematology (local lab)  
X 
X 
X 
X 
X 
X 
  
  
Blood chemistry (local lab)  
X 
X 
X 
X 
X 
X 
  
 
Coagulation (local lab) 
X 
X 
 
 
 
 
 
  
Urinanalysis (local lab) 
X 
X 
  
 
  
X 
  
  
HAV, HBV, HCV, HIV-1 (local 
lab)  
X 
  
 
  
  
  
  
Pregnancy test (if CBP, local 
lab) 
X 
X 
  
 
  
X 
  
  
Biobanking Blood samples 
(central lab)9, 10 
X11 
X  
 
X  
X12 
  
Breast Cancer Status13  
  
  
  
 
  
  
  
  
Clinical exam. (breast) 
  
X 
X  
X 
X 
X 
X 
  
Sonography 
  
X 
 
X 
X 
  
Mammography 
  
X 
  
 
  
X 
X 
  
Further Assessments 
  
  
  
 
  
  
  
 
Background medication 
X 
X 
X 
X 
X 
X 
X 
  
Concomitant medication 
X 
X 
X 
X 
X 
X 
  
  
PRO14, 15 
X11 
X  
X 
X 
X12  
 
SADRs background medication 
X 
X 
X 
X 
X 
X 
X 
 
AESIs / SADRs of IMP during 
FU5,16 
 
 
 
 
 
 
X 
 
Status / survival patients 
 
 
 
 
 
 
X 
 
 
 

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Description of footnotes: 
 1. Assessment of general in- and exclusion criteria; in case existing exclusion criteria are estimated as transient by the investigator, a re-screening can be performed within the time frame of 
screening.  
 2. Refer to sub-protocols for baseline assessments of treatment arms 1-6. Additional arm-specific assessments are required. 
 3. In treatment arms, baseline assessments can be performed 14 days prior to start of study treatment until day 1 before administration of IMP. 
 4. also referred to as “end of treatment” (EOT) 
 5. Not applicable for the observational arm. 
 6. Plus 28 days except for study arm 1 (atezolizumab) and study arm 6 (trastuzumab/pertuzumab): plus 10 weeks. 
 7. Informed consent form for the applicable arm-specific IMP treatment is obtained. 
 8. Assessment of general and arm-specific in- and exclusion criteria; in case not meeting of in- or existing exclusion criteria are estimated as transient by the investigator, a re-evaluation can 
be performed within the time frame for baseline. 
 9. For detailed blood draw schedule please refer to chapter 7.2.2.5. 
10. In case of temporary discontinuation (cycle delay) or premature discontinuation of IMP blood draws for biobanking should be taken as close as possible to the 3 month and 12 month point 
in time after therapy start (+/- 4 weeks). 
11. At baseline visit (all arms) or arms 1-6: day 14 to day 1 prior to IMP administration. 
12. Every 6 month until end of year four after surgery. 
13. Breast cancer status and FU according to S3- and German Society of Gynecological Oncology (AGO)-Guidelines. Assessments are performed within the clinical standard routine of breast 
cancer follow up care, results of the last assessment are documented.  
14. Please refer to chapter 7.2.4 Further Assessments. 
15. PRO-Assessments are performed at baseline, 3 and 6 months after baseline, EOT and then every 6 month until end of year four after surgery. Refer to chapter 7.2.4. 
16. Within the follow-up period, only SADRs and AESIs are collected and are reported to the pharmaceutical company as well as to the NCT trial center in copy (refer to chapter 9.8). 
17. Patients are allocated to the therapy arms according to the report of the NCT molecular tumor board. At baseline, after (re-)assessment of arm-specific and general in- and exclusion criteria 
by the investigator, arm allocation is completed. 
 

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1 Introduction 
 Scientific Background 
Despite high cure-rates for early breast cancer patients (about 421.000 new diagnoses / per year 
in Europe), annually about 129.000 patients die of the disease. Thus, breast cancer is a major 
cause of tumor-related deaths, which is predominantly attributed to tumor progression with 
metastatic dissemination 6-8. 
In the past, conventional treatment decisions in breast cancer were largely guided by standard 
clinical-pathological prognostic and predictive biomarkers such as hormone-receptor, human 
epidermal growth factor receptor 2 (HER2)-status and proliferation markers like KI-67 as well as 
grading. In the last decade, the extensive application of high-throughput genomic and 
transcriptomic sequencing facilitated therapy stratification by deep molecular profiling 9-13. 
Nowadays large-scale initiatives such as the MOSCATO-01 trial across all entities have 
demonstrated the feasibility and the clinical benefit (objective response 11% (95%, confidence 
interval (CI) 7%-17%) of prospective integrative implementation of deep sequencing into the 
clinical routine 14.  
In Heidelberg, the precision oncology platforms NCT DKTK/MASTER for young adults with 
advanced-stage or rare cancers as well as the INFORM registry for recurrent pediatric tumors 
enable 
multidimensional 
genomic-profiling 
(whole-genome/exome 
and 
transcriptome 
sequencing) for unbiased detection of drug targets and biomarkers 15,16,17. 
While these approaches allow cross-entity enrolment, a similar dedicated structure specifically for 
advanced-stage/metastatic breast cancer (CATCH) was implemented at the NCT Heidelberg 
enrolling approximately 120 patients per year 18.  
All programs share a streamlined, standardized workflow for the identification of acquired 
genomic and transcriptomic aberrations following clinical evaluation within an interdisciplinary 
molecular tumor board, which prioritize and rank evidence-based therapeutic options in- and off-
label and in particular assign patients to omics-guided interventional clinical trials. The power of 
pre-defined individual biomarkers is categorized by a reproducible evidence-built scoring system 
based on published data 16,19.  
Despite advances in sequencing reliability and cost reductions, these omics-based precision 
oncology concepts have been predominantly focused on advanced-stage and metastatic cancers, 
limiting the overall benefit mainly to prolongation of progression-free survival in the palliative 
setting rather than of increasing cure rates. 
Efficacy data for personalized-driven treatment based on molecular profiling for patients with early 
breast cancer are so far not available. Standard therapy in the curative setting is mostly not driven 
by specific biomarkers and cannot address the individual genetic tumor landscape of each patient.  
The molecular stratification of an extended post-neoadjuvant treatment for high risk early breast 
cancer (eBC) patients provides an excellent opportunity to test the benefit of precision oncology 
in a clinical curative situation. 
In eBC standard treatment for high-risk molecular subtypes such as Luminal B, HER2-positive 
and Triple-Negative Breast Cancers (TNBC) conventionally comprises cytotoxic chemotherapy, 
which is nowadays predominantly administered as a neoadjuvant (pre-operative) treatment 
regimen. It has been demonstrated that neoadjuvant chemotherapy (NACT) and adjuvant 
chemotherapy have similar rates for distant recurrence (1.02 [95% CI 0.92-1.14]; p=0.66) breast 
cancer mortality (1.06 [0.95-1.18]; p=0.31) and death from any cause (1.04 [0.94-1.15]; p=0.45) 
vs. adjuvant chemotherapy in the long-term analyses (15 years) 20. However, beyond the initial 
intention to downsize locally advanced tumors for surgical purposes, these neoadjuvant treatment 
schemes outperform traditional adjuvant therapies for various reasons:  
Most importantly, given the tight correlation between the extent of residual cancer burden and 
overall survival, neoadjuvant therapies harbour the advantage to identify high-risk patients 

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requiring treatment escalation very early in the course of their disease before developing frank 
metastatic disease2.  
 
Two standard-classifiers can be used to identify high-risk early breast cancer patients after 
NACT3,21-23:  
 
a) In TNBC and HER2+ BC: non pathological complete response (non-pCR) 
b) In HR+, -HER2- BC: non-pCR plus CPS-EG score ≥ 3 in ypN0 or a CPS-EG score ≥ 2 in 
ypN+ (CPS-EG: pre-treatment clinical stage (CS), post-treatment pathologic stage (PS), 
pre-treatment estrogen receptor status E and grade (G) according to). 
 
Hence, the residual local cancer burden after neoadjuvant therapy acts as a surrogate marker for 
the systemic tumor burden, which might give rise to metastatic dissemination 3,21-23.  
While for a large proportion of neoadjuvant-treated patients, no detectable tumor material is left, 
about 20-30 % of the patients present with highly therapy-resistant residual bulk tumors at the 
time point of surgery. This initial lack of response tightly correlates with an increased risk of 
relapse and metastasis as, depending on the molecular subtype, 30-50% of the patients with 
residual invasive disease after neoadjuvant therapy (non-pCR) relapse within the first 5-
years21,24,25. 
In summary, the tumor burden after tumor resection and thereby the assessment of the high risk 
state can identify patients with a substantial risk of relapse who require further treatment 
intensification to improve outcome. 
 Trial Rationale/ Benefit- Risk Assessment  
To reduce the considerable risk of relapse in high-risk eBC patients with residual invasive disease 
after neoadjuvant therapy (non-pCR), intensification of treatment by adding an adjuvant therapy 
line after neoadjuvant intervention (post-neoadjuvant treatment) harbours the prospect to 
substantially lower the risk of relapse, which has been emphasized in two randomized phase III 
trials. The addition of adjuvant capecitabine in the CREATE-X trial in HER2-negative residual 
invasive breast cancers despite neoadjuvant treatment with anthracyclines and taxanes (n=910) 
resulted in an improved disease-free survival (DFS) of 74.1% vs. 67.6% after 5-years (hazard 
ratio (HR) 0.7, 95%, CI 0.53 to 0.92; p=0.01) as well as an extended overall survival (89.2% vs. 
83.6%, HR 0.59; 95% CI, 0.39 to 0.90; p=0.01) 26. Recently, the phase III KATHERINE trial further 
confirmed that the substitution of trastuzumab by T-DM1 (ado-trastuzumab ematansine) in 
patients with residual HER2-positive disease after neoadjuvant chemotherapy and trastuzumab 
substantially lowered the risk of invasive recurrence (DFS events: 12.2% of patients in the T-DM1 
arm, compared to 22% in the trastuzumab arm; HR 0.50; 95% CI, 0.39 to 0.64; p<0.001) 
highlighting the advantages of post-neoadjuvant treatment regimens 27. 
These post-neoadjuvant interventions in early breast cancer already demonstrated significant 
outcome improvements despite lack of biomarker-guided stratification. 
Omics-matched therapeutic intervention according to the unique omic tumor profile at an early 
time point in the disease course possesses the advantage of limited overall tumor burden, 
corresponding lower tumor heterogeneity as which may result in a higher therapeutic efficacy in 
the eradication of pre-metastatic cell clones in the circulation.  
Consequently, the major goal of the strategy is to eliminate cell clones resistant to standard 
neoadjuvant treatment at an early stage, thereby liberating patients from their high risk of local 
and distant relapse.  
The COGNITION molecular diagnostic registry platform of the National Center for Tumor 
Diseases (NCT) has been implemented in April 2019 and enrols eBC patients with an indication 
for neoadjuvant standard therapy. The platform integrates systematic collection of clinical data 
and biomaterial (tissue and blood) as treatment-naïve baseline biopsies and from residual tumors 
after neoadjuvant therapy along with corresponding blood samples (Figure 1).  

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Samples from high-risk patients with treatment-resistant residual tumors after neoadjuvant pre-
operative therapy will be subjected to comprehensive genomic-profiling. Fresh-frozen or formalin-
fixed paraffin embedded (FFPE) breast tissue from residual bulk tumors is obtained after 
neoadjuvant therapy by fine-needle biopsies or during surgery and analyzed by genomic high-
throughput sequencing and evaluated by the interdisciplinary molecular tumor board of the NCT.  
Genomic aberrations and transcriptomic changes (e.g. mutations, copy number alterations, 
mutational signatures, expression patterns) are analysed and discussed in the clinical context 
using an evidence-based biomarker scoring system in an interdisciplinary molecular tumor board 
by the combined expertise of clinicians, bioinformaticians, molecular biologists, pathologists and 
human geneticists in order to delineate potential routes for treatment intensification and to assign 
patients to respective biomarker-guided treatments16,19. 
 
Figure 1. Design of molecular diagnostic registry platform COGNITION and clinical trial COGNITION-
GUIDE 
 
Due to lack of existing biomarker-guided targeted post-neoadjuvant interventional trials and 
ethical constraints in the early curative setting, which prohibit off- label treatment, therapy 
administration has to be accomplished in an interventional clinical trial (COGNITION-GUIDE). 
Importantly the benefit of individualized treatment within precision oncology frameworks in the 
early disease stage, has to be assessed in a rigorous clinical trial with standardized assessments 
and a hypothesis driven statistical analysis28. Based on the success of non-stratified post-
neoadjuvant treatment intensification in eBC and the overall benefit of precision oncology trials in 
advanced-stage disease, one can envisage that additional genomic-matched post-neoadjuvant 
treatment harbours the prospect to achieve further clinical benefit for individual patients. 
 

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The investigational medicinal products (IMPs) used in COGNITION-GUIDE are either approved 
for breast cancer or other indications (atezolizumab, olaparib, trastuzumab/pertuzumab, 
sacituzumab govitecan) or are in late clinical development in advanced breast cancer with an 
expected approval (inavolisib, ipatasertib). Thus, side effects and their management of these 
IMPs are already characterized. 
 
In case of HR+ positive disease (ER ≥1%), patients receive standard-of-care endocrine therapy 
backbone according to German “S3-guideline” and AGO guidelines [Tamoxifen or aromatase 
inhibitor (exemestane, letrozole or anastrozole) -/+ ovarian function suppression (OFS), i.e. with 
zoladex]. Adjuvant bone targeted therapy with bisphosphonates or denosumab is allowed 
according to German guidelines.  
Due to the overall sufficiently favourable pharmacokinetic and -dynamic profiles of endocrine 
therapies, the combinations with endocrine therapy in the COGNITION-GUIDE study are 
supposed to be safe and tolerable 29. In addition, upcoming safety signals in published studies 
and within the COGNITION-GUIDE study are communicated on a regular basis with short turn-
around times according to German and European law. 
Given the tremendous risk of generalized metastasis in this high-risk study cohort with relapse 
rates between 30-50% within 5 years following surgery 21,25 without further therapeutic intervention 
and/or standard post-neoadjuvant treatment, we expect a highly favorable risk/benefit ratio in the 
COGNITION-GUIDE study. 
Short- and long-term toxicities that have been described and are expected for the specific agents 
are described within the corresponding sub-protocols. 
 
 Reference Committee 
1.3.1 Independent Data Monitoring Committee (IDMC) 
The IDMC is composed of three independent experts, assessing the progress and safety data. 
The mission of the IDMC is to ensure the ethical conduct of the trial and to protect the safety 
interests of patients in this trial. 
Meetings of the IDMC are planned after 24 and 36 months after FPI (when results of the safety 
interim-analyses for these timepoints are available). Additionally, safety monitoring is performed 
separately in each treatment arm after 6 and 12 patients have finished at least one cycle of the 
study treatment. This arm-specific safety analysis is reviewed by the IDMC via e-mail discussion. 
Based on its review, the IDMC will provide the sponsor with recommendations for the conduct of 
the trial, modifications and further IDMC meetings, if applicable. Further details including IDMC 
members are specified in the IDMC charter. 
1.3.2 Steering Committee (SC) 
COGNITION-GUIDE is steered in regular intervals by the scientific steering committee including 
all principle site investigators, the scientific leads of the study (CI, Co-CI, scientific program 
coordination, clinical counselor) and patient´s representatives. The SC members meet virtually 
every 6 months from time of first site initiation. The mission of the SC is to ensure the scientific 
basis for decisions on trial modifications and to provide expertise in study conduct, analyses of 
data and the scientific quality of the final study report. 
 
 

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2 Trial Objectives and Endpoints 
 Primary Objective  
• 
to improve clinical outcome in early high-risk breast cancer by biomarker-guided post-
neoadjuvant therapy (systemic treatment in the adjuvant setting following neoadjuvant 
therapy, surgery and post-neoadjuvant standard therapy)  
 
 Secondary Objectives  
• 
To assess Invasive Disease-free Survival (IDFS) as defined by Hudis et al*,1 four years 
after surgery in each study arm separately 
To assess  
• 
Distant Disease-free Survival (DDFS) as defined by Hudis et al**,1 four years after surgery 
• 
Overall Survival (OS) 
• 
Safety and tolerability of biomarker-guided post-neoadjuvant treatment  
in each study arm separately and overall  
• 
To evaluate feasibility of biomarker-guided post-neoadjuvant treatment 
 
 Explorative Objectives 
• 
Subjective tolerability, feasibility and quality of life of biomarker-guided post-neoadjuvant 
treatment evaluated by patient-reported outcomes (PROs) (see chapter 10.2) in each 
study arm separately and overall 
• 
To assess the clinical value of liquid biopsies in the study context  
 
 Primary Endpoint 
IDFS* of patients four years after surgery overall (definition chapter 10.2) 
 Secondary Endpoints 
• 
IDFS* in each study arm separately (definition chapter 10.2) 
• 
DDFS** (definition chapter 10.2) in each study arm separately and overall 
• 
OS (definition chapter 10.2) in each study arm separately and overall 
• 
Safety including incidence of adverse events (definition chapter 10.2) in each study arm 
separately and overall 
 
 Explorative Endpoints 
• 
Patient reported outcomes (definition chapter 10.2) in each study arm separately and 
overall 
• 
To assess the clinical value of liquid biopsies in the study context 
 
*IDFS: time from surgery to whatever comes first a) ipsilateral invasive breast tumor recurrence, b) local/regional invasive 
breast cancer recurrence, c) distant recurrence, d) death attributable to any cause incl. breast cancer, e) contralateral 
invasive breast cancer or f) Second primary non-breast invasive cancer. 
**DDFS: time from surgery to whatever comes first a) distant recurrence, b) death attributable to any cause incl. breast 
cancer or c) second primary non-breast invasive cancer. 
 

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3 Trial Design  
Multicenter, open-label, multi-arm, umbrella phase II study.  
4 Trial Duration and Schedule 
High-risk patients defined by non-pCR-state and CPS-EG-score will be screened and enrolled in 
COGNITION-GUIDE earliest 1 month and latest 3 months after completion of post-neoadjuvant 
standard therapy (including radiotherapy, if indicated). In case of existing exclusion criteria 
estimated by the investigator being potentially transient, a rescreening can be performed within 
this time frame. The arm-allocation takes place after the interdisciplinary molecular tumor board 
of the NCT between general inclusion and start of the study-medication. Further arm-specific in- 
and exclusion criteria are evaluated by the investigator before the start of experimental study 
treatment (baseline) and are specified in the applicable sub-protocol. Study treatment starts within 
14 days after the baseline visit.  
The IMP treatment duration for each patient is expected to be 12 months followed by a substance-
depending safety follow-up (observational arm: 12 months). In the follow-up period breast cancer 
status and survival will be continuously followed according to standard S3- and AGO guidelines 
every 3 months for 3 years and every 6 months from year 4 on until end of study (EOS).  
Conditions leading to patient withdrawal from the study are detailed in Section 5.6 Criteria for 
Withdrawal. In case of relapse, study therapy is stopped.  
A recruitment period of 4 years and an overall study duration of 7.5 years (incl. completion of trial 
report) is anticipated. Start of patient recruitment is planned for the second quarter of 2023.  
The clinical phase of the trial ends, when the last patient has completed endpoint follow-up 4 
years after surgery (LPLV / end of study). 
After finishing all study-relevant procedures, therapy, and follow-up period, the patient will be 
followed in terms of routine care and treated if necessary by the primary responsible oncology 
center. 
 
Trial Duration and Dates 
Total trial duration: 
90 months 
Recruitment period: 
48months 
Minimum endpoint follow-up: 
48 months after surgery 
Duration of clinical phase: 
84 months (FPFV – LPLV) 
First patient first visit (FPFV) 
Q2/2023 
Last patient first visit (LPFV): 
Q1/2027 (FPFV + 48 months recruitment)  
Last patient last visit (LPLV): 
Q1/2030 (FPFV + 84 months clinical phase) 
Trial Report Completed: 
Q4/2030 (LPLV + 6 months) 
 
 

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Figure 2: Timeline for COGNITION-GUIDE in the context of standard therapy and COGNITION 
 
* Depending on standard therapy. In case of capecitabine (approx. 7 months including 18 weeks capecitabine plus 6-7 weeks RT). 
** In case of T-DM1 (10.5 months inclusive RT). 
*** In case of existing exclusion criteria estimated by the investigator as transient, a rescreening can be performed within the time frame of screening. 
OP = surgery, IC = informed consent, i/e = inclusion / exclusion criteria, TB = tumor board, T1 = 1. Baseline biopsy COGNITION, T2 = 2. Biopsy COGNITION, NACT = standard neoadjuvant chemotherapy, PNACT = 
standard post-neoadjuvant (chemo)therapy, RT= radiotherapy, IMP = investigational medicinal product, EOT = end of treatment, EOS = end of study. 
****Safety follow up for IMP arms (28 days, for study arms 1 and 6: 10 weeks). 
 

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5 Selection of Patients 
 Number of Patients and Recruitment 
During a recruitment period of 4 years, 240 patients are enrolled in the clinical trial. Details on 
patient numbers and sample size calculation are depicted in chapter 10.3. Recruitment and 
treatment of patients are performed in five trial centers. 48 pts are recruited in average per site.  
Based on experience within the molecular diagnostic registry platform COGNITION, the following 
patient allocation to the respective study arms is expected: 
 
o Arm 1 Atezolizumab (Immune Evasion) 
 
18-26% (43-62 patients (pts)) 
o Arm 2 Inavolisib (PI3K) 
 
 
 
4-9%     (10-22 pts) 
o Arm 3 Ipatasertib (AKT) 
 
 
 
8-14%   (19-34 pts) 
o Arm 4 Olaparib (PARP, DNA-Repair) 
 
15-21% (36-50 pts) 
o Arm 5 Sacituzumab Govitecan (TROP-2) 
 
18-24% (43-58 pts) 
o Arm 6 Trastuzumab / Pertuzumab (ERBBB)  
2-3%     (5-7 pts) 
o Arm 7 Observation*  
 
 
 
8-14%   (19-34 pts) 
(*Biomarker-negative or inability to conduct molecular profiling) 
 
 General Criteria for Patients’ Selection 
High-risk early breast cancer patients, defined as  
• 
Triple negative breast cancer (TNBC) or human epidermal growth factor receptor 2 
(HER2)+ BC with residual cancer burden (non-pCR, defined as other than ypT0/is ypN0 
after surgery), or 
• 
Hormone-receptor positive (HR+)/HER2- BC with non-pCR after surgery and  
 
CPS-EG score ≥ 3, or 
 
ypN+ and a CPS-EG score ≥ 2  
after neoadjuvant therapy, surgery and standard post-neoadjuvant therapy according to current 
German guidelines. 
Patients identified within COGNITION (or COGNITION-MOMENT, see below) as high-risk-
patients and who are admitted to and discussed in the NCT molecular tumor board (MTB) are 
allocated to one of the different therapy-arms of COGNITION-GUIDE in case of druggable 
genetic/transcriptomic alterations meeting the biomarker criteria of the different therapy arms 
(please refer to 5.3 for the specific molecular inclusion criteria). High-risk patients who are marker-
negative or with failure to conduct molecular profiling are allocated into the observational arm of 
COGNITION-GUIDE. 
 
 Arm-Specific Criteria for Patients’ Selection 
The biomarker-guided eligibility for the respective study arm is evaluated and determined 
exclusively by the NCT molecular tumor board on the basis of results of the COGNITION 
molecular diagnostic registry platform or of results from other molecular studies, when genomic 
profiling is performed according to the streamlined end-to-end workflow of the NCT (e.g., 
COGNITION-MOMENT, where genomic profiling is conducted in collaboration by NCT / DKFZ 
along the lines of COGNITION). Decision making of the tumor board is based on the validated 
evidence levels of ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) published 
by Leichsenberg et al.19. Only those predictive biomarkers for which published evidence m1a, 
m1b, m2a or m2b is available are taken into consideration. In addition, the following conditions 
are applied: 1) Patients with PIK3CA-mutations eligible for inclusion in arm 2 (inavolisib) are not 
allocated in arm 3 (ipatasertib); 2) Patients eligible for inclusion in study arms 1, 2, 3, 4 and 6 are 
not considered for inclusion in arm 5 (sacituzumab govitecan). 

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Further arm-specific in- and exclusion criteria are evaluated by the investigator before the start of 
study treatment and are specified in the applicable sub-protocol.  
Biomarkers, that are determined by whole genome sequencing and RNA sequencing within 
COGNITION (refer to chapter 1.2), are validated or identified in a certified/accredited laboratory 
(see specifications in footnotes 1-3. Biomarkers that allow inclusion in the respective arm are: 
 
• 
Arm 1 (Atezolizumab, Immune Evasion) 1:  
o PD-L1 positivity measure by IHC (≥1% on immune cells within the tumor) 
o MSI-high status (validated by PCR) 
o TMB-H (≥10mut/MB) 
o CD274 amplification  
• 
Arm 2 (Inavolisib, PI3K) 2: 
o  Known/reported oncogenic mutation in PIK3CA 
• 
Arm 3 (Ipatasertib, AKT) 2: 
o Aberrations predicting increased PI3K-AKT pathway activity except PI3K-
mutations 
o HR positive histology 
• 
Arm 4 (Olaparib, PARP, DNA-Repair) 2: 
o  Inactivating somatic or germline BRCA1/2 mutations, including homozygous 
deletions 
o Inactivating germline PALB2 mutations 
• 
Arm 5 (Sacituzumab Govitecan, TROP-2) 3: 
o  Trop-2-overexpression (with IHC and except known/reported homozygous 
polymorphism in UGT1A1*28) 
• 
Arm 6 (Trastuzumab / Pertuzumab, ERBBB) 2:  
o HER2 exon-20 insertion 
o Activating HER2-mutation 
 
In case of more than one MTB-recommendation, the allocation to treatment arms is performed 
according the MTB priority listing, in that higher priority is preferable but patient´s eligibility 
regarding further specified arm-specific in- and exclusion criteria of the applicable sub-protocol 
has to be considered. 
 
 
                                               
 
 
1.PD-L1 positivity will be determined/confirmed using a validated immunohistochemistry assay in a certified pathology laboratory according 
to IMpassion130 trial criteria (see sub-protocol arm 1, reference no. 8) which is PD-L1 expression on ≥1% tumor-infiltrating immune cells 
expressed as a percentage of tumor area. 
MSI status will be determined/confirmed according to criteria and cutoffs used in a validated assay performed by a certified pathology 
laboratory.  
TMB status will be determined/confirmed in a validated assay or analysis workflow performed by a certified/accredited laboratory with the 
cutoff for TMB-H defined as ≥10 mutations per megabase. 
CD274 amplification status will be determined/confirmed according to criteria and cutoffs used in a validated assay or analysis workflow 
performed by a certified/accredited laboratory. 
 
2.Biomarker positivity will be determined/confirmed by gene panel according to criteria and cutoffs used in a validated assay or analysis 
workflow performed by a certified/accredited laboratory. 
 
3.Trop2 expression will be determined/confirmed using a validated immunohistochemistry assay and histochemical scoring in a certified 
pathology laboratory. Trop2 positivity is defined as H-score ≥100, which corresponds to intermediate or high Trop2 expression levels based 
on the biomarker analysis of the ASCENT trial (see sub-protocol arm 5, reference no. 4). 
 

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 General Inclusion Criteria 
General inclusion criteria are relevant for all patients at screening and at baseline. Arm-specific 
inclusion criteria are outlined in the corresponding sub-protocol and are evaluated at baseline. 
Patients meeting all of the following criteria are considered for enrollment into the trial: 
1. Provision of written informed consent 
2. Female and male patients with non-metastatic early (stage I-III) breast cancer aged ≥ 18 
years 
3. Conducted neoadjuvant chemotherapy and surgery as well as conducted standard post-
neoadjuvant treatment +/- radiotherapy (standard according to German guidelines 
except Abemaciclib and Olaparib) 
4. For patients with initially triple negative (TNBC) or HER2-positive breast cancer:  
• 
Non-pCR defined as other than ypT0/is ypN0 
5. For patients with initially hormone receptor positive and HER2-negative breast cancer: 
Non-pCR and CPS-EG score  
• 
≥ 3 and ypN0, or 
• 
≥ 2 and ypN+  
6. ECOG Performance Status ≤ 1 
7. Acute effects of any prior therapy resolved to baseline severity or National Cancer 
Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 
v5.0) Grade ≤ 1 except for adverse effects not constituting a safety risk by investigator 
judgement 
8. Postmenopausal or evidence of non-childbearing status. For women of childbearing 
potential negative urine pregnancy test at post-operative screening and baseline as well 
as highly effective forms of contraception have to be in place thereafter 
• 
Evidence of childbearing potential is defined as fertile, following menarche and 
until becoming post-menopausal unless permanently sterile  
• 
Postmenopausal or evidence of non-childbearing status is defined as:  
o Amenorrhea for 1 year or more without an alternative medical cause   
following cessation of exogenous hormonal treatments plus follicle 
stimulating hormone (FSH) levels in the postmenopausal range in women 
not using hormonal contraception or hormonal replacement therapy 
o Chemotherapy-induced menopause 
o Surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, total 
hysterectomy or tubal ligation at least 6 weeks before IMP treatment) 
o Female patients with age ≥ 60 years 
• 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy 
9. Female patients of childbearing potential and male patients with partners of childbearing 
potential who are sexually active must agree to the use of two forms of contraception in 
combination (male condom and one highly effective method). These should be started 
immediately after signing the informed consent form and continued throughout the period 
of study treatment plus a substance-depending time period (see respective sub-protocol) 
for female patients and a substance-depending time period for male patients. Details on 
contraception and pregnancy testing for male and female patients (and if indicated their 
partners) under IMP treatment are described within the respective sub-protocol 
10. Ability of patient to understand and comply with the protocol for the duration of the study, 
including treatment and scheduled visits and examinations 
11. Adequate bone marrow, renal, and hepatic function defined by laboratory tests* 
* Arm-specific laboratory parameters and reference values to be met at baseline within 14 days prior to experimental 
study treatment are described within the respective sub-protocol. 
 

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 General Exclusion Criteria  
General exclusion criteria are relevant for all patients at screening and at baseline. Arm-specific 
exclusion criteria are outlined in the corresponding sub-protocol and are evaluated at baseline. 
Patients presenting any of the following criteria are not included in the trial: 
1. Other malignancy within the last 5 years except: adequately treated non-melanoma skin 
cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), 
Stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas 
(without bone marrow involvement) curatively treated with no evidence of disease for ≥ 5 
year 
2. Concurrent severe, uncontrolled systemic disease that would place patient at undue risk 
or interfere with planned treatment 
3. Concurrent participation or previous treatment within 30 days in another interventional 
clinical trial 
4. Persistent toxicity (≥ Grade 2 according to NCI CTCAE v5.0 caused by previous cancer 
therapy, excluding alopecia 
5. Clinical signs of active infection (> Grade 2 according NCI CTCAE v5.0) 
6. History of or newly diagnosed human immunodeficiency virus (HIV) infection and 
immunocompromised patients 
7. Active Hepatitis A virus infection 
8. Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface 
antigen (HBsAg) test. Patients with a past or resolved HBV infection, defined as having a 
negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at 
screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV 
DNA viral load per local guidelines 
9. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at 
screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA  
10. Dementia or significant impairment of cognitive state 
11. Epilepsy requiring pharmacologic treatment 
12. Pregnancy and breast feeding 
13. Inability to take oral medication and gastrointestinal disorders likely to interfere with 
absorption of study medication 
14. Major surgery (any invasive operative procedure in which a more extensive resection is 
performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is 
altered) within four weeks before screening and baseline excluding breast-tumor resection 
after neoadjuvant chemotherapy. Patients must have recovered from any effects of any 
major surgery 
15. Systemic chemotherapy or radiotherapy within four weeks  or a longer period depending 
on the characteristics of the agents used 
16. Heart failure classified as New York Heart Association (NYHA) II/III/IV 
17. Severe obstructive or restrictive ventilation disorder 
18. Patients with clinically active tuberculosis 
19. Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug 
20. Is taking or requiring the continued use of any of the prohibited concomitant medications 
listed in the respective subprotocols at baseline 
21. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder or 
non-malignant systemic disease. Examples include, but are not limited to, uncontrolled 
ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord 
compression or, superior vena cava syndrome.  
 

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 Criteria for Withdrawal 
5.6.1 Withdrawal of Patients  
A patient may be withdrawn from the trial treatment or/and all trial-related procedures for the 
following reasons: 
• 
At any time at their own request or at request of the legal representative, withdrawal of 
patient’s consent to start or to continue therapy. The patient is at any time free to 
discontinue treatment, without prejudice to further treatment. 
o In case of treatment discontinuation the patient is followed up according to the 
regular study procedures (safety follow up, endpoint follow up) 
o In case of withdrawal of informed consent the patient is withdrawn from further trial 
related procedures. If informed consent is withdrawn before start of experimental 
study therapy, the patient is replaced, see 5.6.3). 
• 
Pregnancy 
• 
Non-compliance by the patient with protocol requirements  
• 
Patients are withdrawn from the trial treatment in case of unacceptable toxicity or 
progressive disease 
• 
Patients who were not admitted to or discussed in a molecular tumor board (e.g. no tumor 
tissue available) are withdrawn from further trial related procedures (and are replaced, see 
5.6.3). 
• 
Patient is lost to follow-up. If a patient does not return for scheduled visits, every effort 
should be made to re-establish contact. In any circumstance, every effort should be made 
to document patient outcome if possible 
 
5.6.2 Handling of Withdrawals 
In all cases, the reason for withdrawal must be recorded in the CRF and in the patient’s medical 
records. In case of withdrawal of informed consent, the reason should be asked for as extensively 
as possible and documented. Patients should be specifically asked if they are withdrawing 
informed consent to further participation in the study including any further follow up (e.g. status, 
survival), to the use of their study generated data or to the use of any samples collected.  
If the patient withdraws informed consent, no further evaluations are allowed to be performed and 
no additional data can be collected. The sponsor may retain and continue to use data collected 
before such withdrawal of consent according to regulatory requirements and guidelines. 
Patients withdrawn from the trial retain their identification codes (e.g. allocation number or Patient 
ID, if already given). 
All ongoing AEs/ Serious Adverse Events (SAEs) of withdrawn patients have to be followed up 
until no more signs and symptoms are verifiable or the patient is on stable condition. 
5.6.3 Replacement of Patients 
Patients are replaced in the following cases: 
• 
Patients who withdraw informed consent before start of experimental therapy 
• 
Patients who were not admitted to or discussed in a molecular tumor board 
Further replacement of patients is not performed. 
5.6.4 Premature Closure of the Clinical Trial or a Single Center 
The trial or single study arms can be prematurely closed or suspended by the sponsor after 
consulting the coordinating investigator. The Ethics Committee (EC) and the Competent 
Regulatory Authorities must then be informed. Furthermore, the Ethics Committee(s) and 
Competent Regulatory Authorities themselves may decide to stop or suspend the trial. 
Should the trial be closed prematurely, all trial material (investigational medicinal product and 
other material) must be returned to the sponsor or treated according to sponsor’s notice. 

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All involved investigators have to be informed immediately about a cessation/suspension of the 
trial or a single arm. The decision is binding to all trial centers and investigators. 
The trial or single study arms may be prematurely closed, if 
• 
New risks to patients become known which lead to a change of the risk-benefit 
assessment 
• 
Unfavourable side effect profile (high amount of SAEs/ suspected unexpected serious 
adverse reactions (SUSARs)) 
• 
Slow accrual 
• 
New scientific results rendering the research questions addressed overall no longer sound 
and innovative 
in the trial or in a single arm, respectively. 
The sponsor after consulting the coordinating investigator has the right to close a center, at any 
time, in case of: 
• 
Non-compliance with the protocol 
• 
Poor data quality  
• 
No or slow recruitment 
 Prior and Concomitant Illnesses 
Relevant additional illnesses present at the time of informed consent and/or baseline are regarded 
as concomitant illnesses and are documented on the appropriate pages of the eCRF. Included 
are conditions that are seasonal, cyclic, or intermittent (e.g. seasonal allergies; intermittent 
headache). 
Abnormalities which appear for the first time or worsen (intensity, frequency) during experimental 
study treatment (incl. safety follow up) are adverse events (AEs) and must be documented on the 
appropriate pages of the eCRF. 
 Background Medication 
Background medication is used according to the different sub-protocols of the different treatment 
arms.  
Endocrine anti-cancer therapy, if applicable, is captured in the eCRF.  
 Prior and Concomitant Medication / Non-Drug Treatment 
Relevant additional treatments administered to the patients on entry to the trial or at any time 
during experimental study treatment are regarded as concomitant treatments and must be 
documented on the appropriate pages of the CRF. Every given drug is checked for possible cross-
reactions with treatment medication from COGNITION-GUIDE. Concomitant treatments not 
permitted during or prior to experimental study treatment are specified for each sub-protocol 
individually. 
6 Investigational Medicinal Product/-s 
For further details refer to individual sub-protocols. 
 General Information about Investigational Medicinal Product/-s 
Refer to sub-protocols. 
 Therapeutic/ Diagnostic Effects 
Refer to sub-protocols. 
 Known Side Effects 
Refer to sub-protocols. 

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 Dosage Schedule 
Each patient is intended to remain on experimental study treatment for 12 months. In case of 
intolerability to study treatment or disease progression / relapse study therapy is stopped.  
The investigator may temporarily suspend IMP dosing due to IMP related toxicity or an 
unanticipated medical event not associated with study treatment toxicity or with disease 
progression. Dose interruptions for any component of study treatment should not exceed 28 days. 
If the interruption is any longer, the clinical counselor must be informed, if continuation of study 
treatment is intended by the investigator. Patients withheld from treatment beyond 28 continuous 
days are expected to stop study treatment unless confirmation of extension for extenuating 
circumstances received from the NCT study team. 
Administration of IMP and dosage adjustments / toxicity management are specified in the sub-
protocols. 
 Contraception 
Female patients of child bearing potential and male patients with partners of child bearing 
potential, who are sexually active, must agree to the use of 2 forms of contraception in 
combination (male condom plus one of the highly effective methods listed below) or must 
totally/truly abstain from any form of sexual intercourse (see below), throughout their participation 
in the study from the signing of the informed consent and for a substance-depending time period 
after last dose (see respective sub-protocol). 
Acceptable non-hormonal birth control methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly:  
• 
Total/True abstinence: When the patient refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; [Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods, or declaration of abstinence solely for 
the duration of a trial) and withdrawal are not acceptable methods of contraception]  
• 
Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom  
• 
Intrauterine device (IUD) PLUS male condom. Provided coils are copper-banded 
• 
Hormonal methods are not acceptable for breast cancer patients 
 
Regarding IMP-arms, details on contraception are specified in the respective sub-protocol.  
Contraception within the observational arm will be conducted according to standard S3- and AGO-
Guidelines. 
 Overdose 
Refer to sub-protocols. 
 Treatment Assignment 
The trial medication is administered only to patients enrolled in this trial. It is administered 
according to the trial schedule (refer to sub-protocols). 
The allocation to the biomarker-guided treatment-arms is based on the in depth molecular 
characterization of tumors and the evaluation of the interdisciplinary molecular tumor board of 
NCT (refer to chapter 1.2). 
The study is open-label.  
 
 

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Assignment to study arms and dosage overview: 
Arm 1 
Immune 
Evasion* 
Atezolizumab (anti-PD-L1 antibody), i.v.: 
    1200 mg d1, q21d 
Arm 2 
PI3K* 
Inavolisib (PI3K inhibitor):  
    9 mg d1-d28, q28d 
Arm 3 
AKT* 
Ipatasertib (AKT inhibitor):  
    400 mg d1-d28 q28d 
Arm 4 
DNA 
Repair* 
Olaparib (PARP inhibitor): 
    300 mg bid d1-d28, q28d 
Arm 5 
TROP-2* 
Sacituzumab Govitecan (TROP-2 antibody) i.v.:  
    10 mg/kg BW, d1, d8, q21d 
Arm 6 
ERBB2* 
Trastuzumab/Pertuzumab (anti-HER2 antibody), s.c.: 
    initial dose: Trastuzumab 600 mg, Pertuzumab 1200 mg, 
30 000 units hyaluronidase 
    maintainance dose: Trastuzumab 600 mg, Pertuzumab 
600 mg, 20 000 units hyaluronidase; d1, q21d 
Arm 7 
N/A* 
Observational Arm (Biomarker-negative or inability to conduct 
molecular profiling) 
 
*if HR+ concurrently to standard-of-care adjuvant endocrine therapy. For specific therapy regimen 
refer to corresponding sub-protocol. 
 
 Supplies, Packaging and Labeling 
Refer to each individual sub-protocol.  
 Accountability 
The investigator keeps an account of the trial medication and acknowledges the receipt of all 
shipments of the trial medication. All trial medication must be kept in a locked area with access 
restricted to designated trial staff. The investigational medicinal product must be stored dry and 
in accordance with manufacturer’s instructions as specified in each sub-protocol. The investigator 
keeps accurate records of the quantities of trial medication dispensed, used, and returned by 
each patient. The documentation has to include date of dispensary, patient identification, batch/ 
serial numbers or other identification of trial medication. The site monitor checks periodically 
accountability records and the supplies of trial medication held by the investigator to ensure the 
correct accountability of all trial medication used. At the end of the trial, all unused trial medication 
and all medication containers are completely returned or destroyed locally according to sponsor´s 
instructions. It is assured that a final report of the drug accountability is prepared and maintained 
by the investigators of the study sites. 
 Compliance 
Trial medication is dispensed/applied to the patients by the investigator or another authorized 
study personal / physician. In case of IMP (e.g. tablets) is handed out to patients, they are 
instructed to bring all trial medication to the trial site at every visit. Patients are asked to document 
the study drug intake on a provided schedule. Compliance is assessed by count of tablets, 
capsules, vials and so on. Details are recorded on the Drug Accountability Form.  
 
 

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7 Trial Methods 
 Registration and Enrollment 
Patients should be included earliest 1 month and latest 3 months after completion of post-
neoadjuvant standard therapy (incl. radiotherapy, if indicated). In case of existing exclusion 
criteria estimated by the investigator as transient a rescreening can be performed within this time 
frame.  
After the informed consent form has been signed by a patient, the trial site team has to register 
the patient in the eCRF-system by completion of the respective module immediately. During this 
registration, a Patient-ID is automatically generated (number of the site plus number of the patient 
at the site). The Patient-ID is used to identify the patient throughout the clinical study and must 
be used on all study related documentation. Registration is performed even if the subject is a 
screening failure.  
A patient who signed the informed consent and is fulfilling all of the general inclusion criteria and 
not meeting any of the general exclusion criteria is considered eligible and is enrolled in the study. 
Eligibility must be confirmed by the investigator by signing the respective module in the eCRF. A 
patient who signed the informed consent but does not meet all general in- and exclusion criteria 
is considered a screening failure. 
For eligible patients the pseudonym of the COGNITION molecular diagnostic registry platform or 
COGNITION-MOMENT has to be entered in the eCRF.  
The arm-allocation to a specific study arm according to the recommendation of the NCT molecular 
tumor board takes place between general inclusion and start of the study medication. 
 Description of Clinical, Laboratory and Therapeutic Measurements  
The trial schedules for each specific therapy arm are depicted in each sub-protocol separately. 
General study examinations and procedures are described as follows. For design overview 
please refer to the trial schedule overview. 
Clinical status and laboratory parameters are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician, which can involve more 
frequent testing, especially in neutropenic/aplastic patients. It is expected that enrolled patients 
are supervised for by physicians experienced in the treatment and supportive care. 
 
7.2.1 Clinical Assessments  
• 
Informed consent and patient registration: every patient must date and sign the informed 
consent to participate in this trial before starting any trial-related procedures. After signature, 
a patient ID is assigned by the eCRF (refer to 7.1). 
For patients allocated to a therapy arm (arms 1-6), an IMP-specific informed consent is signed 
before start of study treatment (baseline). 
 
• 
Demographics: Gender, year of birth, ethnicity. 
 
• 
General medical and oncologic history: Date of diagnosis, detailed information on tumor 
diagnosis, including ICD-0-3 and ICD10 codes, information on tumor subtype (e.g. hormone 
receptor status, HER2 expression level), information on arm allocation according to 
recommendation of the NCT molecular tumor board, date and outcome of breast cancer 
surgery, detailed information on pre-treatment including type and composition of prior therapy 
as well as response to prior therapy, family history, additional medical history on concomitant 
diseases, prior exposure to toxic agents, prior malignancy including therapy, information on 
smoking. 
 

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• 
Inclusion / exclusion criteria: general inclusion/exclusion criteria as defined in chapters 5.4 
and 5.5 are assessed at screening and before start of study treatment (baseline);  
at baseline, for patients allocated to a therapy arm according to recommendation of the 
molecular tumor board, arm-specific inclusion/exclusion are assessed and must be met as 
specified in the applicable sub-protocol. 
 
• 
Signs / symptoms: Tumor-related and unrelated signs and symptoms at screening and 
baseline.  
 
• 
Vital signs: Height, weight, temperature (°C), and heart rate and blood pressure (after 5 
minutes in a sitting position) are collected at screening and every study visit from baseline 
until safety follow up. Height (in cm) is measured at screening only.  
 
• 
Physical examination: inspection, abdominal, cardiac and lung auscultation, palpation of the 
abdomen and lymph node sites, neurological examination. Physical examination is conducted 
at screening and every study visit from baseline until safety follow up. 
 
• 
Echocardiography (ECHO): at baseline and thereafter at investigator’s discretion or if 
specified in the applicable sub-protocol. If abnormal at baseline, ejection fraction (EF) has to 
be quantified, and thereafter in case of abnormal findings. EF has to be specified according 
to Simpson. 
 
• 
Electrocardiogram (ECG): Twelve-lead ECGs is obtained after the patient has been rested 
in a supine position for at least 5 minutes in each case. The Investigator or designated 
physician reviews the paper copies of each of the timed 12-lead ECGs on each of the study 
days when they are collected. ECG is performed at screening, baseline and thereafter at 
investigator’s discretion or if specified in the applicable sub-protocol. 
ECGs is recorded at 25 mm/sec. All ECGs are assessed by the investigator as to whether 
they are clinically significantly abnormal / not clinically significantly abnormal. If there is a 
clinically significant abnormal finding after the baseline visit, the Investigator records it as an 
AE on the eCRF or as SAE if applicable. The original ECG traces must be stored in the patient 
medical record as source data. 
For the purpose of this study, QTc intervals are calculated according to the formula of Bazett: 
 
For QTc intervals >500 ms and ≤470 ms, check magnesium and potassium levels and correct 
any abnormalities. If possible, stop any medication that may prolong the QTc interval. 
Continue/discontinue or reduce study medication according the respective sub-protocol. 
• 
ECOG Performance Status is performed at screening, baseline and EOT. 
 
• 
Further arm-specific clinical assessments are specified in the respective sub-protocol. 
 
7.2.2 Laboratory Assessments  
7.2.2.1 Safety Assessment 
o Hematology 
(local 
lab): Hemoglobin (Hb), red blood count (RBC), 
MCV/MCH/MCHC, PLT, white blood cells/ count (WBC). Differential cell counts 
(among others: absolute lymphocyte counts and neutrophil count) should be 
performed at screening and every study visit from baseline until safety follow up. 
 

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o Blood chemistry (local lab): Serum cholesterol, triglycerides, blood urea nitrogen 
(BUN) or urea, creatinine, total protein, albumin, aspartate aminotransferase 
(AST)/SGOT, alanine aminotransferase (ALT)/SGPT, gamma glutamyltransferase 
(gamma GT), total bilirubin, ALP, lactate dehydrogenase (LDH), sodium, 
potassium, magnesium, calcium, serum uric acid, creatinine phosphokinase (CPK) 
and creatinine clearance (CrCl) according to Cockcroft-Gault formula: at screening 
and every study visit from baseline until safety follow up using individual 
institutional guidelines and the best clinical judgment of the responsible physician, 
which can involve more frequent testing. 
 
o Coagulation (local lab): INR and aPTT are measured at screening and baseline 
and at investigator’s discretion during treatment. 
 
o Urinalysis (local lab): Urinalysis by dipstick should be performed at screening, 
baseline and EOT and if clinically indicated at investigator’s discretion or if 
specified in the applicable sub-protocol. Microscopic analysis should be performed 
by the hospital’s local laboratory if required. Parameters: pH, glucose, proteins 
(qualitative, dipstick accepted). 
 
o Further arm-specific safety assessments are specified in the respective sub-
protocol. 
These laboratory tests are performed by the hospital’s local laboratory. Additional analyses may 
be performed if clinically indicated. Safety laboratory assessments have to be dated and signed 
by the investigator. 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated and 
recorded on the eCRF as AE after experimental treatment start.  
 
In case a subject shows an AST or ALT ≥3xULN, AST/ALT elevations combined with total bilirubin 
≥ 2xULN without findings of cholestasis (defined as serum alkaline phosphatase activity less than 
2× the upper limit of normal) and no other reason can be found to explain the combination of 
increased AST/ALT and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, 
pre-existing liver disease, or another drug capable of causing the observed injury (Hy’s Law) 
immediate actions are required:  
1) 
 AST/ALT ≥ 3x ULN:  
 repetition of serum liver testing within 48–72 h  
In case AST/ALT remain ≥ 3x ULN:  
 continuation of liver testing 2–3x per week until normalisation/resolution 
 
2) 
a) 
AST/ALT ≥ 8x ULN or  
b) 
5x ULN over 2 weeks or  
c) 
3x ULN and total bilirubin 2x ULN or INR > 1.5 or  
d) 
3x ULN with symptoms (e.g. fatigue, nausea and vomiting, right upper 
quadrant pain, fever, rash) or eosinophilia:  
 immediately stop of the study drug 
Cases of potential drug-induced liver injury (DILI) as defined by Hy’s Law have to be reported as 
adverse event of special interest (AESI) within 24 hrs after knowledge using the SAE form (refer 
to 9.3 and 9.12). 
 
7.2.2.2 Pregnancy Tests  
on blood or urine samples are performed for pre-menopausal women as defined in 5.4, criterion 
8 of childbearing potential (CBP) at screening, baseline (within 14 days), day 1 prior to the start 

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of experimental study treatment, EOT and safety follow up. Within the IMP-arms, pregnancy tests 
for patients of CBP are performed at day 1 of each treatment cycle. 
Tests are performed by the hospital’s local laboratory. If results are positive the patient is 
ineligible/must be discontinued from the study. In the event of a suspected pregnancy during the 
study, the test should be repeated. Details of the pregnancy tests must be recorded in the patient’s 
medical records. Further contraception and pregnancy testing for male and female patients (and 
potential their partners) is described within the respective sub-protocol. 
 
7.2.2.3 HAV, HBV, HCV, and HIV-1 Testing 
at screening and thereafter at investigator’s discretion (local lab). 
 
7.2.2.4 Quantiferon Test 
is performed at screening, if clinically active tuberculosis is suspected by the investigator and 
thereafter at investigator´s discretion.  
 
7.2.2.5 Exploratory Assessments / Blood Draws  
Multi-analyte blood sample draw (for biobanking and exploratory liquid biopsy assessment) is 
conducted dependent on study site:  
 
Table 1 Analyte Types Biobanking Blood Samples 
Analyte Types 
No. Vials 
Analyte Type 
Volume (ml)  Analyte Type  
All Study Sites Except NCT Heidelberg  
4 
CPT Vials or PAX Gene  
à 8/ 10 
ctDNA / PBMCs 
1 
Serum  
à 7,5  
Humoral immune response  
NCT Heidelberg  
4 
CPT Vials or PAX Gene  
à 8/ 10 
ctDNA / PBMCs 
1 
Serum  
à 7,5  
Humoral immune response  
1  
Cell Safe*  
à 10 
CTC Quantification  
*Schedule for Cell Safe:  
Start IMP (Baseline Visit).  
Stop IMP (last day of administration or EOT Visit). 
Follow up: every 12 months after IMP treatment phase until four years of follow-up after surgery or local or distant 
relapse, if earlier; in case of relapse, an additional blood draw is performed timely after knowledge. 
 
 

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Table 2 Schedule Blood Draws 
Schedule Blood Draws (except for Cell Safe) 
• 
Baseline Visit 
Day -14 to d1 IMP: prior infusion / oral drug 
administration  
• 
After 90 d IMP1 (experimental therapy) 
d90 IMP3,4: prior infusion, oral drug 
administration 
• 
Stop IMP1,2,3 (experimental therapy) 
last day IMP administration: prior infusion / 
oral drug administration or at the end of 
treatment visit 
Follow up-Period: 
• 
every 6 months after IMP treatment phase1 until four years of follow-up after surgery or 
local or distant relapse, if earlier; in case of relapse, an additional blood draw is 
performed timely after knowledge (unscheduled study visit).  
1: Observational arm: Baseline, 3 and 12 month after Baseline and every 6 month thereafter until end of year four after 
surgery or  relapse, if earlier. 
2: In case of premature therapy discontinuation an additional blood draw should be performed at 12 month after IMP 
start. Other blood draws are aligned according to above outlined scheme.  
3: In case of temporary discontinuation (incl. cycle delay) or premature discontinuation of IMP blood draws for 
biobanking should be taken as close as possible to the 3 month and 12 month point in time after therapy start (+/- 4 
weeks). 
4: In the trial schedules, the trial visit next to day 90 is marked and intended for blood draw.  
 
 
Figure 3: Blood draw sampling scheme 
*or observation. 
**In case of premature therapy discontinuation an additional blood draw should be performed at 12 months after IMP 
start.  
***if earlier. In case of relapse at any time, an additional blood draw is performed timely after knowledge (unscheduled 
study visit). 
 
7.2.3 Measurement of Efficacy Parameters 
 
Breast Cancer Status 
Breast cancer status is assessed according to standard S3- and AGO Guidelines (clinical breast 
examination, sonography, mammography, other assessments as applicable). Assessments are 
performed within the clinical standard routine of breast cancer follow-up care, the existing time 
schedule can be retained.  
Results of the last mammography / sonography are documented at baseline and at end of 
treatment (EOT) (and additionally, if applicable). Last results of other assessments are 
documented at baseline, EOT and at the study visit of or following the examination performed 
every 3 months during the treatment or observation period according to S3- and AGO-guidelines. 

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In case breast cancer assessments (e.g. mammography) are not performed at the site, the patient 
has to be instructed, to bring the examination reports / doctor´s letters to the next study visit. A 
copy is collected for the patients´ file. 
Documentation of breast cancer assessments are depicted in the trial schedule overview and the 
respective sub-protocol trial schedules. 
In the follow-up period, IDFS- and DDFS-state (definition see chapter 10.2) are assessed  
according to standard S3- and AGO guidelines every 3 months for 3 years after EOT and then 
every 6 months from year 4 on until end of study (EOS) or IDFS and DDFS have occurred (if 
earlier). Breast cancer assessments are performed within the clinical standard routine of breast 
cancer follow-up care as described above. Results of all breast cancer assessments are 
documented at the follow up study visits. 
 
Overall Survival Status 
Overall survival status is collected until EOS (or death, if earlier). 
 
7.2.4 Further Assessments 
IMP-Treatment, Background medication, concomitant medications and non-drug-
treatments should be reported at every study visit from Cycle 1 Day 1 until EOT (IMP) or 
screening and every study visit from baseline until safety follow up (other treatments) and 
documented in the relevant eCRF pages. This includes endocrine anti-cancer therapy, supportive 
care drugs, prophylaxis with antiemetics, and drugs used for treating AEs or chronic diseases. 
Additionally, the status of endocrine anti-cancer therapy is collected during the follow up-period. 
 
AE assessments: refer to chapter 9.2. 
Adverse events should be documented and recorded continuously from signing the informed 
consent form for experimental study treatment until 28 days/ 10 weeks after end of treatment 
(substance-depending Safety Follow up). 
AE assessment is performed for patients treated with IMP (Arms 1-6). AEs will not be collected 
for patients of the observational arm (Arm 7). 
 
Patient Reported Outcomes (PROs) including Quality of Life (QoL):  
assessed by questionnaires of the EORTC Quality of Life Item Library (core questionnaire QLQ-
C30, breast-cancer specific module QLQ-BR45, fatigue module QLQ-FA12, and selected 
symptom items), as well as the Pittsburgh Sleep Quality Index (PSQI), the Patient Health 
Questionnaire for Anxiety and Depression (PHQ-4), the distress barometer, the Functional 
Assessment of Cancer Therapy - cognitive ability scale (FACT-cog), and the Patient Satisfaction 
Questionnaire Short Form (PSQ-18). In addition, the Socio-Economic Questionnaire (SEQ) as 
well as patient-reported information on personal traits, experiences, and life situation are 
assessed at baseline.  
Assessments are performed at baseline prior to IMP administration or observation, 3 and 6 
months after baseline, EOT and then every 6 months until end of year four after surgery (+/- 14 
days). In case of premature termination PRO assessment is performed at EOT and then every 6 
month until end of year four after surgery.  
A Schedule of PRO-Assessments is depicted in Figure 4. 
 

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Figure 4: Overview of PRO Measurements and Schedule 
PROM = PRO Measurement 
 
 Description of Study Visits 
For detailed measurement description, please refer to chapter 7.2. 
 
7.3.1 Screening  
Patients are screened earliest 1 month and latest 3 months after completion of post-neoadjuvant 
standard therapy. In case of existing exclusion criteria estimated by the investigator as transient, 
a rescreening can be performed within this time frame. 
Table 3: Screening 
Screening 
Clinical assessments:  
• 
Informed consent  
• 
Assessment of general inclusion and exclusion criteria 
• 
Assessment demographics   
• 
Assessment of general medical and oncological history 
• 
Tumor-related and unrelated signs/symptoms   
• 
Assessment of vital signs   
• 
Physical examination   
• 
ECG  
• 
ECOG performance status 
• 
Assignment of Patient ID (Pat-ID) and enrollment 
 
Laboratory assessments:  
• 
Hematology (local lab)   
• 
Blood chemistry (local lab)   
• 
Coagulation (local lab)  
• 
Urinalysis (local lab)  
• 
HAV, HBV, HCV, and HIV-1 testing (local lab) 
• 
Quantiferon test (local lab) in case of clinical suspicion of active tuberculosis 

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• 
Assessment of child bearing potential and/or pregnancy test  
 
Further assessments: 
• 
Assessment of concomitant and background medications; check of possible cross-reactions   
 
A patient who signed the informed consent and is fulfilling all of the general inclusion criteria and 
not meeting any of the general exclusion criteria is considered eligible and may be enrolled in the 
study.  
A patient who signed the informed consent but does not meet all general in- and exclusion criteria 
is considered as a screening failure. For these patients, reduced documentation in the eCRF is 
permitted, containing at least the data on informed consent, demographics, inclusion / exclusion 
criteria and the reason for failing screening. 
 
7.3.2 Arm Allocation 
Patients are allocated to the therapy arms according to the report of the molecular tumor board 
and the clinical context of the patient between initial screening (7.3.1) and start of therapy (7.3.3).  
 
7.3.3 Baseline / Before experimental Treatment Start 
The baseline visit should be conducted within 28 days after enrollment and upon availability of 
the recommendation of the molecular tumor board. Study treatment starts within 14 days after the 
baseline visit. 
Before start of the experimental therapy (day -14 to day 1, Baseline) arm-specific in- and exclusion 
criteria of the applicable sub-protocol are assessed and general in- and exclusion criteria are 
reassessed by the investigator. In case of not-fulfilling in- or exclusion criteria estimated by the 
investigator as transient, a reassessment can be performed within the time frame of baseline 
(within 28 days after enrollment). IMP is only administered to patients fulfilling all of the inclusion 
and none of the exclusion criteria. For these patients an additional informed consent form for the 
applicable arm-specific IMP treatment is obtained and arm allocation is completed. 
A patient, who does not meet all in- and exclusion criteria at this point in time is allocated in the 
observational arm. 
Baseline assessments have to be performed latest at cycle 1 day 1 before administration of IMP. 
The patient is asked to complete Baseline PROs and receives the corresponding link and 
individual code.  
For further arm-specific baseline assessments (arms 1-6) refer to the respective sub-protocol and 
trial schedule.  
Baseline assessments for the observational arm (arm 7) are depicted in the trial schedule 
overview.  
 
7.3.4 Trial Visits Treatment Period 
Study visits during the treatment or observation phase are conducted depending on the study 
arm. 
7.3.4.1 IMP treatment arms (arms 1-6): 
Study visits are scheduled based on IMP treatment in 3- or 4-week cycles starting with weekly 
visits during the first cycle up to day 1 of each cycle. 
In case of intolerabilities visit time ranges can differ for the individual patient. Please note, that in 
case of temporary or premature discontinuation of IMP blood draws for biobanking should be 
taken as close as possible to the 3 month and 12 month point in time after therapy start (+/- 4 

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weeks). An additional blood draw should be performed at 12 month in case of premature 
discontinuation.  
For detailed trial visit assessments and schedule refer to the respective sub-protocol.  
7.3.4.2 Observational arm (arm 7):  
Study visits are scheduled on a quarterly base: general study examinations are performed at 
baseline (V2) and 3 (V3), 6 (V4), 9 (V5) and 12 months (V6, EOT) after baseline (+/- 7 days). Visit 
assessments are depicted in the trial schedule overview within this protocol. 
AE assessment and safety FU are not applicable within this arm. SADRs of endocrine anti-cancer 
therapy, if applicable, are collected and documented in the eCRF. 
 
7.3.5 End of Treatment (EOT) Visit  
The end of treatment visit is performed at the last day of the last cycle or latest within 7 days after 
permanent discontinuation of study treatment, if not specified otherwise in the applicable sub-
protocol. In case of premature discontinuation, PRO assessment and biomarker schedule are 
adapted as described in chapter 7.2. 
In the observational arm the EOT visit is performed at month12 (visit 6).  
For further EOT assessment refer to the respective sub-protocol. 
 
7.3.6 After EOT-Safety Observation 
Adverse Events are collected until a substance-depending period (28 days or 10 weeks) after the 
end of treatment (Safety Follow-up / Safety observation). Further safety assessments are 
performed according to the respective sub-protocol. Persisting AEs at this time are followed up 
as described in chapter 9.2.  
 
7.3.7 Follow-up Period 
Follow up visits (endpoint follow up) are conducted following standard S3- and AGO guidelines 
every 3 months for 3 years after EOT and then every 6 months from year 4 on until end of study 
(EOS). Data about current anti-cancer treatment and patient´s status (including survival) will be 
collected.  
- 
Breast-Cancer follow-up is conducted according to the current S3- and AGO guidelines 
as described in chapter 7.2.3. In case breast cancer assessments are not performed at 
the site, the patient has to be instructed, to bring the examination reports / doctor´s letters 
to the next follow up study visit. A copy is collected for the patients´ file.   
- 
Endocrine anti-cancer therapy, PRO assessments and blood samples for biobanking are 
scheduled as described in chapter 7.2 and the trial schedule overview.  
- 
AESIs and SADRs of IMP, if applicable, are reported directly to the pharmaceutical 
companies (and to the NCT trial center in copy) (refer to 9.8). 
- 
SADRs of endocrine anti-cancer therapy, if applicable, are collected and documented in 
the eCRF. 
 
Follow up visits can optionally be conducted by phone call, if no blood samples for biobanking 
have to be collected at the respective visit. However, it must be assured, that doctor´s letters or 
examination reports of breast cancer follow-up care are obtained in copy from the patient for 
endpoint follow up. 
 
 Methods of Data and Sample Collection  
7.4.1 Data Collection and Handling 
All protocol required information including clinical and laboratory data are documented by the 
investigator or an authorized member of the study team in the patient's medical record and in the 

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eCRFs. The investigator at the clinical site is responsible for ensuring that all sections of the 
eCRFs are completed accurately and timely and that entries can be verified against source data. 
The eCRFs has to be filled out according to the specified CRF Completion Guidelines. The 
correctness of entries in the eCRFs are confirmed by dated signature of the investigator. 
PRO data are collected via online questionnaires implemented with LimeSurvey, a DSGVO 
conform, free and open source software for the implementation of online surveys. The software 
is supported and hosted by the Information Technology Core Facility (ITCF) at the DKFZ. A list 
with access codes and the link to the LimeSurvey-Application is provided to the sites. Access to 
the online questionnaires is provided via the link and an individual access code for the respective 
study visit PRO assessment and the individual patient by the site personnel. Provided codes are 
documented in the eCRF for the respective patient and visit, and as a counter-check, the patient's 
ID will be noted in the list with the provided access codes by the site.  
The site personnel is informed about outstanding PRO questionnaires and subsequently reminds 
the patient of these outstanding PRO questionnaires within 4 days. 
All data are reported pseudonymized. 
For further processing please refer to chapter 11 (Data Management). 
7.4.2 Sample Collection and Handling 
Blood samples are taken according to the Trial Schedule for systematic biobanking (7.2.2.5). 
Blood samples for biobanking are sent to:  
NCT Liquid Biobank 
Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg 
Im Neuenheimer Feld 460 
69120 Heidelberg 
Please see Laboratory Manual for detailed instructions. 
8 Ancillary and Post Trial Care  
After EOS patients are routinely followed-up and treated regarding standard of care according to 
the discretion of the treating physician. Breast-Cancer follow up should be conducted according 
to the current S3- and AGO guidelines. 
9  Assessment of Adverse Events 
 Specification of Adverse Events 
9.1.1 Adverse Events 
According to GCP, an adverse event (AE) is defined as follows: Any untoward medical occurrence 
in a patient administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
An AE may be: 
• 
New symptoms/ medical conditions 
• 
New diagnosis 
• 
Changes of laboratory parameters 
• 
Intercurrent diseases and accidents 
• 
Worsening of medical conditions/ diseases existing before inclusion into the trial 
• 
Recurrence of disease 
• 
Increase of frequency or intensity of episodical diseases. 

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Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical trial protocol and the condition(s) leading to these measures 
are not AEs, if the condition leading to the measure was present prior to inclusion into the trial. 
Events that are clearly consistent with the expected pattern of relapse of the underlying disease 
are not be recorded as adverse events. These data are captured as efficacy assessment data 
only. If there is any uncertainty as to whether an event is due to relapse / disease progression, it 
should be reported as an adverse event. 
AEs are classified as "non-serious" or "serious". 
Adverse events are coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and are updated once at EOS with the current MedDRA version. 
 
9.1.2 Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose meets any 
of the following criteria: 
• 
Results in death 
• 
Is life-threatening (the term life-threatening refers to an event in which the patient was at 
risk of death at the time of event and not to an event which hypothetically might have 
cause death if it was more severe)  
• 
Requires patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/ incapacity or 
• 
Results in a congenital anomaly/ birth defect. 
• 
Is an important medical event 
o Medical and scientific judgement should be exercised in deciding whether other 
conditions should also be considered as serious, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalisation 
but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed above. These should usually be considered as serious. 
Examples of such events include bronchospasm requiring intense treatment in an 
emergency room or at home, serious blood dyscrasias or seizures/convulsions 
that do not result in hospitalization, or the development of drug dependence or 
drug abuse. 
o A diagnosis of (secondary) cancer / malignant tumor during the course of study 
treatment should always be considered as medically important. 
 
The following events are not considered AEs/SAEs but have to be documented on the AE eCRF 
page with remark to the following categories: 
• 
Death resulting from relapse/disease progression 
• 
Hospitalisation resulting from relapse/disease progression 
• 
life-threatening resulting from relapse/disease progression 
• 
Hospitalization in accordance with the protocol-required procedures and treatments 
• 
Elective hospitalization 
 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an AE 
(e.g., rated as mild, moderate, or severe, or according to National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] criteria); the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on the CRF. 
 

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9.1.3 Adverse Drug Reaction / Serious Adverse Drug Reaction 
An adverse drug reaction (ADR) is generally defined as a response to a drug which is noxious 
and unintended and occurs at doses normally used in humans. 
An ADR, that fulfils any of the criteria of seriousness as defined for a serious adverse event (SAE) 
(refer to 9.1.2) is a serious adverse drug reaction (SADR). Therefore, a SADR is a SAE with a 
reasonable possibility, that the medicinal product caused the AE (causal relationship). 
9.1.4 Expectedness 
An ‘unexpected’ adverse event is one the nature or severity of which is not consistent with the 
applicable product information, e.g. Investigator’s Brochure (IB), Summary of Product 
Characteristics (SmPC). In this trial the current valid version of the IB of the respective IMP is 
considered reference safety information. Furthermore, reports which add significant information 
on specificity or severity of a known adverse reaction are counted as ‘unexpected’ events.  
9.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
SAEs that are both suspected, i.e. possibly related to IMP, and ‘unexpected’, i.e. the nature and/ 
or severity of which is not consistent with the applicable product information are to be classified 
as Suspected Unexpected Serious Adverse Reactions (SUSARs). 
In case if either the investigator, who primarily reported the SAE, or the second assessor classify 
the SAE as ‘suspected’ and the SAE is also unexpected, it is categorized as a SUSAR. 
All SUSARs are subject to an expedited reporting to the responsible ethics committee(s), the 
competent higher federal authority (BfArM), and to all participating investigators.  
 Period of Observation and Documentation 
All adverse events reported by the patient or detected by the investigator are collected and 
reported continuously from signing the informed consent form for experimental study treatment 
until 28 days (study arms 2, 3, 4 and 5) or 10 weeks (study arms 1 and 6) after end of treatment 
(safety follow-up). Adverse events must be documented on the appropriate pages of the eCRF 
and must also be documented in the patient’s medical records. 
AE assessments are performed for patients treated with IMP (Arms 1-6). AEs are not collected 
for patients of the observational arm (Arm 7). 
All patients who have AEs, whether considered associated with the use of the trial medication or 
not, must be monitored to determine the outcome. The clinical course of the AE will be followed 
up until resolution or normalization of changed laboratory parameters or until it has changed to a 
“stable” or “chronic” condition as assessed by the investigator (or the patient is lost to follow up). 
If an event stops and later restarts within the same cycle, all occurrences must be reported. 
In case a new anti-cancer treatment starts within the safety follow-up period of either IMP, the 
observational period of AEs ends with the beginning of the new treatment. 
For additional reporting of SADRs of background therapy outside the period of observation and 
documentation of AEs refer to chapter 9.14. 
 
 

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9.2.1 Grading of AEs 
The grading of AEs in this trial will be carried out on the basis of the 5-grade scale defined in the 
NCI CTCAE v5.0. 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL* 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated.  
Grade 5: 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
9.2.2 Coherence between AEs and the IMP / Background Medication 
The Investigator must provide an assessment of causal relationship of each of the clinical trial 
IMPs as well as of endocrine therapy (background medication), if applicable, to each AE 
according to the following scale: 
Y (Yes) 
There is a reasonable possibility that the IMP or background medication 
caused the AE. 
N (No) 
There is no reasonable possibility that the IMP or background medication 
caused the AE and other causes are more probable. 
9.2.3 Outcome of AEs 
The outcome of an AE at the time of the last observation will be classified as: 
Recovered/ 
resolved 
All signs and symptoms of an AE disappeared without any sequelae at the 
time of the last interrogation. 
Recovering/ 
resolving 
The intensity of signs and symptoms has been diminishing and/ or their 
clinical pattern has been changing up to the time of the last interrogation in 
a way typical for its resolution. 
Not recovered/ 
not resolved 
Signs and symptoms of an AE are mostly unchanged at the time of the last 
interrogation. 
Recovered/ 
resolved with 
sequel 
Actual signs and symptoms of an AE disappeared but there are sequelae 
related to the AE. 
Fatal 
Resulting in death. If there are more than one AE only the adverse event 
leading to death (possibly related) will be characterized as ‘fatal‘. 
Unknown 
The outcome is unknown or implausible and the information cannot be 
supplemented or verified. 
 
 
 

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9.2.4 Action taken with the IMP / Background Medication 
The action taken with IMP / background medication will be assigned to one of the following 
categories: 
Dose not changed No change in the dose of IMP / background medication. 
Dose reduced 
Reduction in the dose of IMP / background medication. 
Temporary 
discontinuation 
Temporary discontinuation / dose interruption of IMP / background 
medication. 
Dose increased 
Increase in the dose of IMP / background medication. 
Drug withdrawn 
Discontinuation of IMP / background medication. 
Unknown 
The information is unknown or implausible and it cannot be supplemented 
or verified. 
Not applicable 
The question is implausible (e.g. the patient is dead). 
9.2.5 Countermeasures 
The term ‘Countermeasures’ refers to the specific actions taken to treat or alleviate adverse 
events or to avoid their sequels. The following categories will be used to categorize the 
countermeasures to adverse events: 
None 
No action taken 
Drug treatment 
Newly-prescribed medication or change in dose of a medication 
Others 
Other countermeasures, e.g. an operative procedure 
Reporting of Serious Adverse Events and Adverse Events of 
Special Interest by Investigator 
All SAEs and AESIs must be reported by the investigator to the pharmacovigilance department 
at the KKS Heidelberg immediately, but not later than 24 hours after the SAE/AESI becomes 
known using the "Serious Adverse Event" form.  
The reporting is performed by faxing of a completed SAE form to the following fax number: 
+49 (0)6221 / 56-33687
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event as well as an assessment of the causal relationship between the event 
and the trial treatment.  
Follow-up SAE/AESI information is proceeded in the same way. The 24 hour timeline also applies 
to follow-up information.  
Reporting of Pregnancies 
All pregnancies (including those occurring in the partner of a male study subject), where the fetus 
may have been exposed to the IMP, shall be transmitted to pharmacovigilance department of the 
KKS. Pregnancies are followed-up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
The reporting is performed by faxing of a completed pregnancy form to the following fax 
number:  
+49 (0)6221 / 56-33687
Second SAE Assessment 
All SAEs are subject to a second assessment by a designated person, who is independent from 
the reporting investigator and pharmacovigilance department at the KKS Heidelberg.  
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All SAEs are forwarded by E-Mail immediately (not later than 24 hours after receipt) by the 
responsible person at KKS Heidelberg to the designated persons for second assessment. The 
second assessor will fill out a ‘Second Assessment Form’ for each SAE and return it by E-Mail or 
send it back per fax to the responsible person at the KKS Heidelberg within 48 hours, 
Fax number: +49 (0)6221 / 56-33687 
E-Mail: V-KKS.SAE@med.uni-heidelberg.de 
The ‘Second Assessment Form’ will contain the following information:  
 
I) 
Assessment of relationship between SAE and IMP / background medication 
 
II) 
Assessment of expectedness of SAE (derived from IB or SPC)  
 
III) 
Assessment of relationship between SAE and the underlying disease 
IV) 
Statement if the benefit/ risk assessment for the trial did change as a result of SAE.  
 
 Expedited Reporting 
SUSARs are to be reported to the ethics committee(s), regulatory authorities (in this trial: BfArM) 
and to all participating investigators within regulative defined timelines i.e. they are subject to an 
expedited reporting.  
The expedited reporting is carried out by the pharmacovigilance department of KKS Heidelberg. 
Only SUSARs occurring after administration of IMP undergo expedited reporting. 
 Emergency Treatment 
During and following a patient’s participation in the trial, the investigator should ensure that 
adequate medical care is provided to a patient for any AE, including clinically significant laboratory 
values. The investigator should inform a patient when medical care is needed for intercurrent 
illness(es) of which the investigator becomes aware. 
Details on procedures are given in the respective sub-protocol. 
 Adverse events after the regular safety follow up period 
After the study treatment completion and performed safety follow up visit there is no obligation to 
actively report information on new AEs or SAEs occurring in former study patients. This includes 
new AEs/SAEs in patients still being followed up for endpoint or survival. After the end of the 
safety follow-up und during the primary endpoint and survival follow-up, investigators are asked 
to report all AESIs as well as serious adverse events that are believed to be related to prior 
exposure to study treatment (serious adverse drug reaction, SADR) directly to the pharmaceutical 
companies for Pharmacovigilance purposes and characterisation (and in copy to 
studienzentrale_dm@nct-heidelberg.de). 
Additionally, at any time after a patient has completed the study, if an Investigator learns of any 
SAE including sudden death of unknown cause, and he/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator should 
notify the applicable pharmaceutical company. 
Roche Pharma AG (study arms 1-Atezolizumab, 2-Inavolisib, 3-Ipatasertib, 6-Trastuzumab/ 
Pertuzumab) 
E-Mail: grenzach.clinical_safety@roche.com 
AstraZeneca (study arm 4-Olaparib) 
E-Mail: AEMailboxClinicalTrialTCS@astrazeneca.com 
Gilead (study arm 5-Sacituzumab Govitecan) 
E-Mail: Safety_FC@gilead.com or Fax: 1-650-522-5477 
 
For additional reporting of SADRs of background therapy outside the period of observation and 
documentation of AEs refer to chapter 9.14. 

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 Pregnancy 
9.9.1 Maternal exposure 
If a patient becomes pregnant during experimental study treatment, treatment has to be 
discontinued immediately. The outcome of any conception occurring from the date of the first 
dose until 1 months (30 days) after the last dose of IMP, if not otherwise specified in the sub-
protocol, should be documented and followed up.  
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs.  
If any pregnancy, suspected pregnancy, or positive pregnancy test occurs in the course of study 
treatment, it must immediately and no more than 24 hours after getting notice of the pregnancy 
be reported to the KKS Heidelberg (on behalf of sponsor) by fax using a ‘Pregnancy Reporting 
Form’.  
All pregnancies should be followed up and documented, even if the patient was withdrawn from 
the study, until its outcome (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality). An additional informed consent will be obtained in such 
case.  
The outcome must be notified immediately by the investigator to the KKS Heidelberg (on behalf 
of sponsor) within 24 hours of first knowledge as a follow-up to the initial report. 
For any event during the pregnancy, which meets a seriousness criterion, the investigator will 
also follow the procedures for reporting SAEs (complete and send the SAE form to the KKS 
Heidelberg by fax within 24 hours of the investigator's knowledge of the event). 
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death at any time thereafter that the investigator 
suspects as related to the exposure to the IMP should also be reported to the KKS Heidelberg by 
fax within 24 hours of the investigators' knowledge of the event. 
The KKS Heidelberg (on behalf of sponsor) informs the pharmaceutical company’s 
representatives within one working day from the date the KKS, becomes aware of the pregnancy 
related SAE.  
9.9.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during study treatment and 
for a certain time following the last dose respective to the different sub-protocols or, if not further 
specified, for 3 months. 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented. An 
additional informed consent will be obtained in such case.  
The outcome of any conception occurring from the date of the first dose until 3 months (if not 
further specified in the sub-protocol) after the last dose should be followed up and documented. 
 New Cancers 
The development of a new primary cancer (including skin cancer) should be regarded as an SAE. 
New primary malignancies are those that are not the primary reason for the administration of the 
study treatment and have developed after the inclusion of the patient into the study. They do not 
include metastases of the original cancer. Symptoms of BC metastasis or the BC metastasis itself 
should not be reported as an AE/SAE, as they are considered to be disease progression. 

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 Deaths  
All deaths that occur during the study, or before EOS, must be reported as follows: 
o Death clearly the result of BC disease progression has to be documented in the eCRF but 
not reported as an SAE. 
o During experimental study treatment and safety follow up (AE reporting period): Where 
death is not due (or not clearly due) to progression of the BC disease under study, the AE 
causing the death must be reported to the pharmacovigilance department at the KKS 
Heidelberg within 24 hours after the death becomes known using the "Serious Adverse 
Event" form. (9.1.2 Serious Adverse Event). The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should assign 
main and contributory causes of death. Deaths with an unknown cause should always be 
reported as a SAE.  
o After the end of the adverse event reporting period, all deaths should be reported through 
use of the end of study status-form in the eCRF. 
 Adverse Events of Special Interest (AESIs) 
Table 4: AESIs applicable for all IMPs 
General AESIs (applicable for all IMPs) 
1. Potential drug-induced liver injury (DILI) as defined by Hy’s Law (refer to 7.2.2.1) 
- Treatment-emergent ALT or AST > 3 x baseline value in combination with 
total bilirubin > 2 x upper limit of normal (ULN) (of which ≥ 35% is direct 
bilirubin) 
- Treatment-emergent ALT or AST > 3 x baseline value in combination with 
clinical jaundice 
2. Suspected transmission of an infectious agent via a medicinal product (STIAMP), 
defined as follows: Any organism, virus, or infectious particle (e.g. prion protein 
transmitting transmissible spongiform encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent. A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only when a 
contamination of study treatment is suspected 
 
For IMP-specific AESIs refer to respective sub-protocol. 
 Other Reportings 
Refer to sub-protocols. 
 Safety Monitoring of Background Therapy 
During the following phases of the trial, when only endocrine therapy (if applicable) is 
administered  
- 
from screening until baseline 
- 
after the safety follow up visit (IMP-arms) 
- 
during and after observation (observational arm) 
serious adverse drug reactions (SADRs) related to these therapies have to be collected and 
documented in the eCRF for safety monitoring purposes.  
The safety monitoring of background therapy includes SADR reviews by the CI/Co-CI on a regular 
basis.  
Please note, that this documentation does not replace the legally binding reporting requirements 
of the investigator for respective events. 

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10 Statistical Considerations 
 Study Design 
This is an open-label, multicenter phase-II umbrella study in patients with eBC with treatment 
allocation according to results from molecular genomic profiling and target prioritization by a 
multidisciplinary molecular tumor board. 
Patients are allocated to one of the treatment arms. In case of Biomarker-negativity or failure to 
conduct molecular profiling patients are allocated to the observational arm. Thus, the 
observational arm is not a control-arm but rather provides information on patients although high 
risk not eligible for post-neoadjuvant investigational therapy to allow together with all patients 
receiving investigational post-neoadjuvant therapy the evaluation of the totality of all high-risk 
patients eligible for the study. The primary endpoint IDFS is assessed for the totality of all high-
risk patients eligible for the study and compared to data from the literature and data from controls 
from the Südwestdeutsches Brustcentrum (SWBC) Heidelberg cohort (http://www.sw-
brustcentrum.de/) treated during the recruitment period of COGNITION-GUIDE. 
 Analysis Variables 
10.2.1 Primary analysis  
Invasive Disease-free Survival (IDFS) is defined according to Hudis et al.1 as the time from 
surgery to whatever comes first a) ipsilateral invasive breast tumor recurrence, b) local/regional 
invasive breast cancer recurrence, c) distant recurrence, d) death attributable to any cause incl. 
breast cancer, e) contralateral invasive breast cancer or f) Second primary non-breast invasive 
cancer. Patients without event are censored at the last date of follow-up with tumor assessment. 
10.2.2 Secondary Analysis 
Distant Disease Free Survival (DDFS) is defined according to Hudis et al.1 as the time from 
surgery to whatever comes first a) distant recurrence, b) death attributable to any cause incl. 
breast cancer or c) second primary non-breast invasive cancer. Patients without event are 
censored at the last date of follow-up. 
Overall survival is defined as the time from surgery to time of death from any cause. Patients 
without event are censored at the last date of follow-up. 
10.2.3 Explorative Analysis 
Patient-reported outcomes (PRO) 
The following Patient-Reported Outcomes are assessed: 
• 
Health-related QoL is calculated as the new EORTC QLQ-C30 Summary Score 
recommended by the EORTC Quality-of-Life Group. In addition, the EORTC QLQ Function 
and Symptom Scores are calculated according to the actual EORTC Scoring Manual. 
• 
QoL in breast cancer patients is calculated from the EORTC QLQ-BR45 according to the 
EORTC Scoring Manual 
• 
Fatigue is calculated from the EORTC QLQ-FA12 according to the EORTC Scoring Manual. 
• 
Sleep problems are calculated from the PSQI according to the corresponding scoring 
guidelines. 
• 
Perceived cognitive impairment and impact of cognitive changes are calculated from the 
FACT-cog according to the corresponding scoring manual. 
• 
Anxiety is calculated from the PHQ-4 according to the corresponding scoring manual. 
• 
Depression is calculated from the PHQ-4 according to the corresponding scoring manual. 
• 
Distress is assessed on a numerical 0-10 rating scale. 
• 
Patient’s satisfaction with the received treatment is calculated according to the PSQ-18 
scoring manual. 
 

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Mutational Level measured in Liquid Biopsies 
Mutational levels are summarized by mean, standard deviation, median, minimum and maximum, 
and plotted by time. Changes are examined descriptively. 
 
10.2.4 Safety Analysis 
Endpoints include incidence of adverse events and their outcome, severity, including serious 
adverse events, adverse events of special interest and special situations; the relation of adverse 
events to the study treatment and to endocrine anti-cancer therapy (background medication), if 
applicable; dose modifications for toxicity; premature discontinuation of experimental study 
treatment; and number of laboratory values that fall outside of pre-determined ranges and/or show 
prominent worsening from baseline. Toxic effects are graded according to NCI CTCAE v5.0. 
Patient-reported outcomes are excluded from safety reporting. 
 
 Sample Size Calculation 
Based on historical data the DFS in high risk patients with early breast cancers following 
neoadjuvant chemotherapy defined by no pathological complete response (for TNBC and HER2+ 
BC) and a high CPS-EG-score (for HR+HER2- BC) at 4 years after surgery is in the range of 60% 
to 70% 2-5. Therefore, we test the one-sided null hypothesis H0: IDFS (4-year) ≤70%. Assuming 
exponential survival, uniform accrual over 3 year and a follow-up of 2 years after inclusion of the 
last patient, sample size is calculated to achieve a power of 90% to reject the null hypothesis at 
a significance level of 5% given an IDFS rate of 80% at 4 years. A hypothesis test based on the 
Kaplan–Meier estimator is used30. To show this, 215 patients have to be eligible for the statistical 
analysis. To account for up to 10% loss to follow-up, 240 patients have to be recruited in total. 
The following patient allocation to the respective study-arms is expected: 
 
o Arm 1 Atezolizumab (Immune Evasion) 
 
18-26% (43-62 patients (pts)) 
o Arm 2 Inavolisb (PI3K) 
 
 
 
4-9%     (10-22 pts) 
o Arm 3 Ipatasertib (AKT) 
 
 
 
8-14%   (19-34 pts) 
o Arm 4 Olaparib (PARP, DNA-Repair) 
 
15-21% (36-50 pts) 
o Arm 5 Sacituzumab Govitecan (TROP-2) 
 
18-24% (43-58 pts) 
o Arm 6 Trastuzumab / Pertuzumab (ERBBB)  
2-3%     (5-7 pts) 
o Arm 7 Observation*  
 
 
 
8-14%   (19-34 pts) 
(*Biomarker-negative or inability to conduct molecular profiling) 
 Analysis Populations 
10.4.1 Full Analysis Population 
The Full Analysis Population (FAP) includes all enrolled patients with assignment according to 
the recommendations of the molecular tumor board to one of the experimental treatment arms or 
the observational arm. Patients who were allocated to one of the experimental treatment arms 
but did not subsequently receive treatment are included in the FAP. The analysis of data using 
the FAP therefore follows the principles of intention to treat (ITT).  
Patients’ disposition and reasons for ending the study is presented in frequency distribution tables 
and individual data listing. Descriptive statistics of the baseline characteristics are generated 
across all patients. Frequency distributions are presented for the categorical variables. Summary 
statistics and number of assessed patients are calculated, as appropriate, for the quantitative 
variables. Individual data are presented in listings.  
Efficacy analysis includes descriptive analyses of the primary and secondary endpoints overall 
as well as for each study arm separately and where required also joint analysis of different 
treatment arms.  
The evaluation of efficacy to reject or keep the null hypothesis is based on the FAP.  

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10.4.2 Per Protocol Populations 
All enrolled patients of the FAP who have received at least one dose of study treatment in one of 
the experimental treatment arms are subject to the per protocol analysis (per protocol population-
1).  
Furthermore, in a further sensitivity analyses patients with important protocol deviations are 
excluded (per protocol population-2). Definitions of important protocol deviations are given in the 
statistical analysis plan (SAP).  
Additionally, all patients, who were assigned to the observational arm and those who did not 
receive any experimental treatment (actually) although assigned to one of the experimental 
treatment arms are analysed together (per protocol population-3). 
Details of the per protocol analysis are specified in the SAP. 
10.4.3 Safety Population 
All enrolled patients who have received at least one dose of experimental treatment are subject 
to the safety analysis. The safety analysis is performed for the entire study population as well as 
for each treatment arm separately. Details of the safety analysis are specified in the SAP. 
 
  Statistical Methods 
Details of the analysis are specified in the SAP.  
Statistical analysis is performed using SAS Software. 
In cases surgery is performed more than once, time of the first surgery is considered (referring to 
all analyses with regard to surgery). 
10.5.1 Demographic and other Baseline Characteristics 
Categorical baseline characteristics, like sex, history of cancer, performance status (ECOG), 
initial and post-neoadjuvant tumor staging, previous anticancer treatment, concomitant illness at 
trial initiation, and concomitant treatment maintained, are summarized by frequency tables overall 
and for each study-arm. Summary statistics are provided for quantitative variables like age, weight 
and, laboratory values overall and for each study-arm. 
10.5.2 Study Therapy, Treatment Compliance, and Follow-up  
Summary statistics are presented for the dosage of all IMPs in each study-arm received at each 
cycle, dose modifications for toxicity, discontinuation and withdrawal from study treatment, as well 
as if applicable standard endocrine therapy and standard PNACT received including 
discontinuation or withdrawals, and drop-out from the follow-up during the post-study phase. The 
number of cycles administered, actual and total doses administered, dose modifications, delays 
and omissions, as well as reasons for deviation from planned therapy and overall duration of 
treatment, are summarized overall and for each study-arm. 
10.5.3 Analysis of the Primary Endpoint 
The primary endpoint IDFS is analyzed according to the Kaplan-Meier method and confidence 
interval (CI) estimation for IDFS is based on the cumulative hazard function using Greenwood’s 
formula for variance estimation.  
10.5.4 Analysis of Secondary Endpoints 
IDFS, DDFS and OS 
IDFS for each study arm and DDFS as well as OS overall and for each study-arm are analysed 
as described for IDFS above (10.5.3). 
The method of Kaplan and Meier is used to estimate the distributions with respect to IDFS, DDFS 
and OS. Cox proportional hazards regression are used to examine the influence of covariates on 
IDFS, DDFS and OS overall and for each study-arm. 

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10.5.5 Analysis of Explorative Endpoints 
Analysis of Patient-Reported Outcomes (PROs)  
The scales are scored and analyzed according to the applicable scoring manual (refer to 10.2.3). 
The PRO subscales and single item sub-scores are summarized by the mean, standard deviation, 
median, minimum and maximum, and plotted by time overall and for each study-arm. Changes 
from baseline for all domains are examined descriptively overall and for each study-arm.31,32 
Mutational Level measured in Liquid Biopsies 
Mutational levels are summarized by mean, standard deviation, median, minimum and maximum, 
and plotted by time. Changes are examined descriptively. 
10.5.6 Other Analyses 
Patients Disposition are tabulated overall and for each study-arm. In addition, the number of 
patients who withdrew from the study and reasons for discontinuation will be summarized overall 
and for each study-arm. The number and percentage of patients with normal and abnormal ECG 
results are summarized overall and for each study-arm. Summary statistics for baseline values 
and follow-up will be displayed for QT and QTc correction methods overall and for each study-
arm. 
10.5.7 Analysis of Safety Endpoints 
Safety Analysis 
The assessment of safety is based on the frequency of adverse events (see Section 9) and on 
the number of laboratory values that fall outside of pre-determined ranges and/or show prominent 
worsening from baseline during the study phase.  
Adverse events (AE) are summarized by presenting the number and percentage of patients 
having  
any AEs or  
serious adverse events (SAEs) as well as  
adverse events of special interests (AESIs)  
special situations 
and SADRs of background medication.  
Adverse events are additionally summarized by determining and summarizing the highest toxicity 
grade per toxicity for each treatment cycle during the study phase overall and for each study arm. 
Furthermore, the most common AEs (those occurring in at least 10% of the treatment group) will 
be determined. Any other information collected (e.g. severity or relatedness to study drug) are 
summarized as appropriate. Laboratory data are summarized by presenting summary statistics 
of raw data and change from baseline values overall and for each study arm. Incidence rates are 
summarized along with two-sided Pearson-Clopper 95% confidence intervals.  
10.5.8 Handling of Missing Data 
Missing values are not replaced or imputed. For patients with incomplete follow-up, time to last 
follow-up date is used as the censoring time in the analysis of time-to-event data. 
 Safety Monitoring Analyses 
Interim safety analyses are performed in the entire study after 24 and 36 months. Safety 
monitoring is additionally performed in each treatment arm separately after 6 and 12 patients have 
finished at least one cycle of the study treatment. Safety assessments consist of evaluating AEs, 
SAEs, AESIs, laboratory parameters including hematology and chemistry, vital signs, and 
physical examinations. Results of the safety monitoring analyses are provided to the CI, Co-CI, 
scientific coordinator and the clinical counselors as well as after their assessment and rating to 

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the IDMC. The IDMC provides the sponsor with recommendations regarding trial modifications 
after each safety monitoring report.   
11 Data Management 
11.1 Data Collection 
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to an 
electronic data record (eCRF). The data collection is performed using an electronic data capture 
(EDC)-system. 
Data collection into an eCRF can only be done by authorized persons. Access to all study data is 
protected by password. Each entry or change of data is tracked by name and exact date (audit 
trail). Any change of data has to be explained. The investigator signs the CRF electronically as 
per agreed project process. 
A copy of the eCRF is provided by data management and archived at the study site at the end of 
the trial. 
PRO questionnaires are completed online via LimeSurvey by the patient. Access to the online 
questionnaires is provided by a link and via an individual access code. The software is supported 
and hosted by the Information Technology Core Facility (ITCF) at the DKFZ. The collected data 
is stored under the usual data protection agreement with the ITCF at the DKFZ Heidelberg. No 
personal data is stored on the LimeSurvey application.  
11.2 Data Handling 
Data entries on eCRF undergo an automatic online check for plausibility and consistency. 
Additional queries are generated on the basis of further checks combined with a visual control by 
a responsible monitor or data manager. 
The site team has to address and resolve or clarify all queries. 
After all queries have been resolved the trial database is closed and the ability to edit the database 
will be removed. 
Derived data sets, combining eCRF and PROs data are produced. The link between the 
questionnaires and the CRF is maintained by the Patient-ID which is recorded in the eCRF.  
All data management activities are done according to the current Standard Operating Procedures 
(SOPs) of the NCT Trial Center. 
11.3 Storage and Archiving of Data 
All essential trial documents will be archived in accordance with the current legislation, however, 
for at least 25 years after the trial termination. The sponsor is responsible for archiving of the 
TMF.  
The investigator(s) will archive all trial data (source data and Investigator Site File (ISF) including 
Patient Identification List and all relevant correspondence) according to section 4.9 of the ICH 
Consolidated Guideline on GCP (E6) and to local law or regulations. The Patient Identification 
List will be archived for at least 25 years after trial termination. 
If the investigator relocates, retires, or for any reason withdraws from the study, the sponsor / 
NCT trial center should be prospectively notified. The study records must be transferred to an 
acceptable designee, such as another investigator, another institution or to the sponsor. The 
investigator must obtain sponsor´s written permission before disposing of any records, even if 
archiving requirements have been met. 

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12 Ethical and Legal Aspects 
  Good Clinical Practice 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
Good Clinical Practice (GCP) and the ethical principles described in the current version of the 
Declaration of Helsinki. The trial will be carried out in keeping with local legal and regulatory 
requirements.  
Compliance / GCP Statement: The trial will be conducted in accordance with German Drug Law 
(Arzneimittelgesetz, AMG), the German GCP Ordinance (GCP-Verordnung) and the International 
Council on Harmonisation Good Clinical Practice (ICH-GCP E6 (R2)). 
  Patient Information and Informed Consent 
Before being admitted to the clinical trial, the patient must consent in written form to participate 
after the nature, scope, and possible consequences of the clinical trial have been explained in a 
form understandable to him or her. Before start of experimental study treatment, patients of study 
arms 1-6 must consent to an additional informed consent form containing information about the 
applicable arm-specific IMP treatment. 
The original personally signed and dated Informed Consent Form must be kept on file by the 
investigator(s), and documented in the case report form. 
A copy of the signed informed consent document must be given to the patient. The documents 
must be in a language easily understandable to the patient and must clearly state who informed 
the patient, which is confirmed by the dated signature of the responsible investigator. 
If new safety information results in significant changes in the risk/benefit assessment, or if 
significant changes are made in the protocol, the consent form has to be reviewed and updated 
if necessary. All patients (including those already being treated) should be informed of the new 
information and must give their written informed consent to continue the study.  
  Confidentiality 
The data obtained in the course of the trial will be treated pursuant to the General Data Protection 
Regulation (EU-DSGVO, EU 2016/679), the Data Protection Law of the Federal State 
(Landesdatenschutzgesetz), and the § 40 (2a) AMG. 
During the clinical trial, patients will be identified solely by means of an individual identification 
code (Patient ID). Storage of trial findings on a computer will be done in accordance with local 
data protection law and will be handled in strictest confidence. For protection of these data, 
organizational procedures are implemented to prevent distribution of data to unauthorized 
persons. The appropriate regulations of local data legislation will be fulfilled in its entirety. 
The patient consents in writing to relieve the investigator from his/her professional discretion in 
so far as to allow inspection of original data for monitoring purposes by health authorities and 
authorized persons (inspectors, monitors, auditors). Authorized persons (clinical monitors, 
auditors, inspectors) may inspect the patient-related data collected during the trial, ensuring the 
data protection law. 
The investigator will maintain a patient identification list (Patient IDs with the corresponding patient 
names) to enable records to be identified. 
Patients who did not consent to circulate their pseudonymized data will not be included into the 
trial. 
 
 

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 Responsibilities of Investigator 
The Principal Investigator should ensure that all persons assisting with the trial are adequately 
informed about the protocol and any amendments, the trial treatments, and their trial-related 
duties and functions. 
The Principal Investigator should maintain a list of investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties (Log of Staff). 
The investigator(s) should support monitoring, auditing and inspections as described in sections 
13.1 and 13.2. 
  Approval of Trial Protocol and Amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other 
appropriate documents will be submitted to the independent Ethics Committee (EC) as well as to 
the competent federal authority (BfArM or PEI). A written favourable vote of the EC and an 
(implicit) approval by the competent higher federal authority are a prerequisite for initiation of the 
clinical trial. The statement of EC should contain the title of the trial, the trial code, the trial site, 
and a list of reviewed documents. It must mention the date on which the decision was made and 
must be officially signed by a committee member.  
Before the first patient is enrolled in the trial, all ethical and legal requirements must be met. All 
planned substantial changes will be submitted to EC and the competent higher federal authority 
in writing as amendments. They have to be approved by the EC and the competent higher federal 
authority.  
The coordinating investigator or the NCT Trial Center, and if applicable the investigator(s) will 
keep a record of all communication with the EC and the regulatory authorities. 
  Continuous Information to Independent Ethics Committee 
Pursuant to the German Drug Law (AMG) and the GCP Regulation, the EC and the competent 
higher federal authority will be informed of all suspected serious unexpected adverse reactions 
(SUSARs) which occur during the trial. Both institutions will be informed in case the benefit-risk 
assessment did change or any others new and significant hazards for patients’ safety or welfare 
did occur. Furthermore, a report on all observed serious adverse events (SAEs) will be submitted 
once a year (Development Safety Update Report (DSUR). 
The EC and the regulatory authorities must be informed of the end of the trial. They will be 
provided with a summary of trial results within one year after the end of clinical phase (LPLV). 
  Notification of Regulatory Authorities 
The local regulatory authorities as responsible for each particular investigator and the competent 
higher federal authority will be informed before the beginning, during and at the end of the trial 
according to §67 AMG and §13 GCP-V. The NCT Trial Center takes over notification of his/ her 
local regulatory authority and the competent higher federal authority according §67 AMG and §12 
(1, 2, 6) GCP-V.  
  Registration of the Trial 
Prior to the beginning of the clinical phase (FPI) the coordinating investigator will register the trial 
at the public accessible clinical trial register ClinicalTrials.gov possessing the status of a primary 
register according to the International Clinical Trials Registry Platform (ICTRP) and 
correspondingly is listed at the International Clinical Trials Registry Platform of the World Health 
Organization (WHO, http://www.who.int/ictrp/en/). The requirements are fulfilled by the European 
Clinical Trials Register and submission of EMA Module 1 (Clinical Trial Application Form). 
The registration is a prerequisite for a publication in many peer-reviewed journals (see Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals by the International Committee 
of Medical Journal Editors; (http://www.icmje.org/ publishing_10register.html). 

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 Insurance 
According to § 40 AMG, the sponsor has to subscribe to an insurance policy which covers   in its 
terms and provisions its legal liability for injuries caused to participating persons. The insurance 
policy also covers any damage done to the patient, even if the harm done arises out of strictly 
following the procedures described in this protocol and abiding as applicable law and professional 
standards. The insurance was taken out at HDI Global SE (insurance policy number: 
5701032703012, registration number: 14042022103, maximum limit: € 500.000 per participating 
person). 
Any impairment of health which might occur in consequence of trial participation must be notified 
to the insurance company. The patient is responsible for notification. The insured person must 
agree to help clarify the cause and the extent of damage with all appropriate measures. He is also 
obliged to take measures himself to reduce damage as much as possible. During the conduct of 
the experimental treatment phase of the trial, the patient must not undergo other clinical treatment 
except for cases of emergency. Within this trial phase, the patient is bound to inform the 
investigator immediately about any adverse events and additionally drugs taken. The terms and 
conditions of the insurance must be delivered to the patient. 
The insurance company has to be informed about all amendments that could affect patients’ 
safety, and must also receive the actual version of the informed consent. 
 Risk assessment in a pandemic situation 
In case of a pandemic (e.g. Covid-19), the sponsor determines measures to maintain the process 
of the trial as far as possible, such as off-site monitoring, regular contact with the IMP supplier to 
ensure deliveries, regular assessment of the situation at the trial sites, adjustment of trial schedule 
(performance of physical visits only if strictly necessary), adjustment of recruitment if necessary. 
However, patients cannot be left without any cancer therapy due to the high treatment demand. 
13 Quality Assurance 
  Monitoring  
Monitoring will be done by personal visits from a clinical monitor according to SOPs of KKS 
Heidelberg and a specific monitoring manual. The monitor will review the entries into the CRFs 
on the basis of source documents. The investigator must allow the monitor to verify all essential 
documents and must provide support at all times to the monitor. 
By frequent communications (letters, telephone, fax), the site monitor will ensure that the trial is 
conducted according to the protocol and to regulatory requirements. 
A detailed description of the monitoring process will be provided in a separate clinical monitoring 
plan. 
 Inspections/ Audits  
Regulatory authorities and an auditor authorized by the sponsor may request access to all source 
documents, CRF, and other trial documentation. Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 
14 Agreements 
   Financing of the Trial 
This is a non-commercial trial that is financed using funds of the National Center of Tumor 
Diseases (NCT) and by the Federal Ministry of Education and Research (BMBF). Study drugs 
are provided free-of charge by Roche Pharma AG, AstraZeneca and Gilead.  
 

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   Declaration of Interests  
Before the start of the trial, the investigator will disclose to the sponsor any proprietary or financial 
interests he or she might hold in the sponsors / a funding company, in the investigational 
product(s), or any commercial organisation being involved in the clinical trial. The investigator has 
also to confirm that he has not entered into any financial arrangement whereby the value of 
compensation paid could affect the outcome of the clinical trial. 
The investigator agrees to update this information in case of significant changes.  
  Dissemination Policy 
The research efforts and results of COGNITION-GUIDE shall be presented to the scientific 
community as well as the general public. The dissemination policy aims to address the project 
progress and outcome to target audiences on all stages of the project appropriately and to achieve 
a sustainable impact in the corresponding research field and the general public.  
14.3.1 Reports 
The final trial report is prepared within 6 months after LPLV. The study results will be released to 
the participating physicians, referring physicians and the general medical community; they will be 
made publicly available according to legal requirements. 
14.3.2 Publication 
All information concerning the trial is confidential before publication. The results of COGNITION-
GUIDE will be made available to the scientific community via publications in peer-reviewed 
scientific journals, and talks or presentations at scientific meetings. Collaborative results will be 
jointly analyzed and published. All partners are committed to the principles of good scientific 
practice. Manuscripts on behalf of COGNITION-GUIDE will be pre-circulated to all participants 
and co-authors in advance of submission; everyone will be invited to comment or contribute 
additional information or data. Notwithstanding this, absolute confidentiality will be enforced.  
Results will be published preferably in “Open Access” journals. Publications that are not a priori 
in an Open Access format will be deposited in PubMed Central, an Open Access repository. 

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15  Signatures 
The present trial protocol including sub-protocols for study arms 1-6 was subject to critical review 
and has been approved in the present version by the persons undersigned. The information 
contained is consistent with: 
• 
The current benefit-risk assessment of the investigational medicinal product 
• 
Moral, ethical, and scientific principles governing clinical research as set out the principles 
of GCP and in the applicable version of Declaration of Helsinki. 
The investigator will be supplied with details of any significant or new finding, including relevant 
safety information relating to treatment with the investigational medicinal product. 
 
 
Date: 
 
___________________ 
Signature: 
 
___________________________ 
 
Name (block letters): 
Prof. Dr. Andreas Schneeweiss 
 
 
Function: Coordinating 
Investigator / LKP, 
on behalf of the sponsor 
 
 
 
 
Date: 
 
___________________ 
Signature: 
 
___________________________ 
 
Name (block letters): 
Prof. Dr. Richard F. Schlenk 
 
 
Function: Biostatistician / 
Co-CI  
 
 
 
 
 
 
 
 

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16  Declaration of Investigator 
I have read the above trial protocol including sub-protocols for study arms 1-6 and confirm that it 
contains all information to conduct the clinical trial. I pledge to conduct the clinical trial according 
to the protocol. 
I will enroll the first patient only after all ethical and regulatory requirements are fulfilled. I pledge 
to obtain written consent for trial participation from all patients before enrollment. 
I know the requirements for accurate reporting of serious adverse events, and I pledge to 
document and notify such events as described in the protocol. 
I pledge to retain all trial-related documents and source data as described.  
 
Date:  
 
___________________ 
Signature: 
 
___________________________ 
 
Name (block letters): 
 
___________________________ 
 
Trial Center (address): 
 
___________________________ 
 
___________________________ 
 
___________________________ 

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17  References 
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Untch, M. et al. Pathologic complete response after neoadjuvant chemotherapy plus 
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Horak, P. et al. Precision oncology based on omics data: The NCT Heidelberg experience. 
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Leichsenring, J. et al. Variant Classification in Precision Oncology. International journal of 
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Kuroi, K. et al. Prognostic significance of subtype and pathologic response in operable 
breast cancer; a pooled analysis of prospective neoadjuvant studies of JBCRG. Breast 
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von Minckwitz, G. et al. Definition and impact of pathologic complete response on 
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von Minckwitz, G. et al. Response-guided neoadjuvant chemotherapy for breast cancer. 
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Masuda, N. et al. Adjuvant Capecitabine for Breast Cancer after Preoperative 
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von Minckwitz, G. et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive 
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Aronson, J. K. Anecdotes as evidence. BMJ 326, 1346, doi:10.1136/bmj.326.7403.1346 
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Perez, E. A. Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy 
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Steindorf, K. et al. Quality of Life, Fatigue, and Sleep Problems in Pancreatic Cancer 
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18 Appendix 
 
 Sub-Protocols 
• 
Arm 1 Atezolizumab (anti-PD-L1 antibody) 
• 
Arm 2 Inavolisib (PI3K inhibitor) 
• 
Arm 3 Ipatasertib (AKT inhibitor) 
• 
Arm 4 Olaparib (PARP inhibitor) 
• 
Arm 5 Sacituzumab Govitecan (TROP-2) 
• 
Arm 6 Trastuzumab/Pertuzumab (anti-HER2 antibody)