A Multicenter, Open-Label, Non-Comparative, Three-Arm, Phase IIa Trial of Ipatasertib (GDC-0068) in Combination With Non-Taxane Chemotherapy Agents for Taxane-Pretreated Unresectable Locally Advanced or Metastatic TNBC Patients
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Sponsor: MedSIR

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
1 
 
 
Clinical Study Protocol- 
 
 
 
A MULTICENTER, OPEN-LABEL, NON-COMPARATIVE, THREE-ARM, PHASE IIa TRIAL OF 
IPATASERTIB (GDC-0068) IN COMBINATION WITH NON-TAXANE CHEMOTHERAPY 
AGENTS FOR TAXANE-PRETREATED UNRESECTABLE LOCALLY ADVANCED OR 
METASTATIC TRIPLE-NEGATIVE BREAST CANCER PATIENTS (PATHFINDER) 
 
 
Code: MEDOPP253_PATHFINDER 
 
 
 
Drug Tested: 
Ipatasertib (GDC-0068)èp 
EudraCT#: 
2018-004648-44 
Clinical Trials.gov#: 
NCT04464174 
Protocol#: 
MEDOPP253 
Protocol Date: 
27-Apr-2023 
 
 
 
 
PROTOCOL REVIEW HISTORY 
 
• 
CSP: Version 1.0, 30-Sep-2019 
• 
CSP: Version 2.0, 18-May-2020 (only Spain) 
• 
CSP: Version 2.1, 15-Jun-2020 (only Portugal) 
• 
CSP: Version 3.0, 20-Sep-2021 
• 
CSP: Version 4.0, 04-Apr-2022 
• 
CSP:Version 5-0, 27-Apr-2023 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
 
SPONSOR’S SIGNATURE PAGE 
 
 
Study title: A Multicenter, Open-Label, Non-Comparative, Three-Arm, Phase IIa Trial of 
Ipatasertib (GDC-0068) in Combination with Non-Taxane Chemotherapy Agents for Taxane- 
Pretreated Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer Patients 
(PATHFINDER) 
 
 
Study code: MEDOPP253 
 
Version number: 5.0 
Version date: 27-Apr-2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
05/05/2023 
 
Sponsor’s Medical Scientist 
Signature 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
 
11/05/2023 
 
 
Scientific Global Coordinator 
Signature 
Signature date 
(DD-Mmm-YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
This document has been electronically signed and contains the Secure Verification Code: 5f131ace-dfb1-454e-9a12-24e464984ba4 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
3 
 
 
KEY CONTACTS 
 
 
Sponsor 
Name: 
Medica Scientia Innovation Research (MEDSIR) 
Contact Name: 
Alicia García-Sanz, PhD 
Address: 
Torre Glòries, Av. Diagonal 211, Planta 27, 08018 Barcelona (Spain) 
Phone: 
+ 34 932 214 135 
Fax: 
+ 34 932 992 382 
E-mail: 
alicia.garcia@medsir.org 
 
Sponsor’s Medical Scientist 
Name: 
Address: 
 Torre Glòries, Av. Diagonal 211, Planta 27, 08018 Barcelona (Spain) 
Phone: 
+ 34 932 214 135 
Fax: 
+ 34 932 992 382 
E-mail: 
 
Sponsor’s Safety Risk Management 
Name: 
Medica Scientia Innovation Research (MEDSIR) 
Address: 
Torre Glòries, Av. Diagonal 211, Planta 27, 08018 Barcelona (Spain) 
Phone: 
+ 34 932 214 135 
Fax: 
+ 34 932 992 382 
E-mail: 
pharmacovigilance@medsir.org 
 
 
Scientific Global Coordinator 
Name: 
Email: 
Position: 
Medical Oncologist 
Institution: 
IBCC, Quironsalud Group, Barcelona (Spain) 
 
Principal investigator 
Name: 
Antonio Llombart-Cussac, MD, PhD 
Email: 
antonio.llombart@medsir.org 
Position: 
Medical Oncologist 
Institution: 
Arnau de Vilanova Hospital, Valencia (Spain) 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
4 
 
 
STEERING COMMITTEE 
 
Name 
Role 
 
Clinical Expert 
 
 
 
 
 
Clinical Expert 
 
Clinical Expert 
 
 
 
 
 
Medical Scientist 
PATHFINDER Study Investigators 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
5 
 
 
DECLARATION OF INVESTIGATORS 
 
 
Protocol Title: A Multicenter, Open-Label, Non-Comparative, Three-Arm, Phase Iia Trial of 
Ipatasertib (GDC-0068) in Combination with Non-Taxane Chemotherapy Agents for Taxane- 
Pretreated Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer Patients 
(PATHFINDER) 
 
 
I have received, reviewed and understood the following: 
 
a) Protocol version: 5.0, dated 27-Apr-2023 
 
b) Investigator’s Brochure (IB) of ipatasertib (GDC-0068) and Summary of Product 
Characteristics (SmPC) for capecitabine, carboplatin, and gemcitabine with details of clinical 
and nonclinical data that are relevant to the study of the products in human subjects. 
§ 
I have been adequately informed about the development of the investigational products to 
date. I will confirm the receipt of updated IB and SmPCs. I have read this study protocol and 
agree that it contains all the information required to conduct the study. I agree to conduct the 
study as set out in this protocol. 
§ 
I fully understand that any changes instituted by the investigator(s) without previous 
agreement with the Sponsor would constitute a violation of the protocol, including any 
ancillary studies or procedures performed on study patients (other than those procedures 
necessary for the wellbeing of the patients). I am aware that I cannot deviate from or apply 
changes to the protocol without prior approval or the favorable opinion of the Institutional 
Review Board (IRB) or Ethics Committee (EC) and/or before Sponsor’s agreement to avoid 
immediate risk to the trial patients. If this occurs, I agree to inform the Sponsor as to the 
deviation or changes in writing and their reasons, as soon as possible. 
§ 
I will not enroll the first patient in the study until I have received approval from the appropriate 
IRB/EC and until all legal and regulatory requirements in my country have been fulfilled. 
§ 
The study will be conducted in accordance with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and its amendments, the 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines 
(ICH E6(R2) GCP) and applicable regulations and laws. 
§ 
I agree to obtain, in the manner described in this protocol and in (ICH E6(R2) GCP), signed 
informed consent form (ICF) by the patient or witnessed verbal ICF to participate for all 
patients whose participation in this study is proposed to and before any patient’s study specific 
procedure is done. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
6 
 
 
§ 
I will ensure that the study drug(s) supplied by the Sponsor are being used only as described 
in this protocol. 
§ 
I am aware of the requirements for the correct reporting of serious adverse events, and I 
commit to document and to report such events as required by the Sponsor and in accordance 
with Health Authority Regulatory requirements. 
§ 
I agree to supply – upon request – the Sponsor or Sponsor’s representative with evidence of 
current laboratory accreditation, the name and address of the laboratory, and a list of normal 
values and ranges. 
§ 
I agree with the use of results of the study for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. 
§ 
I agree to keep all source documents and case report forms as specified in the relevant 
sections of this protocol. 
§ 
I will provide all required Regulatory Authority forms, up-to-date curriculum vitae of myself, 
sub-investigators and of any member of my study team (if requested) before the study starts, 
which may be submitted to regulatory authorities. 
§ 
I am aware of the possibility of being audited by the Sponsor or its delegate or inspected by 
regulatory authorities for the performance of this study. I will permit monitoring, auditing and 
inspection and provide direct access to source data/documents and reports for these 
purposes. 
§ 
Furthermore, I confirm herewith that the Sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal purposes and 
for submission to Health Authorities worldwide. 
 
 
 
 
Name:  
 
 
 
 
Signature:  
 
Date:  
 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
7 
 
 
TABLE OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse 
events 
of 
special interest 
AKT 
Serine/threonine 
kinase B 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute 
neutrophil 
count 
aPTT 
Activated 
Partial 
Thromboplastin Time 
ASCO 
American Society of 
Clinical Oncology 
AST 
Aspartate 
transaminase 
AUC 
Area under the curve 
BL 
Basal-like 
BLBC 
Basal-like 
breast 
cancer 
BRCA1 
Breast Cancer 1 
BSA 
Body surface area 
CAP 
College of American 
Pathologists 
CBR 
Clinical benefit rate 
cfDNA 
Cell-free DNA 
CI 
Confidence interval 
CNS 
Central 
nervous 
system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CRO 
Clinical 
Research 
Organization 
CT 
Computerized 
tomography 
DDI 
Drug-Drug Interaction 
DILI 
Drug 
Induced 
Liver 
Injury 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DSUR 
Development 
Safety 
Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
8 
 
 
 
ECHO 
Echocardiogram 
ECOG 
Eastern 
European 
Cooperative Oncology 
Group 
EGFR 
Epidermal 
Growth 
Factor Receptor 
EMA 
European 
Medicines 
Agency 
EoS 
End of study 
EoT 
End of Treatment 
ER 
Estrogen receptor 
ESA 
Erythropoiesis- 
stimulating agents 
FDA 
Food 
and 
Drug 
Administration 
FFPE 
Formalin-fixed 
and 
paraffin-embedded 
G-CSF 
Granulocyte-colony 
stimulating factors 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl 
transferase 
HbA1c 
High hemoglobin A1c 
HBcAb 
Hepatitis 
B 
core 
antibody 
HBsAg 
Hepatitis 
B 
surface 
antibody 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HER2 
Human 
Epidermal 
Growth 
Factor 
Receptor 2 
HL 
Hy’s Law 
HR 
Hazard ratio 
IB 
Investigator’s 
Brochure 
ICF 
Informed consent form 
ICH 
International 
Conference 
on 
Harmonization 
IHC 
Immunohistochemistry 
IMP 
Investigational 
medicinal product 
INR 
International 
Normalized Ratio 
IRB 
Institutional 
Review 
Board 
ISH 
In situ hybridization 
ITT 
Intention-to-treat 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
9 
 
 
 
LAR 
Luminal 
androgen 
receptor 
LPLV 
Last patient, last visit 
LVEF 
Left 
ventricular 
ejection fraction 
MBC 
Metastatic 
breast 
cancer 
mCRPC 
Metastatic 
castration 
resistant 
prostate 
cancer 
MedDRA 
Medical Dictionary for 
Regulatory Activities 
MRI 
Magnetic 
resonance 
imaging 
MSL 
Mesenchymal 
stem- 
like 
MTD 
Maximum 
tolerated 
dose 
mTOR 
Mammalian target of 
rapamycin 
mTORC 
Mammalian target of 
rapamycin complex 
MUGA 
Multiple 
gated 
acquisition 
NCCN 
National 
Comprehensive 
Cancer Network 
NGS 
Next-generation 
sequencing 
ORR 
Objective 
response 
rate 
OS 
Overall survival 
PARP 
Poly(ADP- 
Ribose)Polymerase 
pCR 
Pathological complete 
response 
PCR 
Polymerase 
chain 
reaction 
PHL 
Potential Hy’s Law 
PD 
Progressive disease 
PD-L1 
Programmed 
death 
ligand 1 
PDK1 
Phosphoinositide- 
dependent kinase 1 
PET 
Positron 
emission 
tomography 
PFS 
progression-free 
survival 
PgR 
Progesterone receptor 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
10 
 
 
 
PI3K 
Phosphoinositide 
3- 
kinase 
PIK3CA 
p110α 
catalytic 
subunit of PI3K 
PIP3 
Phosphatidylinositol 
(3,4,5)-trisphosphate 
PP 
Per-Protocol 
PR 
Partial response 
PTEN 
Phosphatase 
and 
tensin homolog 
PTT 
Partial Thromboplastin 
Time 
SAE 
Serious adverse event 
SD 
Stable disease 
SmPC 
Summary of Product 
Characteristics 
TBL 
Total bilirubin 
TIL 
Tumor-infiltrating 
lymphocyte 
TNBC 
Triple-Negative Breast 
Cancer 
TTR 
Time to response 
ULN 
Upper limit of normal 
UPN 
Unique patient number 
VEGF 
Vascular-Endothelial 
Growth Factor 
WBC 
White blood cell 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
11 
 
 
TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ................................................................................................................ 15 
2 
BACKGROUND AND STUDY RATIONALE ............................................................................... 41 
2.1 
Breast Cancer Molecular Subtypes .................................................................................... 41 
2.2 
Triple-Negative Breast Cancer (TNBC) .............................................................................. 41 
2.3 
TNBC Subtypes ..................................................................................................................... 42 
2.4 
Current Treatment Options in Metastatic TNBC ............................................................... 43 
2.4.1 
Antiangiogenics ................................................................................................................. 43 
2.4.2 
Poly(ADP-Ribose)Polymerase (PARP) Inhibitors ........................................................ 45 
2.4.3 
Immunotherapy ................................................................................................................. 46 
2.4.4 
Antibody Drug Conjugates .............................................................................................. 46 
2.4.5 
Antiandrogens ................................................................................................................... 47 
2.5 
Relevance of the PI3K-AKT-mTOR signaling pathway .................................................... 48 
2.6 
PI3K/AKT Pathway in Breast Cancer ................................................................................. 49 
2.7 
Ipatasertib (GDC-0068) ........................................................................................................ 50 
2.7.1 
Overview of Clinical Development .................................................................................. 50 
2.7.2 
Clinical Efficacy ................................................................................................................. 51 
2.7.3 
Clinical Safety .................................................................................................................... 55 
2.7.4 
Potential Drug-Drug Interaction (DDI) ............................................................................ 58 
2.8 
Study Rationale ...................................................................................................................... 59 
2.8.1 
Global Rationale ............................................................................................................... 59 
2.8.2 
Study design rationale ...................................................................................................... 60 
2.8.3 
Benefit/Risk assessment ................................................................................................. 61 
3 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................. 62 
3.1 
Study Objectives .................................................................................................................... 62 
3.1.1 
Primary Objective ............................................................................................................. 62 
3.1.2 
Secondary Objectives ...................................................................................................... 62 
3.1.3 
Exploratory Objectives ..................................................................................................... 62 
3.2 
Study Endpoints ..................................................................................................................... 63 
3.2.1 
Primary Endpoint .............................................................................................................. 63 
3.2.2 
Secondary Endpoints ....................................................................................................... 63 
3.2.3 
Exploratory Endpoints ...................................................................................................... 63 
4 
STUDY overview ............................................................................................................................. 64 
4.1 
Study Design .......................................................................................................................... 64 
4.2 
Study Schedule Summary .................................................................................................... 66 
4.2.1 
Screening Phase .............................................................................................................. 66 
4.2.2 
Treatment Phase .............................................................................................................. 67 
4.2.3 
Access to Trial Intervention After End of Trial .............................................................. 67 
4.2.4 
EoT and EoS Visits ........................................................................................................... 68 
5 
PATIENT SELECTION ................................................................................................................... 69 
5.1 
Target Study Population ....................................................................................................... 69 
5.2 
Inclusion Criteria .................................................................................................................... 69 
5.3 
Exclusion Criteria ................................................................................................................... 71 
6 
ASSESSMENTS AND STUDY PROCEDURES ........................................................................ 74 
6.1 
Patient Entry Procedures ...................................................................................................... 74 
6.2 
Patient Allocation ................................................................................................................... 75 
6.3 
Safety Run-In Phase ............................................................................................................. 75 
6.4 
Study Assessments ............................................................................................................... 77 
6.4.1 
Schedule of Assessments ............................................................................................... 77 
6.4.2 
Visit Schedule .................................................................................................................... 77 
6.4.3 
Medical History and Demographic Data ........................................................................ 78 
6.4.4 
Vital Signs .......................................................................................................................... 79 
6.4.5 
Physical Examination ....................................................................................................... 79 
6.4.6 
Tumor and Response Evaluations ................................................................................. 79 
6.4.7 
Laboratory Assessments ................................................................................................. 82 
6.4.8 
Home Glucose Monitoring ............................................................................................... 82 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
12 
 
 
6.4.9 
Pregnancy Tests and Assessment of Fertility .............................................................. 82 
6.4.10 Electrocardiograms (ECGs) and Cardiac Function Assessment ............................... 84 
6.4.11 ECOG performance status .............................................................................................. 85 
6.4.12 Biological Samples for Exploratory Analysis ................................................................. 85 
7 
STUDY DRUGS INFORMATION .................................................................................................. 87 
7.1 
Formulation, Packaging, and Handling .............................................................................. 87 
7.1.1 
Ipatasertib (GDC-0068) ................................................................................................... 87 
7.1.2 
Chemotherapy ................................................................................................................... 88 
7.2 
Dosage and administration .................................................................................................. 88 
7.2.1 
Ipatasertib (GDC-0068) .................................................................................................... 88 
7.2.2 
Loperamide ........................................................................................................................ 89 
7.2.3 
Capecitabine ...................................................................................................................... 89 
7.2.4 
Eribulin ............................................................................................................................... 89 
7.2.5 
Carboplatin plus Gemcitabine ......................................................................................... 90 
7.3 
Treatment Modification ......................................................................................................... 90 
7.3.1 
General Guidelines ........................................................................................................... 90 
7.3.2 
Ipatasertib (GDC-0068): Dose Interruptions ................................................................. 92 
7.3.3 
Ipatasertib (GDC-0068): Dose Modifications ................................................................ 92 
7.3.4 
Chemotherapy: Dose Interruptions and Modifications ................................................ 93 
7.4 
General concomitant medication and additional assistance guidelines ........................ 95 
7.5 
Prohibited Concomitant Medication .................................................................................... 96 
7.6 
Medications Given with Precaution ..................................................................................... 97 
7.7 
Herbal Therapies and Prohibited Food .............................................................................. 98 
7.8 
Cautionary Therapy ............................................................................................................... 98 
7.9 
Medication Errors and Overdose ........................................................................................ 98 
7.10 
Compliance ............................................................................................................................. 99 
7.11 
Drug Storage and Drug Accountability ............................................................................... 99 
8 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ............................................. 100 
8.1 
AEs Definitions ..................................................................................................................... 101 
8.2 
SAEs ...................................................................................................................................... 102 
8.3 
AESIs to Report Immediately ............................................................................................. 104 
8.4 
AEs Management Guidelines ............................................................................................ 105 
8.4.1 
Diarrhea Management Guidelines ................................................................................ 105 
8.4.2 
Fasting Hyperglycemia ................................................................................................... 107 
8.4.3 
Nausea and/or Vomiting ................................................................................................ 110 
8.4.4 
Rash ................................................................................................................................. 110 
8.4.5 
Pneumonitis ..................................................................................................................... 111 
8.4.6 
Mucositis .......................................................................................................................... 113 
8.4.7 
Hepatotoxicity .................................................................................................................. 113 
8.4.8 
Other non-Hematologic Toxicities ................................................................................ 114 
8.5 
AEs Reporting and Other Safety Related Issues Reporting ......................................... 115 
8.6 
SAE reporting and timeframe ............................................................................................ 115 
8.7 
Expedited Reporting to Health Authorities, Investigators, IRBs, and ECs .................. 116 
8.8 
Other Safety-Related Reports ........................................................................................... 117 
8.9 
Pregnancy Reporting .......................................................................................................... 117 
9 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .................................................. 118 
9.1 
Determination of Sample Size ........................................................................................... 118 
9.2 
Justification of Total Sample Size ..................................................................................... 118 
9.3 
Statistical Plan ...................................................................................................................... 119 
9.4 
Analysis Sets ........................................................................................................................ 119 
9.4.1 
Full Analysis and Safety Analysis Set .......................................................................... 119 
9.4.2 
Safety run-in Set ............................................................................................................. 119 
9.4.3 
Exploratory Analysis Set ................................................................................................ 119 
9.5 
Safety Analysis (primary objective) ................................................................................... 119 
9.5.1 
Safety Run-In Analysis ................................................................................................... 119 
9.5.2 
Analysis of Safety-Related Data ................................................................................... 119 
9.6 
Secondary Efficacy Analysis .............................................................................................. 120 
9.6.1 
Response Assessment .................................................................................................. 120 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
13 
 
 
9.6.2 
Time-to-Event Measures Definitions ............................................................................ 120 
9.7 
Secondary Efficacy Analysis .............................................................................................. 121 
9.8 
Exploratory Endpoints ......................................................................................................... 121 
9.9 
Missing Data Management ................................................................................................ 122 
9.10 
Interim Analysis .................................................................................................................... 122 
9.11 
Steering Committee Review .............................................................................................. 122 
10 
ETHICAL CONSIDERATIONS .................................................................................................... 123 
10.1 
Regulatory and Ethics Compliance ................................................................................... 123 
10.2 
IRB/EC .................................................................................................................................. 123 
10.3 
ICF ......................................................................................................................................... 124 
10.4 
Data Protection .................................................................................................................... 125 
11 
SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE. 125 
11.1 
Source Data Documentation .............................................................................................. 125 
11.2 
Study Monitoring and Source Data Verification .............................................................. 126 
11.3 
Retention of Records .......................................................................................................... 126 
11.4 
Data Quality Assurance ...................................................................................................... 127 
12 
DATA MANAGEMENT ................................................................................................................. 128 
12.1 
Data Entry and Management ............................................................................................. 128 
12.2 
Data Clarification ................................................................................................................. 128 
12.3 
Data Coding Procedures .................................................................................................... 128 
13 
STUDY MANAGEMENT .............................................................................................................. 128 
13.1 
Discontinuation of the Study .............................................................................................. 128 
13.2 
Protocol Amendments ......................................................................................................... 129 
13.3 
Protocol Deviations ............................................................................................................. 129 
13.4 
Publication Policy Protection of Trade Secrets ............................................................... 129 
14 
REFERENCES .............................................................................................................................. 131 
 
 
 
LIST OF TABLES 
 
 
Table 1. RECIST Response Outcomes for Patients with Baseline Measurable Disease by 
Mutation Status ......................................................................................................................................... 52 
Table 2. Overview of PFS Results in Study GO29227 ........................................................................ 54 
Table 3. Safety Run-in Dosing Schedule .............................................................................................. 61 
Table 4. Significant Toxicities Definition ............................................................................................... 62 
Table 5. ECOG Performance Status Scale .......................................................................................... 85 
Table 6. Dose Reductions for Ipatasertib (GDC-0068) ....................................................................... 92 
Table 7. Dose Reductions for Capecitabine ......................................................................................... 93 
Table 8. Dose Reductions for Eribulin ................................................................................................... 94 
Table 9. Dose Reductions for Carboplatin plus Gemcitabine ............................................................ 95 
Table 10. Gemcitabine Dose on Day 8 .................................................................................................. 95 
Table 11. Diarrhea Management Guidelines ...................................................................................... 106 
Table 12. Fasting Hyperglycemia Management Guidelines ............................................................. 108 
Table 13. Nausea and vomiting management guidelines ................................................................. 110 
Table 14. Rash Management Guidelines ............................................................................................ 110 
Table 15. Pneumonitis Management Guidelines ............................................................................... 111 
Table 16. Mucositis Management Guidelines ..................................................................................... 113 
Table 17. Hepatotoxicity Management Guidelines ............................................................................. 100 
Table 18. Objective Response Status at Each Evaluation ............................................................... 147 
Table 19. Objective Response Status at Each Evaluation for Patients with Non-Target Disease 
Only ........................................................................................................................................................... 147 
LIST OF APPENDICES 
Appendix 1. Schedule of Assessments and Study Procedures ....................................................... 137 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
14 
 
 
Appendix 2. Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines V.1.1 ............ 143 
Appendix 3. Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy’s 
Law ........................................................................................................................................................... 148 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
15 
 
 
1 
PROTOCOL SYNOPSIS 
 
 
Investigational 
Medicine 
Products 
Ipatasertib (GDC-0068) 
Protocol 
Number 
MEDOPP253 
EudraCT 
Number 
2018-004648-44 
Protocol Title 
A Multicenter, Open-Label, Non- 
Comparative, Three-Arm, Phase 
IIa Trial of Ipatasertib (GDC- 
0068) in Combination with Non- 
Taxane Chemotherapy Agents for 
Taxane-Pretreated Unresectable 
Locally Advanced or Metastatic 
Triple-Negative Breast Cancer 
Patients (PATHFINDER) 
Target 
Disease 
Hormone 
Receptor 
(HR)- 
negative/Human 
Epidermal 
Growth 
Factor 
Receptor 
2 
(HER2)-negative 
unresectable 
locally advanced or metastatic 
breast cancer (MBC). 
Patients 
Women age ≥ 18 years with triple- 
negative 
unresectable 
locally 
advanced or MBC that is not 
amenable 
to 
resection 
with 
curative intent. 
Patients must have received at 
least one, but not more than two, 
prior chemotherapeutic regimens 
for treatment of unresectable 
locally 
advanced 
and/or 
metastatic disease (at least one 
regimen must have contained a 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
16 
 
 
 
 
taxane). 
Earlier 
adjuvant 
or 
neoadjuvant therapy for more 
limited disease will be considered 
as one of the required prior 
regimens if the development of 
unresectable locally advanced or 
metastatic 
disease 
occurred 
within a 12-month period of time 
after 
completion 
of 
chemotherapy. 
Therefore, 
exclusive 
prior 
taxane-based 
therapy 
as 
adjuvant 
or 
neoadjuvant treatment is also 
allowed if the patient had a 
disease-free interval of less than 
12 months after completing this 
treatment. 
Patients are not eligible if they 
have received previous treatment 
with phosphatidylinositol 3-kinase 
(PI3K), and/or mammalian target 
of rapamycin (mTOR), and/or 
AKT inhibitors. 
Evidence of either measurable or 
evaluable 
disease 
(as 
for 
Response Evaluation Criteria in 
Solid 
Tumors 
version 
1.1 
[RECIST v.1.1]) is mandatory, 
with at least a site of disease 
amenable to biopsy. Patients with 
bone-only metastases are also 
eligible. 
Number of 
patients 
54 patients. 
Study 
objectives 
Primary objective: 
To 
evaluate 
the 
safety 
and 
tolerability of ipatasertib (GDC- 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
17 
 
 
0068) 
in 
capecitabine, 
combination 
with 
eribulin, 
or 
carboplatin plus gemcitabine in 
the 
intention-to-treat 
(ITT) 
population 
of 
patients 
with 
taxane-pretreated 
unresectable 
locally advanced or metastatic 
triple-negative  breast  cancer 
(TNBC). 
Secondary objectives: 
 
To  determine  the  efficacy  of 
ipatasertib 
combination 
(GDC-0068) 
in 
with  capecitabine, 
eribulin, 
or 
carboplatin 
plus 
gemcitabine in the ITT population 
and in each treatment arm. 
Exploratory objectives: 
• 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
18 
 
 
 
 
• 
 
 
Study 
endpoints 
Primary endpoint: 
 
• 
Incidence 
of 
adverse 
events (AEs) as assessed 
by the investigator, with 
severity 
determined 
through the use of US 
National Cancer Institute- 
Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(NCI-CTCAE) 
v.5.0. 
 
 
Secondary endpoints: 
 
• 
Progression-free survival 
(PFS), defined as the 
period 
of 
time 
from 
treatment initiation to the 
first occurrence of disease 
progression or death from 
any 
cause, 
whichever 
occurs first, as determined 
locally by the investigator 
through 
the 
use 
of 
RECIST v.1.1. 
• 
Time to response (TTR), 
defined as the time from 
the treatment initiation to 
time of the first objective 
 
 
 
 
 
 
 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
19 
 
 
 
 
tumor response (tumor 
shrinkage 
of 
≥ 
30%) 
observed for patients who 
achieved 
a 
complete 
response (CR) or partial 
response 
(PR), 
as 
determined locally by the 
investigator through the 
use of RECIST v.1.1. 
• 
Objective response rate 
(ORR), defined as a CR or 
PR as determined locally 
by the investigator through 
the use of RECIST v.1.1. 
• 
Duration 
of 
response 
(DoR), defined as the time 
from the first occurrence 
of a documented objective 
response 
to 
disease 
progression or death from 
any 
cause, 
whichever 
occurs first, as determined 
locally by the investigator 
through use of RECIST 
v.1.1. 
• 
Clinical 
benefit 
rate 
(CBR), defined as an 
objective response (CR or 
PR), or stable disease 
(SD) for at least 24 weeks, 
as determined locally by 
the investigator through 
the use of RECIST v.1.1. 
• 
Overall 
survival 
(OS), 
defined as the time from 
treatment  initiation  to 
death from any cause, as 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
20 
 
 
determined locally by the 
investigator through use of 
RECIST v.1.1. 
• 
Best 
percentage 
of 
change from baseline in 
the size of target tumor 
lesions, defined as the 
biggest 
decrease, 
or 
smallest increase if no 
decrease 
will 
be 
observed, as determined 
locally by the investigator 
through use of RECIST 
v.1.1. 
 
 
Exploratory endpoints: 
 
• 
PFS, TTR, ORR, DoR, 
CBR, 
OS, 
and 
best 
percentage of change in 
target 
tumor 
lesions 
determined locally by the 
investigator through the 
use of RECIST v.1.1 in the 
subset of  patients  with 
 
altered tumors. 
 
• 
Relationship 
between 
tissue- and blood-based 
biomarkers and patient 
clinical 
features 
(e.g., 
baseline 
features) 
and 
outcome (e.g., duration of 
PFS). 
• 
Changes in mutation and 
copy 
number 
in 
oncogenes, 
tumor 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
21 
 
 
 
 
suppressors, and/or other 
genes 
associated 
with 
disease 
progression 
assessed 
by 
deoxyribonucleic 
acid 
(DNA) sequencing. 
• 
Changes in levels of tumor 
suppressors, 
immune 
checkpoints, mitotic index, 
apoptotic index, and/or 
immune-cell 
infiltration 
assessed 
by 
immunohistochemistry 
(IHC). 
• 
Associations 
of 
breast 
cancer subtypes defined 
by molecular signatures 
with patient outcomes. 
Type of study 
This is a multicenter, open-label, 
non-comparative, 
three-arm, 
phase IIa clinical trial with safety 
run-in. 
Selection 
criteria 
Inclusion criteria: 
 
Patients must meet ALL of the 
following inclusion criteria to be 
eligible for enrolment into the 
study: 
 
1. Signed informed 
consent 
form 
(ICF) 
prior 
to 
participation in any study- 
related activities. 
 
2. Female patients ≥ 18 years at 
the time of signing ICF. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
22 
 
 
 
 
3. Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
Performance Status of 0 or 1. 
4. Life expectancy of ≥ 12 
weeks. 
5. Histologically 
confirmed 
TNBC per American Society 
of 
Clinical 
Oncology 
(ASCO)/College of American 
Pathologists (CAP) criteria 
based on local testing on the 
most recent analyzed biopsy. 
Triple-negative is defined as 
<1% expression for estrogen 
receptor 
(ER) 
and 
progesterone receptor (PgR) 
and 
negative 
for 
human 
epidermal 
growth 
factor 
receptor 2 (HER2) (0–1+ by 
IHC or 2+ and negative by in 
situ hybridization [ISH) test]. 
6. Unresectable 
locally 
advanced 
or 
metastatic 
disease 
documented 
by 
computerized 
tomography 
(CT) 
scan 
or 
magnetic 
resonance imaging (MRI) that 
is not amenable to resection 
with curative intent. 
7. Measurable 
or 
evaluable 
disease as per RECIST v.1.1. 
Patients 
with 
bone-only 
metastases are also eligible. 
8. Refractory to or relapsed after 
one or two prior standard of 
care chemotherapy regimens 
for  unresectable  locally 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
23 
 
 
 
 
advanced or MBC. Earlier 
adjuvant 
or 
neoadjuvant 
therapy 
for 
more 
limited 
disease will be considered as 
one of the required prior 
regimens if the development 
of 
unresectable 
locally 
advanced 
or 
metastatic 
disease occurred within a 12- 
month period of time after 
completion of chemotherapy. 
Note: Exclusive tumor marker 
elevation 
will 
not 
be 
considered 
sufficient 
for 
diagnosis 
of 
disease 
progression. 
9. Prior therapy must have 
included a taxane in any 
combination or order and 
either in the early, locally 
advanced, 
or 
metastatic 
setting. 
Note: Exclusive prior taxane- 
based therapy as adjuvant or 
neoadjuvant treatment is also 
allowed if the patient had a 
disease-free interval of less 
than 
12 
months 
after 
completing this treatment. 
10. Eligible 
for 
one 
of 
the 
chemotherapy 
options 
(capecitabine, 
eribulin, 
carboplatin plus gemcitabine) 
as 
per 
local 
investigator 
assessment 
and 
slots 
availability. Patients treated 
with (neo)adjuvant platinum 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
24 
 
 
 
 
salts or capecitabine and who 
have relapsed more than one 
year after the last dose of 
either 
treatment 
may 
be 
allowed to be included in the 
treatment arms based on 
ipatasertib 
(GDC-0068) 
in 
combination with carboplatin 
plus 
gemcitabine 
and 
capecitabine, respectively. 
11. Previous 
treatment 
with 
androgen 
receptor 
antagonists, poly ADP-ribose 
Polymerase 
 (PARP) 
inhibitors, 
  
and 
immunotherapy is allowed. 
Those patients who have 
previously received a PARP 
inhibitor will not be included in 
the 
carboplatin 
and 
gemcitabine 
arm 
unless 
PARP inhibitors were used in 
the 
early 
breast 
cancer 
setting 
and 
the 
period 
between the end of PARP 
inhibitor-based regimen and 
onset of metastatic disease is 
at least of 12 months. 
12. Resolution of all acute toxic 
effects of prior anti-cancer 
therapy to grade £ 1 as 
determined 
by 
the 
NCI- 
CTCAE v.5.0 (except for 
alopecia or other toxicities not 
considered a safety risk for 
the patient at investigator's 
discretion). 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
25 
 
 
 
 
13. Willingness and ability to 
provide a tumor biopsy from a 
metastatic site or the primary 
breast tumor at the time of the 
inclusion in order to perform 
exploratory studies. If not 
feasible, 
patient 
eligibility 
should be evaluated by a 
Sponsor’s qualified designee. 
Note: Subjects for whom 
tumor biopsies cannot be 
obtained (e.g., inaccessible 
tumor 
or 
subject 
safety 
concern) may submit an 
archived metastatic tumor 
specimen 
only 
upon 
agreement from the Sponsor. 
14. Patients agree to give blood 
samples (liquid biopsy) at the 
time of inclusion, after two 
cycles of study treatment, and 
upon progression or study 
termination. 
15. Adequate hematologic and 
organ function within 14 days 
before 
the 
first 
study 
treatment on Day 1 of Cycle 
1, defined by the following: 
a) Hematological: 
White 
blood cell (WBC) count > 
3.0 x 109/L, absolute 
neutrophil count (ANC) > 
1.5 x 109/L, platelet count 
> 
100.0 
x109/L, 
and 
hemoglobin > 9.0 g/dL. 
b)  Hepatic: Serum albumin 
≥ 3 g/dL; Bilirubin ≤ 1.5 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
26 
 
 
 
 
times the upper limit of 
normal (× ULN) (≤ 3 x 
ULN in the case of 
Gilbert’s 
disease); 
aspartate transaminase 
(AST) 
and 
alanine 
transaminase (ALT) ≤ 2.5 
× ULN (in the case of liver 
metastases ≤ 5 × ULN); 
alkaline 
phosphatase 
(ALP) ≤ 2 × ULN (≤ 5 × 
ULN in the case of liver 
and/or bone metastases). 
c) Renal: Serum creatinine 
< 1.5 × ULN or creatinine 
clearance ≥ 50 mL/min 
based 
on 
Cockcroft−Gault 
glomerular filtration rate 
estimation. 
d) Coagulation: 
Partial 
Thromboplastin 
Time 
(PTT) 
(or 
activated 
Partial 
Thromboplastin 
Time 
[aPTT]) 
and 
International Normalized 
Ratio (INR) ≤ 1.5 × ULN 
(except 
for 
patients 
receiving anticoagulation 
therapy). 
Note: Patients receiving 
heparin treatment should 
have a PTT (or aPTT) ≤ 
2.5 × ULN (or patient 
value 
before 
starting 
heparin 
treatment). 
Patients 
receiving 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
27 
 
 
 
 
coumarin 
derivatives 
should 
have  an 
INR 
between 2.0 and 3.0 
assessed 
 in  
 two 
consecutive 
measurements  one   to 
four days apart. Patients 
should be on a stable 
anticoagulant regimen. 
16. For women of childbearing 
potential: 
agreement 
to 
remain abstinent (refrain from 
heterosexual intercourse), or 
to use a highly effective non- 
hormonal 
 form 
of 
contraception, 
or 
two 
effective 
forms 
of 
contraception, as defined in 
the 
protocol 
during 
the 
treatment period and for at 
least 28 days after the last 
dose of ipatasertib (GDC- 
0068), three months after the 
last dose of eribulin, and six 
months after the last dose of 
carboplatin and gemcitabine 
or capecitabine, whichever 
occurs later, and agreement 
to refrain from donating eggs 
during this same period. 
Women 
of 
childbearing 
potential 
must 
have 
a 
negative serum pregnancy 
test before study treatment 
initiation. 
 
 
Exclusion criteria: 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
28 
 
 
 
 
Patients will be excluded from the 
study if they meet ANY of the 
following criteria: 
1. Inability to comply with study 
and follow-up procedures. 
2. Previous treatment with PI3K, 
mTOR, or AKT inhibitors. 
3. Known active uncontrolled or 
symptomatic central nervous 
system (CNS) metastases, 
carcinomatous meningitis, or 
leptomeningeal disease as 
indicated 
by 
clinical 
symptoms, cerebral edema, 
and/or progressive growth. 
Patients with a history of CNS 
metastases 
or 
cord 
compression are eligible if 
they have been definitively 
treated (e.g., radiotherapy, 
stereotactic 
surgery), 
are 
clinically 
stable, 
and 
off 
anticonvulsants and steroids 
for at least two weeks before 
first dose of study treatment. 
4. Radiotherapy or limited-field 
palliative radiotherapy within 
seven days prior to study 
enrolment, or patients who 
have not recovered from 
radiotherapy-related toxicities 
to baseline or grade ≤ 1 
and/or from whom ≥ 25% of 
the bone marrow has been 
previously irradiated. 
5. Major surgery (defined as 
requiring general anesthesia) 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
29 
 
 
 
 
or significant traumatic injury 
within 28 days of start of 
study drug, or patients who 
have not recovered from the 
side effects of any major 
surgery. 
6. Grade 
≥ 
2 
peripheral 
neuropathy. 
7. Grade ≥ 2 uncontrolled or 
untreated 
hypercholesterolemia 
or 
hypertriglyceridemia. 
8. History of type I or type II 
diabetes 
mellitus 
either 
requiring insulin or with a 
baseline fasting glucose > 
150 mg/dL (8.3 mmol/L) or 
high 
hemoglobin 
A1c 
(HbA1c) as defined as > 7%. 
Patients who are on a stable 
dose 
of 
oral 
diabetes 
medication during at least two 
weeks prior to initiation of 
study treatment are eligible 
for enrolment. 
9. Lung disease: pneumonitis, 
interstitial 
lung 
disease, 
idiopathic pulmonary fibrosis, 
cystic fibrosis, Aspergillosis, 
active tuberculosis, or history 
of 
opportunistic 
infections 
(pneumocystis pneumonia or 
cytomegalovirus pneumonia). 
10. History 
of 
malabsorption 
syndrome or other condition 
that 
would 
interfere 
with 
enteral absorption or results 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
30 
 
 
 
 
in 
the 
inability 
or 
unwillingness to swallow pills. 
11. History 
of 
or 
active 
inflammatory bowel disease 
(e.g., Crohn's disease and 
ulcerative colitis) or active 
bowel 
inflammation 
(e.g., 
diverticulitis). 
12. Known 
hypersensitivity 
reaction to any investigational 
or therapeutic compound or 
their 
 
incorporated 
substances. 
13. Patients have a concurrent 
malignancy or malignancy 
within five years of study 
enrollment with the exception 
of carcinoma in situ of the 
cervix, non-melanoma skin 
carcinoma, or stage I uterine 
cancer. For other cancers 
considered to have a low risk 
of recurrence, discussion with 
the 
Medical 
Monitor 
is 
required. 
14. Current known infection with 
HIV, hepatitis B virus (HBV), 
or hepatitis C virus (HCV). 
Patients 
with 
past 
HBV 
infection or resolved HBV 
infection (defined as having a 
negative hepatitis B surface 
antibody [HBsAg] test and a 
positive 
hepatitis 
B 
core 
antibody 
[HBcAb] 
test, 
accompanied by a negative 
HBV DNA test) are eligible. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
31 
 
 
 
 
Patients positive for HCV 
antibody are eligible only if 
polymerase chain reaction 
(PCR) is negative for HCV 
RNA. 
15. Active uncontrolled infection 
at the time of enrollment. 
16. Congenital 
long 
QT 
syndrome or screening QT 
interval 
corrected 
using 
Fridericia's formula (QTcF) > 
480 milliseconds. 
17. Patients 
have 
an 
active 
cardiac disease or a history of 
cardiac dysfunction including 
any of the following: 
a) Unstable angina pectoris 
or 
documented 
myocardial 
infarction 
within six months prior to 
study entry. 
b) Symptomatic pericarditis. 
 
c) Documented congestive 
heart failure (New York 
Heart 
Association 
functional 
classification 
III- IV). 
d) Left ventricular ejection 
fraction (LVEF) < 50% as 
determined by multiple 
gated 
acquisition 
(MUGA) 
scan 
or 
echocardiogram 
(ECHO). 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
32 
 
 
 
 
18. Patients have any of the 
following cardiac conduction 
abnormalities: 
a) Ventricular 
arrhythmias 
except 
for 
benign 
premature 
ventricular 
contractions. 
b) Supraventricular 
and 
nodal 
arrhythmias 
requiring a pacemaker or 
not 
controlled 
with 
medication. 
c) Conduction abnormality 
requiring a pacemaker. 
d) Other cardiac arrhythmia 
not 
controlled 
with 
medication. 
19. Patients 
have 
any 
other 
concurrent 
severe 
and/or 
uncontrolled 
 medical 
condition that would, in the 
investigator’s 
judgment 
contraindicate 
patient 
participation in the clinical 
study. 
20. Treatment 
with 
strong 
CYP3A inhibitors or strong 
CYP3A inducers within 14 
days or five drug-elimination 
half-lives, 
whichever 
is 
longer, prior to initiation of 
study treatment. 
21. Pregnant, breastfeeding, or 
intending 
to 
become 
pregnant during the study or 
within 28 days after the last 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
33 
 
 
 
 
dose of ipatasertib (GDC- 
0068), three months after the 
last dose of eribulin, and six 
months after the last dose of 
carboplatin and gemcitabine 
or capecitabine, whichever 
occurs later. 
22. Treatment with approved or 
investigational 
cancer 
therapy within 14 days prior to 
initiation of study drug. 
23. Concurrent participation in 
other interventional clinical 
trial. 
Treatment 
After signing ICF and confirmed 
eligibility, 
patients 
will 
be 
assigned to one of the following 
three treatment arms based on 
local investigator assessment and 
slots availability and will be 
enrolled in groups of 3: 
• 
Arm A: Ipatasertib (GDC- 
0068) 400 milligrams (mg) 
tablets administered orally 
once a day (noon) on Days 1- 
14 of each 21-day cycle plus 
capecitabine 
1000 
mg/m2 
tablets orally twice a day 
(morning 
and 
evening; 
equivalent to 2000 mg/m2 
total daily dose), for 14 days 
(followed by a 7-day rest 
period) every 21-day cycle. 
• 
Arm B: Ipatasertib (GDC- 
0068) 
400 
mg 
tablets 
administered orally once a 
day on Days 1-14 of each 21- 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
34 
 
 
 
 
day cycle plus eribulin 1.23 
mg/m2 (equivalent to eribulin 
mesylate 
at 
1.4 
mg/m2) 
administered 
intravenously 
over 2 to 5 minutes on Days 1 
and 8 of every 21-day cycle. 
• 
Arm C: Ipatasertib (GDC- 
0068) 
400 
mg 
tablets 
administered orally once a 
day on Days 1-14 of each 21- 
day cycle plus carboplatin 
AUC5 on Day 1 administered 
intravenously 
plus 
gemcitabine 
1000 
mg/m2 
administered 
intravenously 
over 30 minutes on Days 1 
and 8, every 21-day cycle. 
We 
expected 
to 
recruit 
18 
patients in each arm. However, 
patients could be assigned to one 
of the other open treatments if 
one arm was stopped due to 
feasibility or safety reasons. At 
the end of the study all 54 patients 
will be recruited, unless all arms 
were discontinued. 
Prophylactic 
loperamide 
is 
recommended for all patients 
during at least the first initial cycle 
of 
treatment 
and 
may 
be 
extended to the next cycle if 
necessary. 
A run-in phase for safety and 
tolerability of ipatasertib (GDC- 
0068) 
in 
combination 
with 
capecitabine, 
eribulin, 
or 
carboplatin plus gemcitabine will 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
35 
 
 
 
 
be conducted as an initial step of 
the non-comparative phase IIa 
study where the subjects will be 
assigned in groups of 3. Patients 
will be followed to observe if they 
experience any significant toxicity 
during the two first cycles. 
Patients will receive treatment 
until 
disease 
progression, 
unacceptable toxicity, death, or 
discontinuation from the study 
treatment for any other reason. 
Patients who develop isolated 
progression in the brain can 
continue with study treatment at 
the discretion of the investigator 
as long as that is considered to be 
in the best interest of the patient 
and no new anticancer treatment 
is initiated. 
Patients discontinuing the study 
treatment period will enter a post- 
treatment follow-up period during 
which survival and new anti- 
cancer therapy information will be 
collected every three months (± 
14 days) from the last dose of 
study treatment up to the end of 
study (EoS). 
Efficacy and 
safety 
assessments 
Patient visits: 
 
Visits 
are 
organized 
in 
programmed cycles of 21 days (if 
there are no delays in treatment 
owing to the occurrence of an 
AE). All visits must occur within ± 
2 working days (± 1 working day 
in Day 8 of each cycle) from the 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
36 
 
 
 
 
scheduled date, unless otherwise 
noted 
in 
the 
schedule 
of 
assessments. 
Assessments scheduled for Days 
1 and 8 of each cycle must be 
performed within 48 hours and 24 
hours prior to study treatment 
administration, 
respectively, 
unless otherwise indicated in the 
schedule of assessments, in 
order to confirm to the patient if 
treatment can be followed up. 
 
 
Tumor assessments: 
 
CT of the chest, abdomen, and 
pelvis or MRI of the abdomen and 
pelvis with a non-contrast CT 
scan of the chest, in patients for 
whom CT scans with contrast are 
contraindicated, will be performed 
every six weeks (± 3 days) from 
the first dose of study treatment 
for the first six months and, 
thereafter, every nine weeks (± 7 
days) until the EoS. Imaging 
should continue to be performed 
until 
radiologic 
evidence 
of 
disease progression, treatment 
discontinuation, the start of new 
anti-cancer treatment, withdrawal 
of consent, death, or the end of 
the study, whichever occurs first. 
For estimation of PFS, TTR, 
ORR, DoR, CBR, OS, and best 
percentage of change in target 
tumor lesions, tumor assessment 
will be based on RECIST v.1.1. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
37 
 
 
 
 
Patients 
who 
discontinue 
treatment without evidence of 
disease progression per RECIST 
v.1.1, 
in 
addition 
to 
post- 
treatment 
follow-up, 
will 
be 
followed every nine weeks (± 7 
days) for tumor assessments until 
documented 
progression 
per 
RECIST 
v.1.1, 
elective 
withdrawal from the study, the 
start 
of 
new 
anti-cancer 
treatment, or study completion or 
termination. 
Bone scans are mandatory at 
baseline for all patients and 
thereafter will be repeated every 
24 weeks (± 7 days) only for 
patients 
with 
bone 
lesions 
identified at baseline, unless 
clinically 
or 
biochemically 
suspected bone progression. 
Brain imaging (MRI) during the 
trial should be performed in 
subjects 
with 
known 
brain 
metastases 
prior 
to 
study 
initiation (every six weeks [± 3 
days] for first six months, then 
every nine weeks [± 7 days]), and 
those with worsening and/or new 
neurological symptoms. 
Each 
assessment 
will 
be 
performed 
as 
scheduled 
according 
to 
the 
calendar 
regardless of any dosing delay to 
prevent the introduction of bias 
into the assessment of efficacy. 
Failure to perform any of the 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
38 
 
 
 
 
required disease assessments 
will result in the inability to 
determine disease status for that 
time point. 
 
 
Safety assessments: 
 
The occurrence and maximum 
grade of side effects observed 
throughout the study will be listed 
and tabulated according to type 
and dose level. Any AEs that the 
investigator reports as unrelated 
to the drug will also be reported. 
In this study, side effects will be 
assessed according to the NCI- 
CTCAE v.5.0. 
Translational 
studies 
Tumor samples for molecular 
analysis: 
Patients must agree to provide a 
tumor tissue sample from a 
metastatic site or the primary 
breast tumor at the time of study 
entry, with the exception of 
patients for whom tumor biopsies 
cannot 
be 
obtained 
(e.g., 
inaccessible tumor or subject 
safety concern) that may submit 
an archived metastatic tumor 
specimen only upon agreement 
from the Sponsor. 
If feasible, patients will also be 
given the option of providing a 
tumor tissue sample at disease 
progression from metastasis or 
primary breast tumor. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
39 
 
 
 
 
Blood samples for molecular 
analysis: These samples will be 
collected during the screening 
period, after two cycles of study 
treatment, and upon progression 
or study termination. 
Statistics 
Sample size: A total sample of 54 
evaluable 
taxane-pretreated 
patients (safety run-in + non- 
comparative 
phase) 
with 
unresectable locally advanced or 
metastatic TNBC will be allocated 
based on investigator’s criteria, in 
accordance to previous patient’s 
treatments and slots availability, 
to one of the following treatment 
arms: 
• 
Arm A: Ipatasertib (GDC- 
0068) plus capecitabine. 
• 
Arm B: Ipatasertib (GDC- 
0068) plus eribulin. 
• 
Arm C: Ipatasertib (GDC- 
0068) and carboplatin plus 
gemcitabine. 
We 
expected 
to 
recruit 
18 
patients in each arm. However, 
patients could be assigned to one 
of the other open treatments if 
one arm was stopped due to 
feasibility or safety reasons. At 
the end of the study all 54 patients 
will be recruited, unless all arms 
were discontinued. 
 
 
Justification of sample size: This 
is a pilot study to determine the 
safety and tolerability of three 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
40 
 
 
 
 
different study combinations with 
non-taxane chemotherapy agents 
and ipatasertib (GDC-0068). The 
analysis 
will 
be 
exploratory 
without 
hypothesis 
testing. 
However, 
the 
Sponsor 
has 
estimated the precision for the 
incidence of adverse events rate 
in 
ipatasertib 
combinations. 
Based on LOTUS Clinical Trial, 
the Sponsor assumes a 100% 
incidence of all grades and 50% 
grade≥3 
adverse 
events, 
respectively. 
Study periods 
Study 
follow-up 
period: 
Patients discontinuing the study 
treatment will enter a post- 
treatment follow-up period during 
which survival and new anti- 
cancer therapy information will be 
collected every three months (± 
14 days) from the last dose of 
study treatment up to the EoS. 
EoS: EoS is defined as the last 
patient’s last visit at the end of the 
follow-up period. This will be the 
last data collection point, which 
can be a clinic visit or a laboratory 
sample. EoS will occur at 12 
months after the last patient 
included in the study, unless 
premature termination of the 
study. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
41 
 
 
2 
BACKGROUND AND STUDY RATIONALE 
 
2.1 
Breast Cancer Molecular Subtypes 
 
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer 
death in women (1). Breast cancer alone is expected to account for 30% of all new cancer 
diagnoses in women. According the Kantar Health CancerMPact® database, the prevalence of 
breast cancer range between 41 and 73 per 100,000 population across Europe, and the 
prevalence of metastatic breast cancer is of 8% in United Kingdom and Italy, and 10% in 
Germany, France, and Spain. 
Breast cancer is a heterogeneous disease with multiple clinical presentations and tumor 
characteristics. Gene expression profiling studies have classified breast tumors into a number of 
distinct biological and intrinsic subtypes with prognostic and therapeutic implications, thus 
providing a new molecular classification of breast cancer (2). 
According to this classification, five different molecular subtypes have been identified: luminal A, 
luminal B, Human Epidermal Growth Factor Receptor 2 (HER2)-enriched, normal breast-like, and 
basal-like (BL). In contrast to BL tumors, which do not express estrogen receptor (ER), 
progesterone receptor (PgR), and ER-related genes, luminal tumors express luminal cytokeratins 
and have the highest levels of ER expression. On the other hand, HER2-enriched tumors 
overexpress HER2-associated genes but do not express genes that define the luminal subtype 
(3). BL and HER2-enriched breast cancers have poor outcomes, and among ER-positive 
subtypes, luminal B tumors have a significantly worse prognosis than luminal A (4). 
This understanding of the molecular biology of breast cancer have increased the treatment 
options of this complex disease, resulting in significant improvements in patient outcomes and a 
more personalized therapy. For this reason, it is very important for physicians to distinguish 
between these molecular subtypes in the clinical practice. Although the best way to perform breast 
tumor intrinsic subtyping is to use microarrays for gene expression analysis, molecular profiling 
is not ready for use in clinical decision making. Therefore, a combination of immunohistochemical 
surrogate markers, using ER and PgR status, HER2 status, histological grade, and Ki67 levels, 
has been validated for molecular subtyping (4,5). 
 
 
 
2.2 
Triple-Negative Breast Cancer (TNBC) 
 
TNBC accounts for approximately 10%–15% of all diagnosed breast cancers. The majority of 
these tumors do not usually express hormone receptors (ER and PgR) and HER2, and this is why 
they are also known as TNBC. However, while most BL tumors are triple-negative and most 
TNBCs are BL, not all TNBCs are BL and not all BL tumors are triple-negative (6). 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
42 
 
 
TNBC has a worse prognosis than other tumor subtypes. This may result from its aggressive 
tumor biology, or rather it may be because this tumor subtype does not respond to either hormonal 
or anti-HER2 therapy. In consequence, these tumors are more likely to have high histological 
grade and usually present a peak risk of recurrence during the first three years, with a rapid 
progression from distant recurrence to death, and with the majority of deaths occurring within the 
first five years after diagnosis (7). 
TNBC shows an exceptional chemosensitivity. It has been demonstrated that patients with TNBC 
have increased rates of pathological complete response (pCR) after neoadjuvant systemic 
therapy compared to luminal tumors, and those patients who achieved pCR, have an excellent 
survival. However, patients with residual disease after neoadjuvant systemic therapy have a 
worse prognosis (8). This different chemosensitivity reflects a clear heterogeneity within this tumor 
subtype. Regarding this issue, a new intrinsic subtype has been recently recognized (9). The 
tumors in this subtype, referred to as claudin-low, tend to be TNBC but are enriched with markers 
linked to epithelial-to-mesenchymal transition and stem cell function, and therefore show a lower 
rate of pCR after neoadjuvant chemotherapy compared to BL tumors (10). 
In an attempt to better identify BL tumors in the daily practice, an expanded surrogate 
immunopanel of ER, PgR, HER2, Epidermal Growth Factor Receptor (EGFR), and CK5/6 has 
been proposed (11). Among triple-negative patients, the additional expression of EGFR and/or 
CK5/6 may identify a subgroup of patients with significantly worse outcome, providing a more 
specific definition of BL breast cancer. 
 
 
 
2.3 
TNBC Subtypes 
 
Molecular profiling using cluster analysis from 21 breast cancer data sets identified six different 
TNBC subtypes characterized by unique gene expression profile and ontologies, including two 
BL (BL1 and BL2), mesenchymal, mesenchymal stem-like (MSL), immunomodulatory, and 
luminal androgen receptor (LAR)-enriched tumors (12). The BL subtypes represented BL-breast 
cancer (BLBC)-like phenotypes, with expression of genes involved in cell cycle and 
deoxyribonucleic acid (DNA) damage repair in the BL1 subtype, and growth factor signaling 
pathways in the BL2 subtype. The two mesenchymal-related subtypes were closely associated 
with epithelial-mesenchymal transition and relative chemo-resistance. Immune-related signatures 
were abundantly found in the immunomodulatory subtype, whereas the LAR subtype highly 
expressed androgen receptor and a luminal-like gene expression signature. 
Interestingly, a correlative analysis comparing Lehmann’s classifications and the PAM50 
subtypes classified the majority of TNBC subtypes as BLBC, MSL, and LAR (13). Furthermore, 
previous sub-classification of TNBC have been revised to a more concise system and consisting 
of only four subtypes: BL1, BL2, mesenchymal, and LAR (14). 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
43 
 
 
On the other hand, a new classification was recently proposed based on the hypothesis of a 
possible 
intersection 
between 
immunological 
and 
metabolic 
signatures 
in 
tumor 
microenvironment. Adams and colleagues suggested a subtype with enriched tumor-infiltrating 
lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression and activated glycolytic 
pathways, that have prognostic significance and implications for therapies targeting immune 
checkpoints and tumor metabolism (15). 
However, apart from few retrospective studies suggesting the potential predictive role of certain 
molecular subtypes in patients treated with neoadjuvant chemotherapy (14,16), it still remains 
unclear whether the molecular classification itself could be a firm predictive biomarker for patients 
with TNBC. 
 
 
 
2.4 
Current Treatment Options in Metastatic TNBC 
 
Compared with luminal breast cancers, TNBC is associated with an aggressive natural history 
and poor clinical outcomes. In a retrospective analysis, TNBC compared with other women 
with breast cancer had an increased likelihood of distant recurrence (hazard ratio [HR] 2.6; 95% 
confidence interval [CI] 2.0-3.5; p<0.0001) and death (HR 3.2; 95% CI 2.3-4.5; p<0.001) within 
five years of diagnosis (7). 
Chemotherapy remains the mainstay of treatment for TNBC with disappointing results because 
despite the high sensitivity of early-stage TNBC to cytotoxic agents, this treatment is associated 
in the metastatic setting with relatively low rates of antitumor response ranging from 10% to 30% 
along with a short median progression-free survival (PFS) that range from around six months in 
the first-line setting to approximately three months in refractory patients (17–19). 
Thus, numerous efforts are currently being undertaken to develop more effective therapeutic 
strategies in order to improve the overall outcome of TNBC patients, and new advances in the 
knowledge of molecular biology of TNBC are increasing the treatment options of this complex 
disease. 
 
 
 
2.4.1 
Antiangiogenics 
 
Angiogenesis plays an important role in cancer progression. Development of new vessels is 
decisive for the growth and spread of tumor cells, because malignant tumors are unable to grow 
beyond a few millimeters without new vasculature (20). In breast cancer, several studies have 
found an inverse correlation between overall survival (OS) and Vascular-Endothelial Growth 
Factor (VEGF) expression (21,22). Linderholm and colleagues analyzed the relationship between 
intratumoral VEGF levels and OS in patients with TNBC and non-TNBC. Compared with non- 
TNBC, patients with TNBC had significantly higher VEGF levels and worse survival (23). In 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
44 
 
 
addition, increased VEGF expression predicts poor response to systemic therapy with tamoxifen 
and chemotherapy (24). For these reasons, a large number of antiangiogenic agents are being 
tested in patients with breast cancer, and more specifically in TNBC. 
Bevacizumab is a humanized monoclonal antibody that can recognize all known isoforms of 
VEGF-A and prevents receptor binding, thereby inhibiting angiogenesis and tumor growth. The 
most common side effects of this agent include hypertension, proteinuria, and headache. As a 
single-agent, bevacizumab has shown modest activity in patients with metastatic breast cancer. 
However, better results have been reported in combination with chemotherapy. To date, five 
phase III clinical trials have evaluated the addition of bevacizumab to chemotherapy in the first- 
and second-line treatment of patients with metastatic breast cancer. In the first-line setting, three 
studies have been performed: Eastern European Cooperative Oncology Group (ECOG) 2100 
(25); AVADO (26); and RIBBON 1 (27). In the second-line setting, the results of two studies have 
been reported: AVF2119g (28) and RIBBON 2 (29,30). PFS was the primary objective of all these 
studies. 
A meta-analysis from three randomized trials of bevacizumab and first-line chemotherapy showed 
that the addition of bevacizumab resulted in statistically significant improvements in PFS, the 
primary endpoint of these studies, and objective response rate (ORR). Subgroup analysis 
demonstrated that TNBC patients achieved a similar benefit from bevacizumab as did non-TNBC 
patients (HR for PFS: TNBC 0.63; non-TNBC 0.64) (31). In the second-line setting, subgroup 
analysis from RIBBON2 trial revealed that the benefit of the combination seems to be greater in 
patients with TNBC compared to hormone receptor-positive tumors (HR for PFS: TNBC 0.53; 
non-TNBC 0.89) (32). 
Finally, the IMELDA randomized phase III study included 284 patients with HER2-negative 
metastatic breast cancer that had received bevacizumab plus docetaxel as first-line therapy (33). 
A total of 185 patients with complete response (CR) or partial response (PR), or stable disease 
(SD), were randomized to receive bevacizumab with or without capecitabine as maintenance 
therapy. The primary endpoint was PFS (from randomization) in the intention-to-treat population. 
The rationale of this study was based on the cumulative toxic effects of prolonged exposure to 
taxane-based chemotherapy and the association of longer first-line chemotherapy duration with 
better OS and PFS. Despite prematurely terminated accrual, sequential maintenance treatment 
with capecitabine plus bevacizumab showed significantly longer median PFS (11.9 vs. 4.3 
months, HR 0.38, 95% CI 0.27-0.55, p<0.0001) and median OS (39.0 vs. 23.7 months, HR 0.43, 
95% CI 0.26-0.69, p=0.0003) than monotherapy with bevacizumab while maintaining the quality 
of life. In a subgroup analysis, the combination of bevacizumab and capecitabine specially favored 
those patients with visceral metastases or with three or more metastatic organ sites. The benefit 
of adding capecitabine was irrespective of hormone receptor status. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
45 
 
 
The IMELDA strategy combines the efficacy of bevacizumab and the benefit of maintenance 
chemotherapy and represents an excellent therapeutic option for the first-line treatment of 
patients with metastatic TNBC. 
 
 
 
2.4.2 
Poly(ADP-Ribose)Polymerase (PARP) Inhibitors 
 
Immunohistochemical profile of BL tumors is similar to those tumors arising in Breast Cancer 1 
(BRCA1) mutation carriers, and subsequently the majority of these inherited tumors have a BL 
phenotype. Likewise, dysfunction of the BRCA1 pathway caused by BRCA1 gene promoter 
methylation is also a frequent event in sporadic BL tumors. 
 
PARP1 and PARP2 play a fundamental role in repairing single-strand breaks through the base 
excision repair mechanism. However, in carriers of germline BRCA mutations, the simultaneous 
inhibition of a compensatory repair mechanism PARP-dependent will induce cell death either 
through mitotic catastrophe or apoptosis (synthetic lethality). 
 
There are a number of PARP inhibitors under clinical evaluation. Talazoparib inhibits PARP with 
an efficacy comparable to olaparib and rucaparib but is approximately 100-fold more potent in 
trapping PARP-DNA complexes leading to a higher cytotoxicity. 
 
The randomized phase III OlympiAD trial provided a significant benefit of olaparib over single- 
agent standard therapy (capecitabine, vinorelbine, or eribulin). A total of 302 patients with HER2- 
negative metastatic breast cancer and a germline BRCA mutation were included. Median PFS, 
the primary endpoint of the study, was longer in the olaparib group than in the standard-therapy 
group (7.0 vs. 4.2 months; HR 0.58; 95% CI 0.43-0.80; p<0.001) (34). 
 
Efficacy of talazoparib was also confirmed in the randomized phase III EMBRACA trial. In this 
study, talazoparib was compared with standard single-agent therapy of the physician’s choice 
(capecitabine, eribulin, gemcitabine, or vinorelbine) in 431 patients with HER2-negative 
metastatic breast cancer and a germline BRCA mutation. Median PFS, the primary endpoint of 
the study, was longer in the talazoparib group than in the standard-therapy group (8.6 vs. 5.6 
months; HR 0.54; 95% CI 0.41-0.71; p<0.001). Furthermore, significant overall improvement in 
quality of life was observed in talazoparib (35). 
 
Based on these results, PARP inhibitors represent a new effective option for women with BRCA- 
mutated, HER2-negative metastatic breast cancer. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
46 
 
 
2.4.3 
Immunotherapy 
 
Multiple lines of preclinical and clinical evidence have demonstrated that tumors can evade 
destruction by the immune system by expressing surface ligands that engage inhibitory receptors 
on tumor-specific T cells and induce immune tolerance. Immune-related signatures have been 
abundantly found within TNBC, more specifically in the immunomodulatory subtype. 
Early results of immunotherapy with immune checkpoint inhibitors in patients with metastatic 
TNBC have demonstrated encouraging activity with durable responses and substantial OS in pre- 
treated patients. Unfortunately, there is a relatively small subset of patients that derive a benefit 
from single-agent treatment. However, the increasing evidence in other cancers that combination 
with chemotherapy could improve the anti-tumor activity of PD-L1-targeted therapy led to the 
evaluation of the combination of chemotherapy and immunotherapy in patients with metastatic 
TNBC with striking results. 
The recently completed randomized phase III IMpassion130 trial enrolled a total of 902 patients 
with untreated metastatic TNBC who were randomized to nab-paclitaxel plus atezolizumab or 
nab-paclitaxel plus placebo (36). Stratification factors were the use of (neo)adjuvant taxane 
therapy (yes vs. no), the presence or absence of liver metastases at baseline, and PD-L1 
expression at baseline (positive vs. negative). 
The two primary endpoints of the study were PFS, in the intention-to-treat (ITT) population and 
PD-L1–positive subgroup, and OS (tested in the ITT population; if the finding was significant, then 
it would be tested in the PD-L1–positive subgroup). 
The addition of atezolizumab significantly increased median PFS in the ITT analysis (7.2 vs. 5.5 
months; HR 0.80; 95% CI 0.69-0.92; p=0.002) and among patients with PD-L1–positive tumors 
(7.5 vs. 5.0 months, HR 0.62; 95% CI 0.49-0.78; p<0.001). 
In the ITT analysis, median OS was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 
months with placebo plus nab-paclitaxel (HR 0.84; 95% CI 0.69-1.02; p=0.08); among patients 
with PD-L1–positive tumors, median OS was 25.0 months and 15.5 months, respectively (HR 
0.62; 95% CI 0.45-0.86). 
This study will probably change the treatment landscape of metastatic TNBC patients, and this 
combination should become a new treatment option in the first-line setting for patients with PD- 
L1 positive metastatic TNBC. 
 
 
 
2.4.4 
Antibody Drug Conjugates 
 
Integrating the tumor specificity provided by unique monoclonal antibodies and cytotoxicity of 
small molecule drugs, antibody-drug conjugates are a series of smart chemotherapeutics that 
have recently shown great promise in treating a number of cancer types. Antibody drug 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
47 
 
 
conjugates are designed to selectively attack and kill cancer cells with minimal toxicity to normal 
tissues. 
New antibody-drug conjugates such as sacituzumab govitecan (IMMU-132), glematumumab 
vedotin, and SGN-LIV1A have demonstrated important antitumor activity in metastatic TNBC and 
are currently evaluated in this population. Sacituzumab govitecan (IMMU-132) is being already 
assessed into a phase III trial for patients with heavily-pretreated metastatic TNBC 
(NCT02574455), considering the promising results of this agent in a single-arm phase II study 
(37). 
Sacituzumab govitecan (IMMU-132) is an antibody drug conjugate that binds to Trop-2 for 
targeted delivery of SN-38 (active metabolite of irinotecan) directly to the tumor cell while 
minimizing systemic exposure of SN-38 to decrease host toxicity. Trop-2 antigen is highly 
expressed in TNBC. For this reason, this drug was evaluated as a third-line and beyond therapy 
option in a single-arm phase II study of 110 patients with metastatic TNBC, demonstrating a 
significant clinical activity as a single-agent in this population (38). ORR was 34% with a median 
duration of response (DoR) of 7.6 months (95% CI 4.8-11.3) and a clinical benefit rate (CBR) of 
46%. Median PFS was 5.5 months (95% CI 4.8-6.6) and median OS was 12.7 months (95% CI 
10.8-13.6). IMMU-132 showed an acceptable toxicity profile with nausea, alopecia, neutropenia, 
and diarrhea being the most common and relevant toxicities. 
 
 
 
2.4.5 
Antiandrogens 
 
LAR subtype is characterized by androgen receptor signaling with a gene expression pattern 
similar to luminal breast cancer. Patients with LAR tumors are more slowly growing when 
metastatic, however they have decreased relapse-free survival in the adjuvant setting relative to 
other TNBC subtypes, perhaps due to lower chemotherapy sensitivity. LAR cell line models are 
sensitive to the androgen receptor partial antagonist bicalutamide and are even more sensitive to 
the next-generation androgen receptor inhibitor enzalutamide. 
AR is expressed in 12–55% of cases of TNBC, because although the LAR subtype is enriched 
for expression of the androgen receptor an its gene targets, other TNBC subtypes also express 
androgen receptor. However, some of the variability in frequency of expression between studies 
is due to diverse immunohistochemistry (IHC) assays used and to different assay cutoffs 
(1 vs. 10%). Optimal IHC assay and cutoff for response to androgen receptor inhibitors in clinic 
remains unknown (39). 
Early results from two clinical phase II studies with single-agent anti-androgens have confirmed 
a promising antitumor activity in patients with metastatic TNBC. First, the efficacy of bicalutamide 
was assessed in 26 patients with metastatic androgen receptor-positive (immunohistochemistry 
[IHC] ≥ 10%) TNBC demonstrated a CBR at 24 weeks of 19% with a median PFS of 12 weeks 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
48 
 
 
(95% CI 11-22) (40). More recently, enzalutamide has been also evaluated in 118 metastatic 
TNBC patients with ≥ 1% of androgen receptor assessed by IHC (41). In this study, CBR at 16 
and 24 weeks were 25% and 20%, respectively. In patients with ≥ 10% of androgen receptor 
expression (N = 75), CBR at 16 and 24 weeks were 35% and 29%, respectively, with 8% of 
patients achieving a CR or PR. Median PFS was 14.7 weeks (95% CI 8.1-19.3). Interestingly, a 
proprietary androgen-driven gene signature called PREDICT AR was created from gene 
expression profiling, and patients whose tumors were positive for this signature had increased 
PFS compared to those without an androgen-driven gene signature (32 vs. 9 weeks) (42). 
 
 
2.5 
Relevance of the PI3K-AKT-mTOR signaling pathway 
 
The serine/threonine kinase B (AKT) is encoded by three closely related genes in mammals, 
AKT1, AKT2, and AKT3. AKT is the central node of the phosphoinositide 3-kinase (PI3K)-AKT- 
mammalian target of rapamycin (mTOR) pathway, in which activation is associated with 
proliferation, cell cycle progression, and survival. The direct product of PI3K activity, the lipid 
second messenger, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), promotes membrane 
association of AKT. AKT is phosphorylated at two critical residues for its full activation: a threonine 
residue in the activation loop of the kinase domain (threonine 308 in AKT1) by phosphoinositide- 
dependent kinase 1 (PDK1) and a serine residue within the hydrophobic motif of the regulatory 
domain (serine 473 in AKT1) by mTOR Complex 2 (mTORC2) (43). In turn, activated AKT 
phosphorylates and regulates the functions of numerous cellular proteins, including FOXO, 
mTORC1, and S6 kinase (44). 
Negative regulation of the PI3K-AKT-mTOR pathway occurs through several mechanisms, and 
at the level of AKT, phospholipid phosphates and protein phosphatases are central regulators. 
The tumor suppressor phosphatase and tensin homolog (PTEN), a phospholipid phosphatase, 
dephosphorylates PIP3, limiting AKT translocation and activation at the cell membrane. 
Additionally, protein phosphates, including protein phosphatase 2A and PH domain and leucine- 
rich repeat protein phosphatases, dephosphorylate the serine and threonine residues that are 
required for the kinase activity of AKT. 
The PI3K-AKT-mTOR pathway is activated by numerous genetic and non-genetic mechanisms 
across the spectrum of cancer (45). The most commonly found alterations in this pathway result 
from decreased expression or inactivating mutations of PTEN, activating mutations of p110α 
catalytic subunit of PI3K (PIK3CA), deregulation of receptor tyrosine kinase signaling, and 
amplification or activating mutations of receptor tyrosine kinases. In addition, alterations in AKT 
itself, including amplification and overexpression of individual AKT isoforms, as well as activating 
mutations in AKT, most commonly an E17K mutation in the PH domain of AKT1 that results in 
PI3K-independent membrane recruitment of AKT1, have been identified in a subset of human 
cancers (46,47). 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
49 
 
 
Hyperactivation of AKT also occurs via deregulated signaling of many cell surface receptors and 
intracellular linkers and signaling molecules, and amplification/mutation of the EGFR/ErbB growth 
factor receptor family members (47). Moreover, AKT activation has been associated with 
resistance to both chemotherapeutic agents and targeted agents such as trastuzumab and 
tamoxifen (48,49). 
Besides being an important driver of cell proliferation, growth, and survival, all of which are 
involved in tumorigenesis, AKT also plays a key role in glucose homeostasis and mediates the 
metabolic effects of insulin downstream of the insulin receptor (a receptor tyrosine kinase) (50,51). 
In summary, AKT is a central node in cell signaling downstream of growth factors, cytokines, and 
other cellular stimuli. It plays an important role in cancer development, progression, and 
therapeutic resistance and is activated in most, if not all, human cancers (52). The ubiquity and 
importance of AKT activation in human cancers provide a strong rationale for developing 
therapeutics targeting AKT. 
 
 
 
2.6 
PI3K/AKT Pathway in Breast Cancer 
 
In breast cancer, the PI3K-AKT-mTOR pathway is more frequently activated by genomic 
aberrations than any other signaling pathway (45). The most common genetic alterations in this 
pathway are activating mutations of PIK3CA, loss-of-function alterations of the tumor suppressor 
PTEN, deregulation of receptor tyrosine kinase signaling, and amplification and mutations of 
receptor tyrosine kinases (53,54). Alterations in AKT itself, including amplification and 
overexpression of individual AKT isoforms, as well as activating mutations in AKT, have been 
identified in a subset of human cancers (46–48). All of these mechanisms of pathway activation 
ultimately funnel through AKT as the central node that drives cell survival, growth, proliferation, 
angiogenesis, metabolism, and migration (44). 
Large-scale comprehensive genomic analyses have characterized the heterogeneous nature of 
TNBC, including a subgroup with a PI3K/AKT pathway activation signature characterized by 
PIK3CA or AKT1 activating mutations and PTEN alterations (53). Overall, PIK3CA/AKT1/PTEN- 
altered tumors are frequently observed in breast cancer and are reported in approximately 35% 
of patients with TNBC and in approximately 50% of luminal breast cancers (53). 
To date, the relationship between PI3K/AKT pathway activation and prognosis in breast cancer 
is mixed, with some data demonstrating association with favorable outcomes, some data with 
poor prognosis, and a number of studies showing insignificant results (55). Information 
demonstrating significant differences in the prevalence of these gene alterations between primary 
and metastatic tumor tissues is limited, while enrichment in metastatic patients is probable (54). 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
50 
 
 
2.7 
Ipatasertib (GDC-0068) 
 
Ipatasertib (GDC-0068) is a potent and selective small-molecule inhibitor of all three isoforms of 
the serine/threonine kinase AKT. Ipatasertib (GDC-0068) selectively binds to the active 
conformation of AKT and inhibits its kinase activity (56). Consistent with its mechanism of action 
in nonclinical studies, ipatasertib (GDC-0068) has proven to be especially effective on cells with 
activated AKT, including PTEN-null and PI3K-mutated tumor models, leading to suppression of 
the phosphorylation of its direct substrates. Consistent with the role of AKT in insulin signaling, 
ipatasertib (GDC-0068) also exhibited dose-dependent and reversible elevation of serum glucose 
in nonclinical studies. In vivo activity studies support the use of ipatasertib (GDC-0068) as a 
single-agent or in combination with chemotherapeutic, hormonal, or targeted agents for the 
treatment of patients with advanced or metastatic solid tumors (57). 
 
 
 
2.7.1 
Overview of Clinical Development 
 
Ipatasertib (GDC-0068) is being developed by Genentech/Roche as a single-agent and in 
combination with other therapies for the treatment of cancers in which activation of the PI3K-AKT- 
mTOR pathway may be relevant for tumor growth or therapeutic resistance. 
As of 30 June 2018, the first-in-human phase I dose-escalation study in patients with advanced 
solid tumors has been completed and it determined the safety profile and the maximum tolerated 
dose (MTD) for single-agent ipatasertib (GDC-0068). Interim analysis has been completed for the 
Phase Ib dose-escalation Study PAM4983g (NCT01362374) in patients with advanced solid 
tumors. This study determined the safety profile, pharmacokinetic (PK) interactions of ipatasertib 
(GDC-0068) in combination with other anticancer agents, and the recommended phase II dose 
(RP2D) for ipatasertib (GDC-0068) in each combination. 
Primary analyses have been also completed for two randomized phase II studies to evaluate the 
safety and efficacy of ipatasertib (GDC-0068) in combination with paclitaxel in patients with locally 
advanced or metastatic TNBC (Study GO29227; NCT02162719) and in patients with early TNBC 
(Study GO29505; NCT02301988). 
Additional phase Ib and phase III trials have been initiated in patients with breast cancer (Studies 
CO40115; NCT03424005), (CO40016; NCT03337724), (CO39611; NCT03280563), and 
(CO40151; NCT03800836) and enrollment is ongoing. 
 
Further clinical development of ipatasertib (GDC-0068) will be based on identifying tolerable 
dosing regimens that provide adequate exposure as well as evidence of pharmacodynamic and/or 
clinical activity, either as a single-agent or in combination with other anticancer therapies. In 
addition, the predictive effect of biomarkers will be further evaluated in future studies in prostate 
cancer, breast cancer, and other malignancies with high prevalence of PI3K-AKT pathway 
alteration. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
51 
 
 
 
 
2.7.2 
Clinical Efficacy 
 
2.7.2.1 
Single-Agent Ipatasertib (GDC-0068) 
 
• 
Study PAM4743g 
 
In the phase I clinical study of ipatasertib (GDC-0068), Study PAM4743g (NCT01362374) anti- 
tumor activity in patients was evaluated by radiographic responses using RECIST v.1.0 
guidelines. Exploratory FDG-PET assessments were also evaluated in a cohort of patients with 
breast cancer with PI3K-AKT-mTOR pathway-activated tumors (58). 
As of 2 February 2015, a total of 30 patients were enrolled in Stage 1 (dose-escalation phase); 
16 and six patients were enrolled in Stage 2 and 3 (expansion phases), respectively. Post- 
treatment tumor assessment data are available for 47 of the 52 enrolled patients. 
Overall, for the 47 patients for whom response data were available across all doses of the phase 
I study, 16 patients (34.0%) achieved SD or incomplete response as a best response per RECIST 
v.1.0 as assessed by the investigators, including 11 of 25 patients (44.0%) treated at the 
maximum tolerated dose (MTD) of 600 milligrams (mg) daily. PFS greater than six months was 
observed in six patients with breast (N = 2), chondrosarcoma (N = 1), colorectal (N = 1), lung (N 
= 1), and prostate cancer (N = 1). No PR or CR were observed. 
 
In Stage 2 of this phase I study, patients with metastatic castration resistant prostate cancer 
(mCRPC) (N = 5) or diagnostic positive (tumors with activated PI3K-AKT pathway) breast cancers 
(N = 10) were enrolled and received ipatasertib (GDC-0068) at the 600 mg dose. Twelve patients 
(eight with breast cancer and four with mCRPC) had tumor assessments: five of the eight patients 
(62.5%) with breast cancer, and three of the four patients (75%) with mCRPC achieved SD or 
incomplete response as assessed by the investigator. 
Of the 47 patients for whom post-treatment tumor assessment was available, 41 patients had 
known tumor molecular status of archival tumor tissues; radiographic SD as best response was 
observed in six of the nine patients (67%) who had complete loss of PTEN expression, PIK3CA, 
or AKT1 mutations in their tumor, whereas three patients (33%) had progressive disease (PD) as 
best response. For patients without alterations, 10 of the 32 patients (31%) had SD, and 22 (69%) 
had PD as best response. 
Radiographic SD was not observed in patients who had known KRAS mutations (G12V/D/A or 
Q61L, N = 7). 
 
 
 
2.7.2.2 
Ipatasertib (GDC-0068) In Combination with Other Anticancer Agents 
 
• 
Study PAM4983g 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
52 
 
 
Preliminary efficacy data (as of interim analysis cutoff date 02 May 2016) are available from the 
ongoing Phase Ib Study PAM4983g with ipatasertib (GDC-0068) combined with docetaxel in Arm 
A, mFOLFOX6 in Arm B, paclitaxel in Arm C, or enzalutamide in Arm D (58). 
Across all treatment arms, eight of 101 efficacy-evaluable patients (8%) had a confirmed PR to 
study treatment (e.g., two confirmed PR in each arm) including the following: two patients in Arm 
A (7%) with TNBC (N = 1) and esophageal cancer (N = 1); two patients in Arm B (6%) with 
colorectal cancer (CRC) (N = 1) and esophageal cancer (N = 1); two patients in Arm C (7%) with 
luminal breast cancer (N = 2); and two patients in Arm D (11.8% of patients with measurable 
disease) with mCRPC (N = 2). Of the eight patients who had confirmed PRs, six patients remained 
progression-free for more than six months, including patients who had prior exposure to the same 
chemotherapy or abiraterone/enzalutamide treatment or investigational PI3Kalpha inhibitors. 
In patients who had measurable disease and known molecular status of archival tumor tissues in 
Arms A, B, C, and D, confirmed response rates by RECIST v.1.1 are summarized by 
PIK3CA/AKT1 mutation status (Table 1). Four of 14 patients (28.6%) with known PIK3CA/AKT1 
activating mutation in their tumor archival tissues had a PR, versus two of 46 patients (4.3%) with 
no detectable PIK3CA/AKT1 mutations. 
 
 
Table 1. RECIST Response Outcomes for Patients with Baseline Measurable Disease by 
Mutation Status. 
 
 
Arm A 
(N = 26 TNBC 
patients) 
Arm B 
(N = 33 
CRC/Esophageal 
patients) 
Arm C 
(N = 25 
ER+/HER2- 
patients) 
Arm D 
(N = 17 mCRPC 
patients) 
AKT1/PIK3CA Activating Mutation 
Best Response  
 
 
 
CR 
0 
0 
0 
0 
PR 
1 (3.8%) 
1 (3.0%) 
2 (8.0%) 
0 
SD 
1 (3.8%) 
3 (9.1%) 
4 (16%) 
0 
PD 
1 (3.8%) 
0 
0 
0 
Not evaluated 
1 (3.8%) 
0 
0 
0 
AKT1/PIK3CA Non-Altered 
CR 
0 
0 
0 
0 
PR 
1 (3.8%) 
1 (3.0%) 
0 
0 
SD 
9 (34.6%) 
10 (30.3%) 
5 (20%) 
0 
PD 
3 (11.5%) 
7 (21.2%) 
2 (8.0% 
0 
Not evaluated 
1 (3.8%) 
3 (9.1%) 
3 (12%) 
1 (5.9%) 
AKT1/PIK3CA Unknown 
CR 
0 
0 
0 
0 
PR 
0 
0 
0 
2 (11.8%) 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
53 
 
 
 
 
Arm A 
(N = 26 TNBC 
patients) 
Arm B 
(N = 33 
CRC/Esophageal 
patients) 
Arm C 
(N = 25 
ER+/HER2- 
patients) 
Arm D 
(N = 17 mCRPC 
patients) 
SD 
4 (15.4%) 
4 (12.1%) 
5 (20%) 
4 (23.5%) 
PD 
3 (11.5%) 
3 (9.1%) 
4 (16%) 
7 (41.2%) 
Not evaluated 
1 (3.8%) 
1 (3%) 
0 
3 (17.6%) 
 
CR=complete response; CRC=colorectal cancer; ER=estrogen receptor; HER2=human 
epidermal growth factor receptor 2; mCRPC= metastatic castration resistant prostate cancer; 
PD=progressive disease; PR=partial response; SD=stable disease; TNBC=triple-negative 
breast cancer. 
Note: Cutoff date 02 May 2016. 
Note that N indicates the number of efficacy-evaluable patients. 
 
 
A total of 16 patients remained progression-free for more than six months. Three of these patients 
(11% of Arm A) with tumor types of cervix (N = 1) and lung (N = 2) were administered docetaxel 
and ipatasertib (GDC-0068). Six of these patients (18% of Arm B) with tumor types of appendiceal 
(N = 1), CRC (N = 3), esophageal (N = 1), and sexual cordons (N = 1) were administered 
mFOLFOX6 and ipatasertib (GDC-0068). Three of these patients (11% of Arm C) with breast 
cancer (luminal [N= 2], TNBC [N = 1]) were administered paclitaxel and ipatasertib (GDC-0068). 
And four of these patients (12% of Arm D) with prostate cancer were administered enzalutamide 
and ipatasertib (GDC-0068). 
 
 
• 
Study GO29227 (LOTUS) 
 
This randomized phase II trial investigated the addition of ipatasertib (GDC-0068) to paclitaxel as 
first-line therapy for inoperable, locally advanced, or metastatic TNBC not amenable to curative 
treatment (59). 
 
A total of 124 patients were randomized (ratio 1:1) to receive weekly paclitaxel (80 mg/m2 Days 
1, 8, and 15 of a 28-day cycle) with either ipatasertib (GDC-0068) (400 mg Days 1–21 of a 28- 
day cycle) or placebo. The co-primary endpoints were PFS in ITT population and PFS in the 
PTEN-low (assessed by a Ventana IHC assay) population. The OS in ITT, PTEN-low and 
PIK3CA/AKT1/PTEN-altered populations was a prespecified secondary endpoint. 
 
With a median follow-up of 10.4 and 10.2 months in each arm, the addition of ipatasertib (GDC- 
0068) significantly prolonged median PFS in the ITT population (6.2 versus 4.9 months, HR 0.60, 
95% CI 0.37-0.98; p=0.037), but not in the PTEN-low population (38.7%) (6.2 versus 3.7 months, 
HR 0.59, 95% CI 0.26-0.132; p=0.18) (See Table 2). In the PIK3CA/AKT/PTEN-altered tumor 
population (as assessed by a FoundationOne assay) (33.8%), the addition of ipatasertib (GDC- 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
54 
 
 
0068) achieved a more pronounced effect (9.0 versus 4.9 months, HR 0.44, 95% CI 0.22-0.87; 
p=0.037). 
 
Final analysis of the LOTUS trial has shown numerically longer overall survival with ipatasertib 
plus paclitaxel vs placebo plus paclitaxel in the ITT population (25.8 months vs 16.9 months, HR 
0.81; 95% CI 0.53-1.23).Similarly, median OS favoured ipatasertib plus paclitaxel vs placebo plus 
paclitaxel in the PTEN-low (23.1 vs 15.8 months) and PIK3CA/AKT1/PTEN-altered (25.8 vs 22.1 
months) subgroups. 
 
Table 2. Overview of PFS Results in Study GO29227. 
 
 
Ipatasertib (GDC-0068) 
plus Paclitaxel 
Placebo plus paclitaxel 
ITT Population 
Number of patients in 
population 
62 
62 
Number of patients with 
event (%) 
39 (62.9%) 
45 (72.6%) 
Median duration (months) 
(90% CI) 
6.18 (4.57, 7.33) 
4.93 (3.58, 5.36) 
Unstratified HR (90% CI) 
0.62 (0.43, 0.89) 
Unstratified p-value (Log- 
Rank test) 
0.0266 
Stratified HR (90% CI) (per 
protocol) 
0.60 (0.40, 0.91) 
Stratified p-value (Log-Rank 
test) (per protocol) 
0.0372 
Patients with PIK3CA/AKT1/PTEN-altered tumors (determined by FoundationOne NGS 
assay) 
Number of patients in 
subpopulation 
26 
16 
Number of patients with 
event (% 
12 (46.2%) 
13 (81.3%) 
Median duration (months) 
(90% CI) 
9.03 (4.57, 12.88) 
4.93 (3.58, 5.39) 
Unstratified HR (90% CI) 
0.44 (0.22, 0.87) 
Patients with PIK3CA/AKT1/PTEN non-altered tumors (determined by FoundationOne 
NGS assay) 
Number of patients in 
subpopulation 
28 
33 
Number of patients with 
event (%) 
21 (75.0%) 
23 (69.7%) 
Median duration (months) 
(90% CI) 
5.32 (3.61, 6.67) 
3.65 (2.86, 5.52) 
Unstratified HR (90% CI) 
0.76 (0.46, 1.27) 
 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
55 
 
 
 
 
 
• 
Study GO29505 (FAIRLANE) 
 
This randomized phase II trial investigated the addition of ipatasertib (GDC-0068) to paclitaxel as 
neoadjuvant therapy for patients with early-stage TNBC (59). 
A total of 151 patients were randomized (ratio 1:1) to receive ipatasertib (GDC-0068) (400 mg 
Days 1–21 of a 28-day cycle) (76 patients) or placebo (75 patients) in combination with paclitaxel 
(80 mg/m2 days 1, 8, 15, and 22 of a 28-day cycle). A pCR was reported in a higher proportion of 
patients in the ipatasertib (GDC-0068) plus paclitaxel arm (17.1%) than in the placebo plus 
paclitaxel arm (13.3%). The ORR was consistent with other endpoints in a given population of 
patients with PTEN-low and PIK3CA/AKT1/PTEN-altered tumors. In patients with PTEN-low 
tumors, a 3.3% difference in pCR rate was observed between the ipatasertib (GDC-0068) plus 
paclitaxel arm (15.8%) and the placebo plus paclitaxel arm (12.5%) (61). 
 
 
 
2.7.3 
Clinical Safety 
 
• 
Study PAM4743g 
Protocol-defined dose-limiting toxicities (DLTs) were reported for two patients (58). Two of the six 
evaluable patients treated with ipatasertib (GDC-0068) 800 mg daily on Days 1-21 of each 28- 
day cycle experienced grade 3 asthenia (N = 1) and grade 3 nausea (N = 1), which the 
investigators assessed as related to ipatasertib (GDC-0068) and which fulfilled the DLT criteria 
during Cycle 1. 
The event of asthenia improved following dose reduction of ipatasertib (GDC-0068), and the event 
of nausea was managed with anti-emetic medications and resolved while dosing with ipatasertib 
(GDC-0068) was continued. Therefore, the MTD of single-agent ipatasertib is 600 mg daily on 
Days 1-21 of each 28-day cycle. 
Safety data are available for 51 patients treated with ipatasertib (GDC-0068) in the dose- 
escalation and expansion stages of Study PAM4743g, including 29 patients treated at a dose of 
600 mg. All 51 patients (100%) experienced at least one adverse event (AE) per the US National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. 
Forty-seven of 51 patients (92.2%) experienced at least one AE that was assessed by the 
investigators as related to ipatasertib (GDC-0068). The AEs reported in ≥ 10% of patients that 
were assessed by the investigators as related to ipatasertib (GDC-0068) were nausea (70.6%), 
diarrhea (68.6%), vomiting (51.0%), asthenia (37.3%), hyperglycemia (33.3%), decreased 
CI=confidence interval; HR=hazard ratio; NGS=next generation sequencing; PIK3CA=PI3K 
p110alpha isoform; PTEN=phosphatase and tensin homolog. 
Note: Clinical cutoff date of 7 June 2016. Percentages are based on the number of patients in 
the respective (sub)population. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
56 
 
 
appetite (23.5%), dyspepsia (19.6%), abdominal pain upper (11.8%), dysgeusia (11.8%), and 
rash (11.8%). 
 
Ten of 51 patients (19.6%) experienced a grade ≥ 3 AE that was assessed by the investigator as 
related to ipatasertib (GDC-0068); such events reported for two or more patients included 
asthenia (N = 3) and diarrhea (N = 4). No grade 4 or grade 5 AEs related to ipatasertib (GDC- 
0068) as assessed by the investigators were reported. 
There were five serious adverse events (SAEs) that were assessed by the investigator as related 
to ipatasertib (GDC-0068): grade 3 asthenia (N = 1, 2.0%), grade 3 diarrhea (N = 1, 2.0%), grade 
3 hyperglycemia (N = 1, 2.0%), grade 2 renal failure (N = 1, 2.0%), and grade 3 toxic skin eruption 
(N = 1, 2.0%). 
 
Three patients experienced SAEs of Grade 5 (malignant neoplasm progression, disease 
progression, and ischemic stroke), none of which was assessed as related to ipatasertib (GDC- 
0068) by the investigator. 
 
 
• 
Study PAM4983g 
Common adverse events of ipatasertib (GDC-0068) in combination with docetaxel (Arm A) 
 
Safety data were available for 27 treated patients, including 13 patients with TNBC treated with 
ipatasertib (GDC-0068) at the MTD dose of 600 mg daily in combination with docetaxel. All 27 
patients (100%) experienced at least one AE per NCI-CTCAE v.4.03. No DLTs were observed 
(58). 
Grade ≥ 3 AEs reported at least two patients included neutropenia (N = 5), febrile neutropenia (N 
= 3), hypophosphatemia (N = 2), and diarrhea (N = 2). 
 
There were six SAEs in four patients that were assessed by the investigator as related to 
ipatasertib (GDC-0068): Grade 3 hypocalcemia (N = 1, 3.7%), grade 3 hypomagnesemia (N = 1, 
3.7%), grade 3 hypophosphatemia (N = 1, 3.7%), grade 3 rash maculopapular (N = 1, 3.7%), 
grade 2 diarrhea (N = 1, 3.7%), and grade 2 rash (N = 1, 3.7%). 
 
One SAE of grade 5 (septic shock, not related to ipatasertib [GDC-0068] in combination with 
docetaxel) was reported in Arm A. 
 
 
Common adverse events of ipatasertib (GDC-0068) in combination with paclitaxel (Arm C) 
 
As of 2 May 2016, safety data were available for 27 treated patients, including 21 patients with 
luminal breast cancer treated at the RP2D of ipatasertib (GDC-0068) 400 mg daily in combination 
with paclitaxel. 
Twenty-six of 27 patients (96.3%) experienced at least one AE per NCI-CTCAE v.4.03. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
57 
 
 
One patient treated at 600 mg ipatasertib (GDC-0068) in combination with paclitaxel experienced 
a grade 3 dehydration DLT (concurrent with grade 3 diarrhea onset), which was assessed by the 
investigator as related to ipatasertib (GDC-0068), paclitaxel, and illness. Grade 3 dehydration 
resolved after study drug withdrawal. 
Grade ≥ 3 AEs reported in two or more patients included diarrhea (N = 6), hyperglycemia (N = 4), 
neutropenia (N = 3), anemia (N = 2), pneumonia (N = 2), pyrexia (N = 2), and dehydration (N = 
2). 
At the RP2D of 400 mg ipatasertib (GDC-0068) daily in combination with paclitaxel, nine of 21 
patients (42.9%) experienced grade ≥ 3 AEs, versus five of six patients (83.3%) receiving 
ipatasertib (GDC-0068) 600 mg daily in combination with paclitaxel. 
There were two SAEs that was assessed by the investigator as related to ipatasertib (GDC-0068): 
Grade 3 diarrhea (N = 1, 3.7%) and grade 3 dehydration (N = 2, 7.4%). 
Three grade 5 SAEs (pancreatic carcinoma, mesothelioma, and respiratory failure) were reported 
from Arm C, none of which was assessed as related to ipatasertib (GDC-0068) in combination 
with paclitaxel by the investigator. 
 
 
• 
Study GO29227 (LOTUS) 
As of the primary analysis of 7 June 2016, a total of 124 patients with locally advanced or 
metastatic TNBC were randomized to receive ipatasertib (GDC-0068) at 400 mg on a 21-day on 
7-day off schedule or placebo, each in combination with paclitaxel chemotherapy (60,62). One 
hundred twenty-three patients received at least one dose of study treatment and 61 patients were 
treated with ipatasertib (GDC-0068). 
The number of patients with at least one AE was 61 of 61 patients (100%) and 60 of 62 patients 
(96.8%) in the ipatasertib (GDC-0068) 400 mg plus paclitaxel arm versus placebo plus paclitaxel 
arm, respectively. 
The most frequent (≥ 5% in any treatment group) AEs of grade ≥ 3 were diarrhea (23.0% vs. 0% 
in the ipatasertib [GDC-0068] 400 mg plus paclitaxel arm vs. placebo plus paclitaxel arm), 
neutropenia (9.8% vs. 1.6%), neutrophil count decreased (8.2% vs. 6.5%), and fatigue (3.3% vs. 
6.5%). 
 
A total of 27.9% of patients in the ipatasertib (GDC-0068) 400 mg plus paclitaxel arm and 14.5% 
of patients in the placebo plus paclitaxel arm had experienced at least one SAE. 
A total of 11 SAEs across both arms were assessed by the investigator as related to ipatasertib 
(GDC-0068)/placebo in combination with paclitaxel. Related SAEs reported in more than one 
patient were diarrhea and febrile neutropenia, both in the ipatasertib (GDC-0068) 400 mg plus 
paclitaxel arm. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
58 
 
 
 
 
• 
Study GO29505 (FAIRLANE) 
A total of 151 patients with early-stage TNBC had been randomized to receive ipatasertib (GDC- 
0068) (76 patients) or placebo (75 patients) in combination with paclitaxel (61). 
Common AEs with an incidence of at least 20% in either treatment arm were diarrhea (ipatasertib 
[GDC-0068] plus paclitaxel: 86.8% vs. placebo plus paclitaxel: 32.0%), nausea (47.4% vs. 
30.7%), constipation (13.2% vs. 21.3%), vomiting (22.4% vs. 5.3%), alopecia (52.6% vs. 53.3%), 
rash (25.0% vs. 18.7%), asthenia (42.1% vs. 38.7%), fatigue (30.3% vs. 32.0%), dysgeusia 
(23.7% vs. 22.7%), headache (18.4% vs. 20.0%), and insomnia (19.7% vs. 20.0%). 
 
Diarrhea was the only grade ≥ 3 AE reported in at least 5% of patients in either treatment arm 
(ipatasertib [GDC-0068] plus paclitaxel: 13 patients [17.1%] vs. placebo plus paclitaxel: One 
patient [1.3%], all of grade 3) and in at least 3% more patients in the ipatasertib (GDC-0068) plus 
paclitaxel arm than in the placebo plus paclitaxel arm. 
Ipatasertib (GDC-0068)/placebo-related SAEs were GI disorders (ipatasertib [GDC-0068] plus 
paclitaxel: One patient [1.3%] vs. placebo plus paclitaxel: zero patients), general disorders and 
administration site conditions (Zero vs. one patient [1.3%]), and metabolism and nutrition 
disorders (One [1.3%] vs. zero patients). Grade 3 events included diarrhea (one patient in 
ipatasertib [GDC-0068] plus paclitaxel arm) and dehydration (one patient in ipatasertib [GDC- 
0068] plus paclitaxel arm). 
 
 
 
2.7.4 
Potential Drug-Drug Interaction (DDI) 
 
Considering that the below list of medications is not comprehensive, the investigator should 
consult the prescribing information when determining whether a concomitant medication can be 
safely administered with study treatment. In addition, the investigator should contact the Medical 
Monitor if questions arise regarding medications not listed below. 
1. Ipatasertib (GDC-0068) is expected to be mild to moderate inhibitor of CYP3A in vivo. A 
clinical study in patients showed that ipatasertib (GDC-0068) at a dose of 600 mg resulted in 
a 2.22-fold increase in midazolam (sensitive CYP3A substrate) exposures. Ipatasertib (GDC- 
0068) is primarily metabolized by CYP3A, and hence, strong inhibitors and inducers of 
CYP3A may increase or decrease ipatasertib (GDC-0068) exposures, respectively. 
Therefore, the following drugs should be avoided, or used with caution, when administering 
ipatasertib (GDC-0068). If the use of one of these drugs is necessary, a risk/benefit 
assessment should be made prior to its concomitant use with ipatasertib (GDC-0068) per 
protocol guidelines: 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
59 
 
 
• 
Strong CYP3A inhibitors: such as, but not limited to, atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandamycin, voriconazole, and/or grapefruit juice or grapefruit supplements. 
• 
Strong CYP3A inducers: such as, but not limited to, rifampin, carbamazepine, rifapentine, 
phenytoin, phenobarbital, and/or St. John’s wort (hyperforin). 
• 
CYP3A4 substrates with a narrow therapeutic index: such as, but not limited to alfentanil, 
astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, ergot alkaloids ergotamine, and/or dihydroergotamine. 
Patients should be closely monitored. Refer to the updated list of substrates, inhibitors and 
inducers elaborated by the U.S. Food and Drug Administration (FDA) agency for further 
guidance on CYP450−drug interactions, through the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInte 
ractionsLabeling/ucm093664.htm 
2. In vitro studies indicated that ipatasertib (GDC-0068) was a substrate and inhibitor of P- 
glycoprotein (P-gp) transporter at the highest test concentration (729 μM). However, based 
on the parameters outlined in the U.S. FDA’s Drug Interaction Studies (63) and the European 
Medicines Agency (EMA)'s Guideline on the Investigation of Drug Interactions (64), 
ipatasertib (GDC-0068) should not be a perpetrator of a P-glycoprotein mediated DDI in the 
intestine after a 400 mg dose. 
Additional in vitro transporter studies suggest that ipatasertib (GDC-0068) is a very mild 
inhibitor of breast cancer resistance protein, inhibitor of the organic anion transporter P1B1, 
OATP1B3, the multidrug and toxin extrusion protein 1 and MATE-2K. However, the clinical 
significance of the in vitro membrane transport interactions is currently unknown. 
An in vitro study showed the N-dealkylated metabolite of ipatasertib (GDC-0068) (M1) was 
substrate and inhibitor of organic cation transporter (OCT)1 and OCT2. However, the Cmax of 
M1 following a 400 mg human dose of ipatasertib (GDC-0068) was much lower than the IC50 
values reported for all transporters; thus, M1 is not expected to be a likely perpetrator of 
transporter-mediated DDIs. 
 
 
 
2.8 
Study Rationale 
 
2.8.1 
Global Rationale 
 
Results from GO29227 randomized phase II trial (LOTUS) support further evaluation of first-line 
ipatasertib (GDC-0068) and paclitaxel for patients with metastatic TNBC in the ongoing 
IPATunity130 trial (NCT03337724). This study is a randomized phase III trial evaluating the 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
60 
 
 
efficacy of ipatasertib (GDC-0068) and paclitaxel versus placebo and paclitaxel in patients with 
PIK3CA/AKT1/PTEN-altered TNBC or luminal metastatic breast cancer who are not suitable for 
endocrine therapy. However, it is also of interest to assess the potential synergy between 
ipatasertib (GDC-0068) and other non-taxane chemotherapy regimens in patients previously 
treated with a taxane-containing regimen. 
These assessments are also justified by the significant synergy reported in the preclinical setting 
between different inhibitors of the PI3K/AKT/mTOR pathway and non-taxane chemotherapy 
drugs, such as eribulin, capecitabine, platinum drugs, and gemcitabine. All these chemotherapy 
regimens are thoroughly employed in treating patients with TNBC. 
A synergy between PI3K/AKT/mTOR inhibitors and eribulin has been observed in TNBC cell lines 
as for the anti-proliferative, pro-apoptotic, and anti-metastatic effects (65). In these models, the 
combined therapy exhibited increased antitumor activity compared to single-agent treatments. 
Particularly, this combination is able to reduce the mammosphere formation, and markers for 
epithelial-mesenchymal transition (EMT) (66). It is well established that eribulin suppresses 
experimental metastasis of breast cancer cells, consistent with a phenotypic switch from EMT to 
mesenchymal-epithelial states (67). 
In relation to capecitabine, 5-fluorouracil (5-FU) induced expression of the A disintegrin and 
metalloproteases protein 12 isoform L (ADAM12-L). The overexpression of ADAM12-L in breast 
cancer cells following 5-FU treatment leaded to the acquisition of resistance to 5-FU. ADAM12-L 
overexpression also resulted in increased levels of pAKT. Decreasing the levels of pAKT seems 
to restore 5-FU sensitivity in 5-FU-resistant breast cancer cells lines. On the other hand, ADAM12 
knockdown reduced breast cancer cell survival and invasive abilities (68). These findings propose 
specific ADAM12-L inhibition could optimize 5-FU-based chemotherapy of breast cancer. 
Furthermore, PI3K/AKT/mTOR inhibitors could fully restore cisplatin sensitivity in cisplatin- 
resistant TNBC cells lines and synergistically act with cisplatin (69). The combination significantly 
increased the effect on cisplatin sensitivity of each of the compounds alone. This synergistic effect 
has been also identified when combining PI3K/AKT/mTOR inhibitors and carboplatin (70). 
Finally, preclinical data suggests that gemcitabine resistance in breast cancer cells is mainly 
mediated by activation of the PI3K/AKT signaling pathway, consistent with an elevated expression 
of pAKT gene leading to cell proliferation (71). Accordingly, targeting the PI3K/AKT/mTOR 
pathways may help develop effective therapies in patients with gemcitabine-resistant breast 
cancer. 
 
 
 
2.8.2 
Study design rationale 
 
The open-label, non-comparative, phase IIa PATHFINDER trial aims to analyze the safety, 
tolerability, and preliminary efficacy of ipatasertib (GDC-0068) in combination with non-taxane 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
61 
 
 
chemotherapy agents (capecitabine, eribulin, and carboplatin plus gemcitabine) in taxane- 
pretreated unresectable locally advanced or metastatic TNBC patients. 
A run-in phase for safety and tolerability of ipatasertib (GDC-0068) in combination with standard 
doses of the selected non-taxane chemotherapy regimens will be conducted as an initial step of 
the non-comparative phase IIa in this patient population. This phase aims at evaluating and 
establishing the dosing schedule of ipatasertib (GDC-0068), by analyzing the toxicity profiles of 
each of the combined regimens. 
With the Background of PAM4983g, GO29227 and IPATunity130 trial, the safe starting dose of 
Ipatasertib (GDC-0068) has been established as 400 mg. 
 
 
2.8.3 
Benefit/Risk assessment 
 
Advanced TNBC is the subtype of breast cancer with the worst prognosis, with a median OS of 
only 18-21 months (1,7). Current approaches in treatment of this kind of tumors include treatment 
with taxenes as first-line treatment. For those tumours which present PDL1 expression, the 
standard treatment is nab-paclitaxel in combination with atezolizumab. Patients with BRCA1/2 
germline mutation are an exception, as olaparib has demonstrated a clear benefit in PFS for this 
population (34). After tumor progression at the end of the first-line treatment - and with exception 
to those tumours with BRCA1/2 mutation -, besides chemotherapy, there isn’t any approved 
targeted treatment that have shown a significant survival benefit in patients with advanced TNBC. 
This highlights the importance of developing new drugs and treatments for patients with a TNBC 
that has progressed. 
 
With the lack of a standard therapy for patients with TNBC that has progressed after treatment 
with taxenes, the frequently used treatments are capecitabne, eribulin and carboplatin plus 
gemcitabine. These treatments have been widely tested in breast cancer and present a well- 
known and acceptable toxicity and safety profile. 
 
Alterations in the PI3K signaling pathway are involved in resistance mechanisms in breast cancer, 
and particularly in TNBC, where 35% of TNBC patients present these alterations (45,53,54). 
Ipatasertib is an inhibitor of AKT, a key member of the PI3K signaling pathway, which has shown 
an acceptable safety profile when used as monotherapy and in combination with paclitaxel at a 
dose of 400 mg/day. In addition, studies with added AKT inhibitors as first-line treatment for 
metastatic TNBC (such as LOTUS) have shown a significant OS improvement compared to their 
placebo counterpart arm (described in Section 2.7.2.2). 
 
Therefore, in light of the data shown by numerous clinical trials, the benefit-risk assessment for 
the administration of ipatasertib in combination with capacetabine, eribulin or carboplatine plus 
gemcitabine, is considered positive in patients with non-resectable locally advanced or metastatic 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
62 
 
 
TNBC. And given the high incidence of diarrhea observed in some studies, this study takes a 
preventive approach by recommending prophylactic loperamide to all patients during at least the 
first initial cycle of treatment (as described in Section 7.7.2), as well as by reducing the dose of 
capecitabine taken by the patient. 
 
 
 
3 
STUDY OBJECTIVES AND ENDPOINTS 
 
3.1 
Study Objectives 
 
3.1.1 
Primary Objective 
 
• 
To evaluate the safety and tolerability of ipatasertib (GDC-0068) in combination with 
capecitabine, eribulin, or carboplatin plus gemcitabine in the ITT population of patients 
with taxane-pretreated unresectable locally advanced or metastatic TNBC. 
 
 
 
3.1.2 
Secondary Objectives 
 
• 
To determine the efficacy of ipatasertib (GDC-0068) in combination with capecitabine, 
eribulin, or carboplatin plus gemcitabine in the ITT population and in each treatment arm. 
 
 
 
3.1.3 
Exploratory Objectives 
 
 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
63 
 
 
3.2 
Study Endpoints 
 
3.2.1 
Primary Endpoint 
 
• 
Incidence of AEs as assessed by the investigator, with severity determined through the 
use of National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI– 
CTCAE) NCI-CTCAE v.5.0. 
 
 
 
3.2.2 
Secondary Endpoints 
 
• 
PFS, defined as the period of time from treatment initiation to the first occurrence of 
disease progression or death from any cause, whichever occurs first, as determined 
locally by the investigator through the use of Response Evaluation Criteria In Solid 
Tumors (RECIST) v.1.1. 
• 
Time to response (TTR), defined as the time from the treatment initiation to time of the 
first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who 
achieved a CR or PR, as determined locally by the investigator through the use of 
RECIST v.1.1. 
• 
ORR, defined as a CR or PR, as determined locally by the investigator through the use 
of RECIST v.1.1. 
• 
DoR, defined as the time from the first occurrence of a documented objective response 
to disease progression or death from any cause, whichever occurs first, as determined 
locally by the investigator through use of RECIST v.1.1. 
• 
CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, as 
determined locally by the investigator through the use of RECIST v.1.1. 
• 
OS, defined as the time from treatment initiation to death from any cause, as determined 
locally by the investigator through use of RECIST v.1.1. 
• 
Best percentage of change from baseline in the size of target tumor lesions, defined as 
the biggest decrease, or smallest increase if no decrease will be observed, as determined 
locally by the investigator through use of RECIST v.1.1. 
 
 
 
3.2.3 
Exploratory Endpoints 
 
• 
PFS, TTR, ORR, DoR, CBR, OS, and best percentage of change in target tumor lesions, 
as determined locally by the investigator through the use of RECIST v.1.1 in the subset 
of patients with 
altered tumors. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
64 
 
 
• 
Relationship between tissue- and blood-based biomarkers and patient clinical features 
(e.g., baseline features) and outcome (e.g., duration of PFS). 
• 
Changes in mutation and copy number in oncogenes, tumor suppressors, and/or other 
genes associated with disease progression assessed by DNA sequencing. 
• 
Changes in levels of tumor suppressors, immune checkpoints, mitotic index, apoptotic 
index, and/or immune-cell infiltration assessed by IHC. 
• 
Associations of breast cancer subtypes defined by molecular signatures with patient 
outcomes. 
 
 
 
4 
STUDY OVERVIEW 
 
4.1 
Study Design 
 
This is a multicenter, open-label, non-comparative, three-arm, phase IIa clinical trial that is 
designed to evaluate the safety, tolerability, and efficacy of ipatasertib (GDC-0068) in combination 
with eribulin, capecitabine, or carboplatin plus gemcitabine for taxane-pretreated patients with 
unresectable locally advanced or metastatic TNBC that is not amenable to resection with curative 
intent. 
Patients must have received at least one, but not more than two, prior chemotherapeutic regimens 
for treatment of unresectable locally advanced and/or metastatic disease (at least one regimen 
must have contained a taxane). Earlier adjuvant or neoadjuvant therapy for more limited disease 
will qualify as one of the required prior regimens if the development of unresectable locally 
advanced or metastatic disease occurred within a 12-month period of time after completion of 
chemotherapy. Therefore, exclusive prior taxane-based therapy as adjuvant or neoadjuvant 
treatment is also allowed if the patient had a disease-free interval of less than 12 months after 
completing this treatment. 
Evidence of either measurable or evaluable disease as for RECIST v.1.1 is mandatory. Patients 
with bone-only metastases are also eligible. 
After signing informed consent form (ICF) and confirmed eligibility, patients will be assigned to 
one of the following three treatment arms based on local investigator assessment and slots 
availability. We expected to recruit 18 patients in each arm. However, patients could be assigned 
to one of the other open treatments if one arm was stopped due to feasibility or safety reasons. 
At the end of the study all 54 patients will be recruited, unless all arms were discontinued. 
 
 
• 
Arm A: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day (noon) on 
Days 1-14 of each 21-day cycle plus capecitabine 1000 mg/m2 tablets orally twice a day 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
65 
 
 
(morning and evening; equivalent to 2000 mg/m2 total daily dose), for 14 days (followed by a 
7-day rest period) every 21-day cycle. 
• 
Arm B: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day on Days 1-14 
of each 21-day cycle plus eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) 
administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle. 
• 
Arm C: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day on Days 1-14 
of each 21-day cycle plus carboplatin area under the curve (AUC)5 on Day 1 administered 
intravenously plus gemcitabine 1000 mg/m2 administered intravenously over 30 minutes on 
Days 1 and 8, every 21-day cycle. 
A run-in phase for safety and tolerability of ipatasertib (GDC-0068) in combination with standard 
doses of capecitabine (Arm A), eribulin (Arm B), and carboplatin plus gemcitabine (Arm C) will be 
conducted as an initial step of the non-comparative phase IIa in this patient population (see 
Section 6.3). 
Patients will be followed to observe if they experience any significant toxicity during the first two 
treatment cycles. Once the dosing schedule of ipatasertib (GDC-0068) has been established, the 
study enrollment will proceed including the rest of patients within each treatment arm (N = 54 
patients in all arms) in order to gaining further safety and efficacy data of the combined regimens. 
 
For estimation of PFS, TTR, ORR, DoR, CBR, OS, and best percentage of change in target tumor 
lesions, tumor assessment will be based on RECIST v.1.1 (See Appendix 2) and will be 
performed every six weeks (± 3 days) for the first six months and every nine weeks (± 7 days) 
thereafter until disease progression, the start of new anti-cancer treatment, withdrawal of consent, 
death, or the end of the study, whichever occurs first. Tumor assessments will be performed on 
the specified schedule regardless of treatment delays. Patients who discontinue treatment without 
evidence of disease progression per RECIST v.1.1, in addition to post-treatment follow-up, will 
be followed every nine weeks (± 7 days) for tumor assessments until documented progression 
per RECIST v.1.1, elective withdrawal from the study, the start of new anti-cancer treatment, or 
study completion or termination. 
Bone scans are mandatory at baseline for all patients and thereafter will be repeated every 24 
weeks (± 7 days) only for patients with bone lesions identified at baseline, unless clinically or 
biochemically suspected bone progression. 
Brain imaging (by magnetic resonance imaging [MRI]) during the trial should be performed in 
subjects with known brain metastases prior to study initiation (every six weeks [± 3 days] for first 
six months, then every nine weeks [± 7 days]), and those with worsening and/or new neurological 
symptoms. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
66 
 
 
Safety assessments will include the incidence, nature, and severity of AEs and laboratory 
abnormalities graded per the NCI-CTCAE v.5.0. Laboratory safety assessments will include the 
regular monitoring of hematology, blood chemistry, coagulation, and pregnancy test. A schedule 
of assessments is provided in Appendix 1. 
For central molecular evaluation of the 
-altered status and perform 
exploratory studies, patients must have consented to provide sufficient newly obtained tumor 
biopsy tissue with the exception of patients for whom tumor biopsies cannot be obtained (e.g., 
inaccessible tumor or subject safety concern) that may submit an archived metastatic tumor 
specimen only upon agreement from the Sponsor. Patients will also be given the option of 
providing a tissue biopsy sample obtained at disease progression for exploratory analyses; this 
decision will not affect overall study eligibility. Furthermore, patients have agreed to give blood 
samples (liquid biopsy) at the time of inclusion, after two cycles of study treatment, and upon 
progression or study termination. The 
altered status is defined as the 
presence of 
 alterations or 
 
as determined 
by any tissue- or blood-based molecular diagnostic assay (using a CLIA or equivalently accredited 
diagnostic laboratory). To protect the integrity of the study and minimize potential bias in 
evaluating clinical benefit of the patients, the results of any test about the 
alteration status and any interim safety analyses will not be made known to either investigators, 
contract research organizations, or patients prior to RECIST progression. 
 
 
 
4.2 
Study Schedule Summary 
 
The study will consist of a 28-days screening phase, a treatment phase, and a post-treatment 
follow-up phase (end of treatment [EoT] and end of study [EoS] visits) that includes safety, 
efficacy, and survival follow-up. 
 
 
 
4.2.1 
Screening Phase 
 
During this phase, subject eligibility is determined, including the documentation of baseline 
characteristics. This phase of the study will begin once the ICF is signed by the patient and 
procedures to be performed are described in Appendix 1. One re-screening is allowed in patients 
that are screening failure in this study. Patient has to reconsent ICF before any study procedure 
is done. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
67 
 
 
4.2.2 
Treatment Phase 
 
The study treatment period is defined as the time between the study entry and the last dose of 
study treatment received within the trial. A run-in phase for safety and tolerability of ipatasertib 
(GDC-0068) in combination with capecitabine, eribulin, or carboplatin plus gemcitabine will be 
conducted as an initial step of the non-comparative phase IIa study that will follow scheme as 
outlined in Section 6.3. 
Patients will receive study treatment according to the protocol and will be discontinued if one of 
the following situations arises: 
• 
Radiologically confirmed and documented unequivocal disease progression (with the 
exception of patients who develop isolated progression in the brain). 
• 
AEs that according to the protocol or in the judgment of the investigator may cause severe or 
permanent harm or which rule out continuation of study drug. 
Note: See detailed criteria for study treatment discontinuation due to toxicity in Section 7.3. 
 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
• 
Serious non-compliance with the study protocol. 
 
• 
Death. 
 
• 
Lost to follow-up. 
 
• 
Patient withdraws consent. 
 
• 
The study site or the Sponsor decides to close the study. 
 
 
 
4.2.3 
Access to Trial Intervention After End of Trial 
 
Roche will offer continued access to IMP Ipatasertib (GDC-0068) free of charge to eligible 
participants in accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, as outlined below. 
 
A participant will be eligible to receive Roche IMP Ipatasertib (GDC-0068) after completing the 
study if all of the following conditions are met: 
 
• 
The participant has a life-threatening or severe medical condition and requires continued 
Roche IMP treatment for his or her well-being. 
• 
There are no appropriate alternative treatments available to the participant. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
68 
 
 
• 
The participant and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A participant will not be eligible to receive Roche IMP Ipatasertib (GDC-0068) after completing 
the study if any of the following conditions are met: 
 
• 
The Roche IMP is commercially marketed in the participant's country and is reasonably 
accessible to the participant (e.g., is covered by the participant's insurance or wouldn't 
otherwise create a financial hardship for the participant). 
• 
The Sponsor has discontinued development of the IMP or data suggest that the IMP is 
not effective for METASTATIC TRIPLE-NEGATIVE BREAST CANCER PATIENTS . 
• 
The Sponsor has reasonable safety concerns regarding the IMP as a treatment 
for METASTATIC TRIPLE-NEGATIVE BREAST CANCER PATIENTS . 
• 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
participant's country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is available 
at the following website: 
 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
 
 
 
4.2.4 
EoT and EoS Visits 
 
Patients discontinuing the study treatment period will enter a post-treatment follow-up period. The 
first safety follow-up assessment (EoT visit) will be scheduled for all patients within 30 days (± 7 
days) after the last dose of study treatment. All grade ≥ 3 AEs related to IMP will be followed up 
by the investigator until the event or its sequelae resolve or stabilize at the level acceptable to the 
investigator, and the Sponsor concurs with that assessment. 
Afterwards, follow-up contacts will continue every three months (± 14 days) up to the EoS and 
survival status and new anticancer therapy information will be collected. Telephone contact is 
acceptable. 
The EoS is defined as the last patient last visit at the end of the follow-up period. This will be the 
last data collection point, which can be a clinic visit or a telephone call. EoS will occur at 12 months 
after the last patient included in the study, unless premature termination of the study. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
69 
 
 
5 
PATIENT SELECTION 
 
This study can fulfil its objectives only if appropriate patients are enrolled. The following eligibility 
criteria are designed to select patients for whom the protocol treatment is considered appropriate. 
All relevant medical and non-medical conditions should be taken into consideration when deciding 
whether this protocol is suitable for a particular patient. 
 
 
 
5.1 
Target Study Population 
 
Female patients age ≥ 18 years with taxane-pretreated unresectable locally advanced or 
metastatic TNBC amenable to biopsy. 
Patients with either measurable or evaluable disease as per RECIST v.1.1 must have received at 
least one, but not more than two, prior chemotherapeutic regimens for treatment of unresectable 
locally advanced and/or metastatic disease (at least one regimen must have contained a taxane). 
Earlier adjuvant or neoadjuvant therapy for more limited disease will be considered as one of the 
required prior regimens if the development of unresectable locally advanced or metastatic disease 
occurred within a 12-month period of time after completion of chemotherapy. 
 
 
 
5.2 
Inclusion Criteria 
 
Patients must meet ALL of the following inclusion criteria to be eligible for enrolment into the 
study: 
1. Signed ICF prior to participation in any study-related activities. 
 
2. Female patients ≥ 18 years at the time of signing ICF. 
 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 
 
4. Life expectancy of ≥ 12 weeks. 
 
5. Histologically confirmed TNBC per American Society of Clinical Oncology (ASCO)/College of 
American Pathologists (CAP) criteria based on local testing on the most recent analyzed 
biopsy. Triple-negative is defined as <1% expression for estrogen receptor (ER) and 
progesterone receptor (PgR) and negative for Human Epidermal Growth Factor Receptor 2 
(HER2) (0–1+ by immunohistochemistry (IHC) or 2+ and negative by in situ hybridization 
[ISH) test]. 
6. Unresectable locally advanced or metastatic disease documented by computerized 
tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to 
resection with curative intent. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
70 
 
 
7. Measurable or evaluable disease as per RECIST v.1.1. Patients with only bone lesions are 
also eligible. 
8. Refractory to or relapsed after one or two prior standard of care chemotherapy regimens for 
unresectable locally advanced or metastatic breast cancer (MBC). Earlier adjuvant or 
neoadjuvant therapy for more limited disease will be considered as one of the required prior 
regimens if the development of unresectable locally advanced or metastatic disease occurred 
within a 12-month period of time after completion of chemotherapy. 
Note: Exclusive tumor marker elevation will not be considered sufficient for diagnosis of 
disease progression. 
9. Prior therapy must have included a taxane in any combination or order and either in the early, 
locally advanced, or metastatic setting. 
Note: Exclusive prior taxane-based therapy as adjuvant or neoadjuvant treatment is also 
allowed if the patient had a disease-free interval of less than 12 months after completing this 
treatment. 
10. Eligible for one of the chemotherapy options (eribulin, capecitabine, carboplatin plus 
gemcitabine) as per local investigator assessment and slots availability. Patients treated with 
(neo)adjuvant platinum salts or capecitabine and who have relapsed more than one year after 
the last dose of either treatment may be allowed to be included in the treatment arm based 
on ipatasertib (GDC-0068) in combination with carboplatin plus gemcitabine and 
capecitabine, respectively. 
11. Previous treatment with androgen receptor antagonists, poly ADP-ribose Polymerase (PARP) 
inhibitors, and immunotherapy is allowed. Those patients who have previously received a 
PARP inhibitor will not be included in the carboplatin and gemcitabine arm unless PARP 
inhibitors were used in the early breast cancer setting and the period between the end of 
PARP inhibitor-based regimen and onset of metastatic disease is at least of 12 months. 
12. Resolution of all acute toxic effects of prior anti-cancer therapy to grade £ 1 as determined by 
the NCI-CTCAE v.5.0 (except for alopecia or other toxicities not considered a safety risk for 
the patient at investigator's discretion). 
13. Willingness and ability to provide a tumor biopsy from a metastatic site or the primary breast 
tumor at the time of the inclusion in order to perform exploratory studies. If not feasible, patient 
eligibility should be evaluated by a Sponsor’s qualified designee. 
Note: Subjects for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or 
subject safety concern) may submit an archived metastatic tumor specimen only upon 
agreement from the Sponsor. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
71 
 
 
14. Patients agree to give blood samples (liquid biopsy) at the time of inclusion, after two cycles 
of study treatment, and upon progression or study termination. 
15. Adequate hematologic and organ function within 14 days before the first study treatment on 
Day 1 of Cycle 1, defined by the following: 
a) Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count 
(ANC) > 1.5 x 109/L, platelet count > 100.0 x109/L, and hemoglobin > 9.0 g/dL. 
b) Hepatic: Serum albumin ≥ 3 g/dL; Bilirubin ≤ 1.5 times the upper limit of normal (× ULN) 
(≤ 3 x ULN in the case of Gilbert’s disease); aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases ≤ 5 × ULN); alkaline 
phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN in the case of liver and/or bone metastases ≤ 
5 × ULN). 
c) Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min based on 
Cockcroft−Gault glomerular filtration rate estimation. 
d) Coagulation: Partial Thromboplastin Time (PTT) (or activated Partial Thromboplastin 
Time [aPTT]) and International Normalized Ratio (INR) ≤ 1.5 × ULN (except for patients 
receiving anticoagulation therapy). 
Note: Patients receiving heparin treatment should have a PTT (or aPTT) ≤ 2.5 × ULN (or 
patient value before starting heparin treatment). Patients receiving coumarin derivatives 
should have an INR between 2.0 and 3.0 assessed in two consecutive measurements 
one to four days apart. Patients should be on a stable anticoagulant regimen. 
16. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse), or to use a highly effective non-hormonal form of contraception, or 
two effective forms of contraception, as defined in the protocol during the treatment period 
and for at least 28 days after the last dose of ipatasertib (GDC-0068), three months after the 
last dose of eribulin, and six months after the last dose of carboplatin and gemcitabine or 
capecitabine, whichever occurs later, and agreement to refrain from donating eggs during this 
same period. Women of childbearing potential must have a negative serum pregnancy test 
before study treatment initiation. 
 
 
 
5.3 
Exclusion Criteria 
 
Patients will be excluded from the study if they meet ANY of the following criteria: 
 
1. Inability to comply with study and follow-up procedures. 
 
2. Previous treatment with PI3K, mTOR, or AKT inhibitors. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
72 
 
 
3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, 
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or 
cord compression are eligible if they have been definitively treated (e.g., radiotherapy, 
stereotactic surgery), are clinically stable, and off anticonvulsants and steroids for at least two 
weeks before first dose of study treatment. 
4. Radiotherapy or limited-field palliative radiotherapy within seven days prior to study 
enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline 
or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously irradiated. 
5. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 
28 days of start of study drug, or patients who have not recovered from the side effects of any 
major surgery. 
6. Grade ≥ 2 peripheral neuropathy. 
 
7. Grade ≥ 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia. 
 
8. History of type I or type II diabetes mellitus either requiring insulin or with a baseline fasting 
glucose > 150 mg/dL (8.3 mmol/L) or high hemoglobin A1c (HbA1c) as defined as > 7%. 
Patients who are on a stable dose of oral diabetes medication during at least weeks prior to 
initiation of study treatment are eligible for enrolment. 
9. Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis 
pneumonia or cytomegalovirus pneumonia). 
10. History of malabsorption syndrome or other condition that would interfere with enteral 
absorption or results in the inability or unwillingness to swallow pills. 
11. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) 
or active bowel inflammation (e.g., diverticulitis). 
12. Known hypersensitivity reaction to any investigational or therapeutic compound or their 
incorporated substances. 
13. Patients have a concurrent malignancy or malignancy within five years of study enrollment 
with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage 
I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion 
with the Medical Monitor is required. 
14. Current known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients 
with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B 
surface antibody [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
73 
 
 
accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody 
are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 
15. Active uncontrolled infection at the time of enrollment. 
 
16. Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula 
(QTcF) > 480 milliseconds. 
17. Patients have an active cardiac disease or a history of cardiac dysfunction including any of 
the following: 
a) Unstable angina pectoris or documented myocardial infarction within six months prior to 
study entry. 
b) Symptomatic pericarditis. 
 
c) Documented congestive heart failure (New York Heart Association functional 
classification III- IV). 
d) Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated 
acquisition (MUGA) scan or echocardiogram (ECHO). 
18. Patients have any of the following cardiac conduction abnormalities: 
 
a) Ventricular arrhythmias except for benign premature ventricular contractions. 
 
b) Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication. 
c) Conduction abnormality requiring a pacemaker. 
 
d) Other cardiac arrhythmia not controlled with medication. 
 
19. Patients have any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment contraindicate patient participation in the clinical study. 
20. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days or five drug- 
elimination half-lives, whichever is longer, prior to initiation of study treatment. 
21. Pregnant, breastfeeding, or intending to become pregnant during the study or within 28 days 
after the last dose of ipatasertib (GDC-0068), three months after the last dose of eribulin, and 
six months after the last dose of carboplatin and gemcitabine or capecitabine, whichever 
occurs later. 
22. Treatment with approved or investigational cancer therapy within 14 days prior to initiation of 
study drug. 
23. Concurrent participation in other interventional clinical trial. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
74 
 
 
6 
ASSESSMENTS AND STUDY PROCEDURES 
 
The schedule of activities to be performed during the study is provided in the Appendix 1. All 
activities must be performed and documented for each patient. 
Patients will be closely monitored for safety and tolerability throughout the study. Patients should 
be assessed for toxicity prior to each dose; dosing will occur only if the clinical assessment and 
local laboratory test values are acceptable. 
 
 
 
6.1 
Patient Entry Procedures 
 
Written ICF from the patient must be signed before performing any study procedure. 
 
Before giving their consent, patients will be informed about the nature of the study drug and will 
receive pertinent information regarding study objectives, study treatment, follow-up procedures, 
biological samples collection and its legal implications, possible benefits, and potential risk and 
AEs. Patients will be also informed that they have the right to withdraw from the study at any time 
and for any reason, without being required to state their reasons for doing so. This decision will 
not affect any future medical treatment. 
After receiving the document, the patient will read it (or receive information verbally in front 
witnesses) and will sign the approved ICF. The patient will receive a signed copy of the ICF and 
ICFs for enrolled patients and for patients who are not subsequently enrolled will be maintained 
at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrollment. The investigator will maintain a screening log to record details 
of all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. After a failed screening attempt, one re-screening will be allowed to patient who did 
not meet one or more criteria required for participation in this study. A potential re-screened 
patient should sign a new ICF before any screening test or study related procedure is performed. 
At inclusion, each patient will be given a unique patient number (UPN) for this study, provided by 
the Sponsor. If a patient is re-screened, her patient number will remain the same as the assigned 
in the initial screening. All data will be recorded in the appropriate case report form (CRF) using 
this identification number. 
Confirmation of patient’s eligibility for study participation will be recorded in the CRF. The 
investigator is responsible for safeguarding patient information (e.g., age, name, address, 
telephone number, and study identification number), ensuring access to this information by Health 
Authorities if necessary. These records will remain confidential for the period of time established 
by current legislation. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
75 
 
 
6.2 
Patient Allocation 
 
After signing ICF and confirmed eligibility patients will be assigned to one of the following three 
treatment arms: 
• 
Arm A: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day (noon) on 
Days 1-14 of each 21-day cycle plus capecitabine 1000 mg/m2 tablets orally twice a day 
(morning and evening; equivalent to 2000 mg/m2 total daily dose), for 14 days (followed by a 
7-day rest period) every 21-day cycle. 
• 
Arm B: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day on Days 1-14 
of each 21-day cycle plus eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) 
administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle. 
• 
Arm C: Ipatasertib (GDC-0068) 400 mg tablets administered orally once a day on Days 1-14 
of each 21-day cycle plus carboplatin AUC5 on Day 1 administered intravenously plus 
gemcitabine 1000 mg/m2 administered intravenously over 30 minutes on Days 1 and 8, every 
21-day cycle. 
Patient allocation will be based on local investigator assessment and slots availability. We 
expected to recruit 18 patients in each arm. However, patients could be assigned to one of the 
other open treatments if one arm was stopped due to feasibility or safety reasons. At the end of 
the study all 54 patients will be recruited, unless all arms were discontinued. 
 
 
 
 
 
6.3 
Safety Run-In Phase 
 
A run-in phase for safety and tolerability of ipatasertib (GDC-0068) in combination with standard 
doses of capecitabine (Arm A), eribulin (Arm B), and carboplatin plus gemcitabine (Arm C) will be 
conducted as an initial step of the non-comparative phase IIa in this patient population. 
Up to three patients will be initially included in the first dosing level of 400 mg/day of ipatasertib 
(GDC-0068) (Dose level 1, Table 3). If one significant toxicity is observed during the first 2 cycles 
(Table 4), three additional patients will be enrolled at 400 mg/day cohort to determine the number 
of total significant toxicities observed in six patients. 
 
 
Table 3. Safety Run-In Dosing Schedule. 
 
Continuous dosing schedule 
Ipatasertib (GDC-0068)* 
Dose level 1 (starting dose) 
400 mg/day 
Dose level 2 
300 mg/day 
Dose level 3 
Not permitted 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
76 
 
 
 
Continuous dosing schedule 
Ipatasertib (GDC-0068)* 
* In the safety run-in phase of the study, ipatasertib (GDC-0068) will be administered in 
combination with initial standard doses of capecitabine (Arm A), eribulin (Arm B), and 
carboplatin plus gemcitabine (Arm C). Dose adjustments of ipatasertib (GDC-0068) and/or 
chemotherapy (if toxicities are attributable to chemotherapy) will be evaluated according to the 
significant drug-related toxicities. 
 
 
If two or more significant toxicities (Table 4) are observed in three or six patients treated with 400 
mg/day of ipatasertib (GDC-0068), it can be decided to evaluate 300 mg/day of ipatasertib (GDC- 
0068) (dose level 2) and/or to reduce the chemotherapy treatment (if toxicities are attributable to 
chemotherapy) according to the corresponding dose levels (Table 7 to Table 9), following the 
same procedure as described for the 400 mg/day cohort (dose level 1). 
If two or more significant toxicities (Table 4) are observed in three or six patients treated with 300 
mg/day of ipatasertib (GDC-0068) and/or with chemotherapy in a lower dose level, patient 
enrollment will be interrupted for that treatment arm. 
 
 
Table 4. Significant Toxicity Definition. 
 
Toxicity 
Any of the following criteria 
Hematological 
• 
Grade 3/4 neutropenia lasting > 7 days. 
• 
Grade ≥ 3 febrile neutropenia. 
• 
Grade ≥ 4 anemia. 
• 
Grade 4 thrombocytopenia. 
• 
Grade 3 thrombocytopenia associated with 
clinically significant bleeding. 
Gastro-intestinal 
• 
Grade ≥ 3 vomiting or nausea lasting ≥ 72 hours 
despite optimal anti-emetic therapy. 
• 
Grade ≥ 3 diarrhea lasting ≥ 72 hours despite 
optimal anti-diarrheal therapy. 
Metabolic 
• 
Grade 
3 
or 
asymptomatic 
grade 
4 
hyperglycemia lasting > 7 days despite optimal 
treatment. 
• 
Symptomatic grade 4 hyperglycemia. 
Hepatic 
• 
Grade 3 elevation of ALT or AST lasting > 7 
days. 
• 
Grade 4 elevation of ALT or AST. 
• 
Grade 2 elevation of serum bilirubin lasting > 7 
days. 
• 
Grade ≥ 3 elevation of serum bilirubin. 
• 
Any case of potential drug-induced liver injury 
that meet Hy’s Law. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
77 
 
 
During the safety run-in phase of the study, patients will be evaluable if they completed at least 
70% of the protocol-specified doses for each individual drug during Cycle 1. If a patient receives 
< 70% of the protocol-specified cumulative dose for an individual during Cycle 1 because of the 
study drug-related toxicity, then the toxicity will be considered a significant toxicity. If a patient 
receives <70% of the protocol-specified doses for an individual drug during Cycle 1 because of 
unrelated adverse events, non-compliance or protocol deviation, then the patient will be replaced. 
The dosing schedules of ipatasertib (GDC-0068) and/or chemotherapy will be selected based on 
the overall evaluation of clinical data from the safety run-in phase, including toxicities, AEs/SAEs, 
and laboratory parameters. 
Patients assigned to each cohort will remain in their study cohort during the entire study period. 
 
Once the dosing schedules of ipatasertib (GDC-0068) and chemotherapy have been established, 
an early interim analysis will be performed in order to continue with the phase IIa. 
The interim analysis will be performed independently in each arm after the last evaluable patient 
in the run-in phase has completed the two first cycles of study treatment in order to assess the 
toxicity profile of each regimen. This data will be shared with F. Hoffmann-La Roche Ltd. 
The study enrollment will proceed finalizing the number of patients within each treatment arm in 
order to gaining further safety and efficacy data of the combined regimens. 
 
 
6.4 
Study Assessments 
 
6.4.1 
Schedule of Assessments 
 
Study assessments are outlined in Appendix 1. 
 
 
 
6.4.2 
Visit Schedule 
 
Written patient ICF should be obtained prior to undergoing any study related procedures. 
 
All screening tests and evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria within 28 days prior to the first administration of study medication. Tumor 
assessments and LVEF evaluation available and performed as part of clinical practice prior to 
obtain the signature of the ICF, and within 28 days prior to treatment start or within 12 weeks prior 
to Cycle 1 Day 1 respectively, are accepted; moreover, bone scans performed within 60 days 
prior to Cycle 1 Day 1 are accepted. Therefore, such evaluations are not required to be repeated 
during the screening period. 
The investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
78 
 
 
Visits are organized in programmed cycles of 21 days (if there are no delays in treatment owing 
to the occurrence of an AE). All visits must occur within ± 2 working days (± 1 working day in Day 
8 of each cycle) from the scheduled date, unless otherwise noted in the schedule of assessments. 
Assessments scheduled for Days 1 and 8 of each cycle must be performed within 48 hours and 
24 hours prior to study treatment administration, respectively, unless otherwise indicated in the 
schedule of assessments, in order to confirm to the patient if treatment can be followed up. 
If a mandatory procedure described in the protocol falls on a bank holiday and/or weekend, this 
procedure should be performed on the day before or after the holiday (e.g., within a period of ± 2 
working days). 
Day 8 visits can be omitted, at the Investigator’s discretion, for patients enrolled in Arms B or C 
that permanently discontinue chemotherapy and continue with ipatasertib (GDC-0068) as single 
agent. However, laboratory assessments and clinical visits could be scheduled as needed for 
follow-up of ipatasertib (GDC-0068)-related adverse events. A telephone call may be also 
acceptable. 
EoT visit will be performed within 30 days after last dose of study treatment. Afterwards, follow- 
up contacts will continue every three months (± 14 days) up to the EoS and survival status and 
new anticancer therapy information will be collected. Telephone contact is acceptable. 
EoS will occur at 12 months after the last patient included in the study, unless premature 
termination of the study. 
 
 
 
6.4.3 
Medical History and Demographic Data 
 
Demographic data, general medical history, and prior medical history of breast cancer will be 
collected during the screening period. 
Demographic data includes age, sex, and self-reported race/ethnicity. 
 
General medical history includes clinically significant diseases, surgical interventions, history of 
smoking, alcoholism, drug addiction, as well as any medications (e.g., prescribed drugs, over- 
the-counter drugs, medicinal plants, homeopathic remedies, or food supplements) used by the 
patient in the 28 days prior to screening visit. 
Previous medical history of breast cancer (including prior antineoplastic treatments and 
procedures including radiotherapy and surgeries) will be also assessed with further detail. In 
particular, it will be evaluated the number of chemotherapy regimens for unresectable locally 
advanced or MBC, including start and stop date and best response, and the prior use of a taxane 
or PI3K, mTOR, or AKT inhibitors in any combination or order and either in the early, locally 
advanced, or metastatic setting. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
79 
 
 
Moreover, patients will complete a medication diary each day to assess the actual intake of 
medication taken outside of the clinic/hospital setting. Patients will receive the diary on the first 
day of each cycle, with site staff completing information on any prescribed medication, including 
the recommended dosage and route of administration. Patients should use the diary to record 
daily ipatasertib (GDC-0068) and capecitabine (for patients assigned to the treatment arm A) 
dosing, and any other medication (prescribed or over-the-counter) taken on that cycle of 
treatment. The intake of analgesic, anti-histamine, and loperamide medication will be reported in 
the relative page of the Concomitant Medications CRF. 
 
 
 
6.4.4 
Vital Signs 
 
Vital signs will be collected during the screening period and on Days 1 and 8 of each cycle. These 
will include the measurement of height (only during screening), weight, respiratory rate, pulse 
rate, systolic and diastolic blood pressure while the patient is in a seated position after resting for 
at least five minutes, and oral, axillary, or tympanic temperature. Abnormal or significant changes 
in vital signs from baseline should be recorded as AEs, if appropriate. 
 
 
 
6.4.5 
Physical Examination 
 
A complete physical examination will be performed during the screening period and on Day 1 of 
each cycle. This examination should include an evaluation of head, eyes, ears, nose, and throat 
as well as cardiovascular, dermatological, musculoskeletal, respiratory, digestive, genitourinary, 
and neurological systems. In addition, for breast cancer patients, this physical exam should also 
include, as part of tumor assessment, evaluation of the breast and regional lymph nodes as well 
as the presence and degree of increase of other lymph nodes, hepatomegaly, and splenomegaly. 
Limited physical exams will be performed on Day 8 of each cycle and will only focus on the 
following symptoms: diarrhea, nausea, vomiting, mucositis, dyspnea/cough, and skin toxicity. 
Changes to abnormalities identified during the baseline period should be recorded at all 
subsequent physical examinations. New or worsening abnormalities should be recorded as AEs, 
if applicable. 
 
 
 
6.4.6 
Tumor and Response Evaluations 
 
All known sites of disease must be documented at screening and re-assessed at each subsequent 
tumor evaluation. Tumor response will be assessed for all patients, unless they withdraw from the 
study for any reason not attributable to disease progression confirmed radiologically or clinically 
as per RECIST v.1.1 criteria and who have not received an acceptable complete assessment of 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
80 
 
 
the disease. The measurable and non-measurable disease must be documented at screening 
and be re-assessed at every tumor assessment thereafter. 
Tumor assessment during the screening period should include an evaluation of all known and/or 
suspected lesions/sites of the disease, including color photography of skin lesions, based on the 
baseline assessment of target and non-target lesions according to RECIST v.1.1 criteria as the 
reference for comparison at each subsequent tumor assessment. The same radiographic 
procedure employed at screening should be used throughout the study (e.g., the use of the same 
contrast protocol for CT scans). 
At baseline, all patients should be assessed as follows: 
 
• 
Evaluation of chest, abdomen, and pelvis: 
 
o 
This assessment should be evaluated preferably by CT scan or MRI, since these methods 
are the best currently available and reproducible techniques to measure lesions selected 
for response assessment, within 28 days prior to the first administration of study 
medication. 
o 
In the event a positron emission tomography (PET)/CT scan is used for tumor 
assessments, CT portion of PET/CT is usually of lower quality, and should not be used 
instead of dedicated diagnostic CT. If the CT scan is of high quality, with oral and 
intravenous contrast, may be used with caution. Additional information from PET may 
bias CT assessment. 
o 
After baseline, this evaluation will be performed every six weeks (± 3 days) from the first 
dose of study treatment for the first six months and, thereafter, every nine weeks (± 7 
days) until the EoS visit. 
 
 
• 
Brain imaging: 
 
o 
A brain MRI will be only performed in patients with known brain metastases preceding 
the study inclusion within 28 days prior to the first administration of study medication. 
o 
After baseline, this evaluation will be performed every six weeks (± 3 days) from the first 
dose of study treatment for first six months, then every nine weeks (± 7 days), unless 
clinically suspected brain progression. 
 
 
• 
Bone scan: 
 
o 
Bone scan imaging is mandatory at baseline for all patients. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
81 
 
 
o 
Thereafter, for patients with bone lesions identified at baseline, bone scan will be 
performed every 24 weeks (± 7 days), unless clinically or biochemically suspected bone 
progression. 
o 
If no bone involvement is demonstrated, then it is no necessary to repeat the bone 
assessment unless clinically or biochemically suspected bone progression. 
o 
If an isotope-based bone scan was performed > 28 days but ≤ 60 days prior to start of 
study treatment, the bone scan does not need to be repeated. 
Bone scan should be used only to identify presence of bone lesions and if bone lesions are 
present, confirmation and accurate measurement must be done with CT scan or MRI. Lytic bone 
lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques such as CT scan or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability. Blastic bone 
lesions are non-measurable. If a bone scan cannot be performed during the course of the study 
because of the unavailability of the Tc-99m isotope, the investigator may choose an alternative 
imaging modality. 
If clinically indicated, CT scan or MRI of other areas of disease as appropriate should be 
performed. Any potentially measurable lesion that has been previously treated with radiotherapy 
should be considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy administration, it can be considered 
as a measurable lesion. 
Patients who discontinue treatment without evidence of disease progression per RECIST v.1.1, 
in addition to post-treatment follow-up, will be followed every nine weeks (± 7 days) for tumor 
assessments until documented progression per RECIST v.1.1, elective withdrawal from the study, 
the start of new anti-cancer treatment, or study completion or termination. 
Each assessment will be performed as scheduled according to the calendar regardless of any 
dosing delay to prevent the introduction of bias into the assessment of efficacy. Failure to perform 
any of the required disease assessments will result in the inability to determine disease status for 
that time point. 
At the investigator’s discretion, CT scans, MRI, and/or bone scans may be obtained at any time 
when clinically indicated or if progressive disease is suspected. For symptomatic deterioration 
attributed to disease progression, every effort should be made to document progression through 
the use of objective criteria per RECIST v.1.1. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
82 
 
 
6.4.7 
Laboratory Assessments 
 
Laboratory tests will be performed at the study site's local laboratory during the screening period 
and within 48 hours prior to Day 1 of each cycle (including Cycle 1, Day 1) following ≥ 8-hour fast. 
This assessment does not need to be repeated at Cycle 1, Day 1 if it was performed at screening 
within 48 hours prior to start of study treatment. These tests should include: hematology 
[hemoglobin, hematocrit, red blood cell count, platelet count, and WBC with differential count 
(ANC, lymphocytes, monocytes, eosinophils, and basophils)] and biochemistry with renal function 
analysis (serum creatinine, creatinine clearance according to the Cockcroft-Gault formula), liver 
function [AST, ALT, ALP, gamma-glutamyl transferase (GGT), total and direct bilirubin], amylase, 
lipase, glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, 
sodium, potassium, calcium, chloride, magnesium, uric acid, total protein, albumin, and lactate 
dehydrogenase. 
In addition, the following tests are essential assessments at screening, before Cycle 1, Day 1 
dosing: 
• 
HbA1c. 
 
• 
Screening viral serology: HIV, HBsAg, total HBcAb, HCV antibody; additional tests for HBV 
DNA or HCV RNA will be required to confirm eligibility in patients with a positive antibody 
result. 
• 
Coagulation: PTT (or aPTT) and INR. 
 
 
 
Finally, only for patients included in Arms B or C, a complete blood count [hemoglobin, hematocrit, 
red blood cell count, platelet count, and WBC with differential count (ANC, lymphocytes, 
monocytes, eosinophils, and basophils)] will be also performed within 24 hours prior to Day 8 of 
each cycle. 
 
6.4.8 
Home Glucose Monitoring 
 
For any patient who initiates home glucose monitoring (see Section 8.4.2 for management 
guidance of fasting hyperglycemia), a glucose log will be made available for capturing these 
results. The blood glucose log should be reviewed at each clinic visit (see Appendix 1). 
 
 
 
6.4.9 
Pregnancy Tests and Assessment of Fertility 
 
Only female patients of childbearing potential must undergo pregnancy tests done locally: 
 
• 
At screening: In order to ratify eligibility, a negative serum pregnancy test must be confirmed 
either within 96 hours of Cycle 1, Day 1 study treatment administration, or within seven days 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
83 
 
 
of Cycle 1, Day 1 (in this case, confirmed by a negative urine pregnancy test on Cycle 1, Day 
1 prior to dosing). 
• 
During study treatment: Urine/serum pregnancy tests will be performed within 48 hours of 
Day 1 of each following treatment cycle prior to dosing. If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test. In case an additional pregnancy test is 
indicated during the trial, a serum test should be performed. 
• 
At EoT visit (30 days after the last dose of study treatment). 
 
 
 
It is not known whether ipatasertib (GDC-0068) can cross the placenta and may cause harm to 
the fetus when administered to pregnant women or affect reproductive capacity. Therefore, 
ipatasertib (GDC-0068) should not be administered to pregnant women. Women of childbearing 
potential should take necessary precautions to avoid pregnancy while receiving ipatasertib (GDC- 
0068) and for the protocol-defined period following the last dose of ipatasertib (GDC-0068). 
Female patients of childbearing potential must agree to use a highly effective, non-hormonal form 
of contraception (such as surgical sterilization), or two effective forms of contraception or true 
abstinence during the treatment period and within 28 days after the last dose of ipatasertib (GDC- 
0068), three months after the last dose of eribulin, and six months after the last dose of carboplatin 
and gemcitabine or capecitabine, whichever occurs later as it is described on relative Summary 
of Product Characteristics (SmPC). 
The following highly effective methods of contraception are acceptable: 
 
• 
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception]. 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) 
at least six weeks before taking study treatment. In case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow-up hormone level 
assessment. Tubal ligation will not be considered a highly effective non-hormonal methods 
of contraception and will not be acceptable. 
 
 
Or two of the following effective forms of contraception: 
 
• 
Oral contraceptives. 
 
• 
Placement of an intrauterine device or intrauterine system. 
 
• 
Condom with spermicidal foam/gel/film/cream/suppository. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
84 
 
 
• 
Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gem/film/cream/suppository. 
 
 
In case of pregnancy during treatment or within one month after the last dose of study treatment, 
the patient must permanently stop study treatment immediately, withdraw from the trial, and the 
pregnancy must be reported on the Clinical Trial Pregnancy Form as specified in Section 8.9. 
 
 
 
6.4.10 Electrocardiograms (ECGs) and Cardiac Function Assessment 
 
All patients must have a standard 12-lead ECG and an LVEF measurement of at least 50% by 
ECHO (preferably) or MUGA scan at baseline. 
LVEF assessment must be done within 12 weeks prior to Cycle 1, Day 1. Afterwards, cardiac 
function evaluation should be repeated if clinically indicated. 
A 12-lead ECG should be obtained within 28 days prior to the first administration of study 
medication and be printed and kept with the patient’s record. ECG measurements will include QT 
interval and QTc corrected as per QTcF. Afterwards, ECG should be repeated if clinically 
indicated (symptoms, use of drugs known to prolong QTc, etc.). In detail, patients using drugs 
known to cause QTc prolongation should be monitored closely with ECG obtained at a frequency 
no less than every 12 weeks. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. Lead 
placement should be as consistent as possible. ECG recordings must be performed after the 
patient has been resting in a supine position for at least ten minutes. All ECGs are to be obtained 
prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood 
draws). Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG resting 
period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper copies of ECG tracings will be kept as part of the patient's permanent study file at the site. 
If at a particular post-dose timepoint the mean QTcF is > 500 ms and/or > 60 ms longer than the 
baseline value, another ECG must be recorded, ideally within the next five minutes, and ECG 
monitoring should continue until QTcF has stabilized on two successive ECGs. The Medical 
Monitor should be notified. Standard-of-care treatment may be instituted per the discretion of the 
investigator. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
85 
 
 
6.4.11 ECOG performance status 
 
Performance status will be measured using the ECOG performance status scale at screening and 
on Day 1 of each cycle (Table 5). It is recommended, where possible, that a patient’s performance 
status be assessed by the same person throughout the study. 
 
 
Table 5. ECOG Performance Status Scale. 
 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, E.G., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
(http://www.ecog.org/general/perf_stat.html) 
 
 
 
6.4.12 Biological Samples for Exploratory Analysis 
 
6.4.12.1 Tumor Samples 
 
Patients must agree to provide a tumor tissue sample from a metastatic site or the primary breast 
tumor at the time of study entry, with the exception of patients for whom tumor biopsies cannot 
be obtained (e.g., inaccessible tumor or subject safety concern) that may submit an archived 
metastatic tumor specimen only upon agreement from the Sponsor. 
If feasible, patients will also be given the option of providing a tumor tissue sample 
from metastasis or primary breast tumor obtained at disease progression. 
Exploratory studies will be performed on tumor biopsies, or formalin-fixed and paraffin-embedded 
(FFPE) or frozen tumor samples (blocks), or unstained glass slides. 
Details on tumor tissue samples preparation, processing, storage, and shipment will be provided 
in a separate study manual. 
 
 
 
6.4.12.2 Blood Samples 
 
Blood samples are required for all patients during the screening period, after two cycles of study 
treatment, and upon progression or study termination. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
86 
 
 
An aliquot from any of those time-points will be preserved to collect cell-free DNA (cfDNA) 
analysis and compare genomic DNA data from tissue samples and cfDNA data from liquid 
biopsies. 
Details on blood samples processing will be provided in a separate study manual. 
 
 
 
6.4.12.3 Molecular Assessments 
 
The multiple assays, described below, may be performed with the material derived from tumor 
samples and/or the blood samples collected from each patient as part of this study. We will use 
both a hypothesis-driven and a discovery-based approach. It is likely that not all assays described 
below will be performed on samples provided by each patient, possibly because of insufficient 
material or inadequate sample quality. 
We anticipate that as molecular and genomic technologies improve, as yet unspecified 
technologies will be applied. 
Biomarker samples (blood, plasma, and tissue) for mandatory exploratory biomarker research 
include, but not limited to, the following assays and assay platforms: 
• 
Single-nucleotide polymorphisms that may impact exposure or other responses, or next- 
generation sequencing (NGS) results interpretation; 
• 
Somatic mutations and copy-number variations by NGS or PCR-based methods in tumor 
tissue and cfDNA; 
• 
Expression 
analysis 
of 
genes 
related 
to 
 pathway 
activity, 
immune 
infiltration/activation, apoptosis, and breast cancer biology (e.g., intrinsic subtypes); 
• 
IHC-based analysis or quantitative digital IHC of tumor suppressors, such as 
, and 
markers of immune infiltration and activation, such as 
 
, 
 
When a patient withdraws from the study, samples collected prior to the date of withdrawal may 
still be analyzed, unless the patient specifically requests that the samples be destroyed, or local 
laws require destruction of the samples. However, if samples have been tested prior to 
withdrawal, results from those tests will remain as part of the overall research data. 
Given the complexity and exploratory nature of the analyses, data derived from exploratory 
studies, including germline mutations, will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be available 
in accordance with the effective Sponsor policy on study data publication. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
87 
 
 
7 
STUDY DRUGS INFORMATION 
 
7.1 
Formulation, Packaging, and Handling 
 
The investigational medicinal product (IMP) for this study is ipatasertib (GDC-0068). 
Capecitabine, eribulin, carboplatin, gemcitabine, and loperamide is a non-IMP in the study. 
The IMP required for completion of this study (Ipatasertib (GDC-0068)) will be provided by F. 
Hoffmann-La Roche Ltd. The study site will acknowledge receipt of IMPs supplied by Roche by 
returning the appropriate documentation form to confirm the shipment condition and content. Any 
damaged shipments will be replaced. 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfill GMP (annex 13) requirements for labeling. Label text 
will be translated into local language. 
 
IMPs will be disposed of at the study site according to the study site’s institutional standard 
operating procedure with the appropriate documentation. The site must obtain written 
authorization from the Sponsor before any IMP is destroyed, and IMP destruction must be 
documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by the 
study site should be recorded throughout the course of the study. 
The non-IMP used on the study such as Capecitabine, Eribulin, Carboplatin, and Gemcitabine 
will be provided by each investigational site if feasible. 
 
 
 
7.1.1 
Ipatasertib (GDC-0068) 
 
Ipatasertib (GDC-0068) drug product is intended for oral administration and will be supplied as 
film-coated tablets 100 mg and 200 mg. The ingredients in the tablets include microcrystalline 
cellulose, butylated hydroxy anisole, croscarmellose sodium, colloidal silicon dioxide, povidone, 
stearic acid, and Opadry®II Yellow film coat. 
The ipatasertib (GDC-0068) tablets are packaged in high-density polyethylene bottles with 
desiccant; The desiccant is part of the bottle cap. The storage condition is, "do not store above 
25°C, protect from moisture". Information on the shelf life of the ipatasertib (GDC-0068) tablets is 
provided on the label. The IMP is for investigational use only and is to be used only within the 
context of this study. The study drug supplied for this study must be maintained under adequate 
security and stored under the conditions specified on the label until dispensed for patient use or 
returned to the Sponsor/Roche. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
88 
 
 
The unique patient number (UPN) should be recorded on the box label in the spaces provided at 
the time of assignment to patient. Ipatasertib (GDC-0068) is an agent that must be handled and 
administered with care. Patients should be instructed by site personnel to keep their medication 
in the bottles provided and not transfer it to any other container. In addition, site personnel must 
ensure that patients clearly understand the directions for self-medication. Patients will be 
instructed to bring their study drug and medication diary with them to each study visit. 
Patients should be given a sufficient supply to last until their next study visit. The period between 
re-dispensing and last tablet consumed should not exceed one month. Unused drug and/or empty 
bottles should be returned to the site at the next study visit. Returned unused medication must 
not be re-dispensed to patient. 
For additional information of the IMP, see the current ipatasertib (GDC-0068) Investigator’s 
Brochure. 
 
 
 
7.1.2 
Chemotherapy 
 
Chemotherapy should only be administered under the supervision of a qualified physician 
experienced in the appropriate use of cytotoxic medicinal products. 
For information on the formulation, packaging, preparation and dispensing of each chemotherapy 
agent, please see the local prescribing information and relative Summary of Product 
Characteristics (SmPC) of capecitabine, eribulin, carboplatin, and gemcitabine. 
 
 
 
7.2 
Dosage and administration 
 
7.2.1 
Ipatasertib (GDC-0068) 
 
Ipatasertib (GDC-0068) will be administered at the starting dose of 400 mg orally daily, beginning 
on Cycle 1, on Days 1−14 of each 21-day cycle until disease progression, intolerable toxicity, 
death, elective withdrawal from the study, or study completion or termination, whichever occurs 
first. Considering its co-administration with chemotherapeutic agents has not been yet 
investigated, ipatasertib (GDC-0068) in combination with capecitabine, eribulin, or carboplatin 
plus gemcitabine can be given without regard to order dosing. 
For patients assigned to Arm A it is suggested to administrate ipatasertib (GDC-0068) orally daily 
(noon) and capecitabine orally twice daily (morning and evening). 
Patients assigned to Arms B and C will receive ipatasertib (GDC-0068) prior to the intravenous 
infusion of eribulin and carboplatin plus gemcitabine, respectively. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
89 
 
 
Each dose of ipatasertib (GDC-0068) should be taken with a minimum of three ounces (90 mL) 
o 
If a dose is missed (not taken within eight hours after the scheduled 
dosing time), the patient should resume dosing with the next scheduled dose. Missed or 
 
doses will not be made up. 
.No food or fluids 
 will be allowed for eight hours prior to each Day 1 study visit 
until after study laboratory samples for fasting glucose and fasting lipid profile, as applicable, are 
obtained. 
 
 
 
7.2.2 
Loperamide 
 
Diarrhea is a common adverse event associated with ipatasertib (GDC-0068) treatment. In this 
current study, to improve diarrhea management and patient experiences, loperamide (2 mg twice 
a day or 4 mg once a day) will be administered daily as prophylaxis for diarrhea during at least 
the first initial cycle of treatment and may be extended to the next cycle if necessary and if allowed 
by local guidance. 
If side effects of loperamide are not tolerated, doses may be reduced at any time. Investigators 
are encouraged to continue this dosing for the reminder of the study using their discretion based 
on clinical judgments. 
If diarrhea occurs despite loperamide prophylaxis, it should be managed per guidelines in Section 
8.4.1; upon resolution or when study treatment is restarted, loperamide prophylaxis should be 
considered to resume and continue based on clinical judgments (if allowed by local guidance). 
 
 
 
7.2.3 
Capecitabine 
 
The starting dose of capecitabine is 1000 mg/m2 administered orally twice daily (morning and 
evening; equivalent to 2000 mg/m2 total daily dose), for 14 days (followed by a 7-day rest period) 
every 21-day cycle. Capecitabine tablets should be swallowed with water within 30 minutes after 
a meal. 
 
 
 
7.2.4 
Eribulin 
 
The starting dose of eribulin as the ready to use solution is 1.23 mg/m2 (equivalent to eribulin 
mesylate at 1.4 mg/m2) which should be administered intravenously over 2 to 5 minutes on Days 
1 and 8 of every 21-day cycle. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
90 
 
 
7.2.5 
Carboplatin plus Gemcitabine 
 
Carboplatin AUC5 will be administered intravenously on Day 1 plus gemcitabine 1000 mg/m2 
administered intravenously over 30 minutes on Days 1 and 8, every 21-day cycle. 
 
 
 
7.3 
Treatment Modification 
 
Safety and tolerability of all patients will be closely monitored throughout study treatment and the 
follow-up period using the NCI-CTCAE v.5.0. Patients will be assessed in order to detect any AEs 
before administering new study treatment during each treatment visit. Treatment will only be 
administered if clinical evaluation and local laboratory test results are acceptable. 
 
 
 
7.3.1 
General Guidelines 
 
Every effort should be made to administer study treatment on the planned dose and schedule. 
However, in the event of significant treatment-related toxicity, administration of study treatment 
may need to be adjusted as described in the following Sections. 
Reasons for dose modifications (interruption or reduction) and discontinuation, the supportive 
measures taken, and the outcome will be documented in the patient's chart and recorded in the 
CRF. Reasons for not adhering to the following guidance should also be documented in the 
patient’s chart. Sites are strongly encouraged to reach out to the Medical Monitor for any guidance 
on this matter. 
General guidelines for dosage/schedule modification are summarized as follows: 
 
• 
Study treatment (ipatasertib [GDC-0068], chemotherapy, or both) may be interrupted to 
manage toxicity. A dosing gap of up to three consecutive weeks is permitted. Dose hold for 
longer than three weeks for a treatment-related AE will require permanent discontinuation of 
the attributable treatment component (ipatasertib [GDC-0068], chemotherapy, or both). 
• 
Patients who have both ipatasertib (GDC-0068) and chemotherapy treatments interrupted for 
more than consecutive 21 days for a treatment-related AE will require permanent 
discontinuation and will be considered off study. Treatment resumption for patients recovering 
from treatment-related toxicity after consecutive 21 days of treatment interruption but deemed 
to be deriving obvious clinical benefit per the investigator’s best medical judgment is left at 
the investigator’s discretion after Sponsor consultation. 
• 
Treatment with chemotherapy always guides the first day of each cycle. 
 
• 
If the treatment with chemotherapy is temporarily interrupted due to toxicity and the initiation 
of the new cycle is delayed, new cycle Day 1 clinical visits and study procedures (e.g., 
physical examination, ECOG performance status, ECG, blood chemistry, and hematology) 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
91 
 
 
may also be omitted if performed within seven days prior to study drug resumption. However, 
laboratory assessments and clinical visits should be scheduled as needed for follow-up of 
AEs. If treatment delay is required due to hematologic toxicities, the frequency of blood count 
assessments should be increased as clinically indicated. In addition, tumor assessment 
according to Appendix 1 should not be delayed. Once the toxicity has resolved to the 
required level, study treatment and study procedures will be resumed, according to the 
original study cycle day count. 
• 
If the treatment with ipatasertib (GDC-0068) cannot be resumed on the first day of the cycle, 
the patient may continue with chemotherapy if medically appropriate (per investigator 
discretion). Ipatasertib (GDC-0068) omitted doses will not be replaced within the same cycle. 
• 
Arm A, B, and C: If any of chemotherapy treatments cannot be administered on the first day 
of the cycle, delay treatment with ipatasertib (GDC-0068) and chemotherapy concurrently for 
up to seven days shifting the Day 1 within the same cycle. In this way, the study cycle will be 
restarted such that administration of ipatasertib (GDC-0068) in combination with 
chemotherapy agents remain synchronized. 
• 
Arm B: If eribulin cannot be administered on Day 8 of the cycle, the interrupted dose of eribulin 
may be administered later in the same cycle and may be delayed for a maximum of one week. 
If this eribulin dose is finally administered, treatment with ipatasertib (GDC-0068) will be 
continued until Day 21 of this cycle and Day 1 of subsequent cycle will be delayed one week. 
If during two consecutive cycles, eribulin Day 8 dose is delayed, eribulin dose should be 
resumed at one dose level below the previous dose according to Table 8 in the subsequent 
cycle. 
• 
Arm C: If gemcitabine cannot be administered on Day 8 of the cycle, this omitted dose will 
not be replaced within the same cycle. 
• 
Patients whose treatment is interrupted or permanently discontinued due to an AE, including 
abnormal laboratory value, must be followed until resolution or stabilization of the event, 
whichever comes first, which includes all study assessments appropriate to monitor the event. 
• 
For toxicities assessed by the investigator to be unrelated to study treatment and unlikely to 
develop into serious or life-threatening events, treatment may be continued at the same dose 
without reduction or interruption. 
• 
Dose reductions or interruptions may not be required for anemia (non-hemolytic) if 
satisfactorily managed by transfusions. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
92 
 
 
7.3.2 
Ipatasertib (GDC-0068): Dose Interruptions 
 
Ipatasertib (GDC-0068) treatment may be temporarily interrupted in patients who experience 
toxicity considered to be related to study drug. In the event of multiple toxicities, dose interruption 
should be based on the worst toxicity observed. Patients are to be instructed to contact 
investigator as soon as any adverse sign or symptom occurs. 
During ipatasertib (GDC-0068) treatment interruption due to drug-related toxicity, a patient will 
miss all subsequent ipatasertib (GDC-0068) planned doses within that same cycle or even delay 
the initiation of the subsequent cycle. However, if the ipatasertib (GDC-0068)-related AE recovers 
before Day 14 of the same cycle, re-dosing is allowed in that cycle. Ipatasertib (GDC-0068) 
omitted doses will not be replaced within the same cycle. 
If a toxicity is considered to be due solely to ipatasertib (GDC-0068), chemotherapy may be 
administered if there is no contraindication. 
If ipatasertib (GDC-0068) has been withheld for more than 21 consecutive days (as measured 
from the first day of interruption of scheduled ipatasertib [GDC-0068] dosing) because of 
treatment-related toxicity, the patient should be discontinued from ipatasertib (GDC-0068) but 
may continue on study with chemotherapy alone. However, if, in the judgment of the investigator, 
the patient is likely to derive clinical benefit from resuming ipatasertib (GDC-0068) after a hold of 
more than 21 consecutive days, study drug may be restarted with the approval of the Medical 
Monitor. 
 
 
 
7.3.3 
Ipatasertib (GDC-0068): Dose Modifications 
 
If the patient does not tolerate the daily dosing of ipatasertib (GDC-0068), dosing with food may 
be used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or diarrhea. 
No more than two dose reductions of ipatasertib (GDC-0068) per patient will be allowed (See 
Table 6). Any patient requiring an ipatasertib (GDC-0068) dose reduction below 200 mg/day 
should discontinue the ipatasertib (GDC-0068) treatment permanently but may continue on the 
active treatment phase of the study receiving chemotherapy as per the investigator’s discretion. 
Once ipatasertib (GDC-0068) dose has been reduced for a given patient, all subsequent cycles 
should be administered at that dose level, unless further dose reduction is required. Dose re- 
escalation is not permitted for ipatasertib (GDC-0068). 
 
 
Table 6. Dose Reductions for Ipatasertib (GDC-0068). 
 
Dose Level 1 
Ipatasertib (GDC-0068) 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
93 
 
 
 
Starting dose 
400 mg/day 
First dose reduction 
300 mg/day 
Second dose reduction 
200 mg/day 
Third dose reduction 
Not permitted 
1 If the patient continues to experience specified drug-related 
adverse events after the second reduction, the treatment should 
be discontinued. 
 
 
7.3.4 
Chemotherapy: Dose Interruptions and Modifications 
 
The amount of capecitabine, eribulin, and gemcitabine is calculated according to the patient’s 
body surface area (BSA). Weight and height should be recorded at baseline and the BSA 
calculated, thereafter at every scheduled visit for all patients should be re-weighed. The amount 
to be administered must be recalculated if the patient’s body weight has changed by > 10% 
(increased or decreased) from baseline. Re-calculation based upon smaller changes in body 
weight or BSA are at investigators’ discretion. The carboplatin dose is calculated using the Calvert 
formula. 
Dose modifications for chemotherapy agents will be performed as clinically appropriate, based 
on the investigator’s medical judgment. Details in this section can be used as guidance; however, 
only the specific dose levels shown should be mandatory used (Table 7 to Table 10). 
Once chemotherapy dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required. Dose re-escalation is 
not permitted for chemotherapy. 
If the treatment with chemotherapy has been withheld for more than 21 consecutive days (as 
measured from the first day of interruption of scheduled chemotherapy dosing) because of 
treatment-related toxicity, the patient should be discontinued from chemotherapy, but may 
continue on study with ipatasertib (GDC-0068) alone. However, if, in the judgment of the 
investigator, the patient is likely to derive clinical benefit from resuming chemotherapy after a hold 
of more than 21 consecutive days, study drug may be restarted with the approval of the Medical 
Monitor. 
 
 
Table 7. Dose Reductions for Capecitabine. 
 
Dose Level 1 
Capecitabine 
Starting dose 
2000 mg/m2 
First dose reduction 
75% 
Second dose reduction 
50% 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
94 
 
 
 
Dose Level 1 
Capecitabine 
Third dose reduction 
Not permitted 
1 If the patient continues to experience specified drug-related 
adverse events after the second reduction, the treatment should 
be discontinued. 
 
 
The administration of capecitabine should be delayed on Day 1 of each cycle for any of the 
following: 
• 
ANC < 1.5 x 109/L complicated or not by fever or infection. 
 
• 
Platelets < 100.0 x 109/L. 
 
• 
Grade 3 or 4 non-hematologic toxicities. 
 
 
 
No adjustment to the starting dose of capecitabine is recommended in patients with mild renal 
impairment (creatinine clearance = 51 to 80 mL/min [Cockcroft and Gault]). In patients with 
moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction 
to 75% of the capecitabine starting dose is recommended. 
 
 
Table 8. Dose Reductions for Eribulin. 
 
Dose Level 1 
Eribulin 
Starting dose 
1.23 mg/m2 (1.4 mg/m2 eribulin mesylate) 
First dose reduction 
0.97 mg/m2 (1.1 mg/m2 eribulin mesylate) 
Second dose reduction 
0.62 mg/m2 (0.7 mg/m2 eribulin mesylate) 
Third dose reduction 
Not permitted 
1 If the patient continues to experience specified drug-related adverse events 
after the second reduction, the treatment should be discontinued. 
 
 
The administration of eribulin should be delayed on Day 1 or Day 8 of each cycle for any of the 
following: 
• 
ANC < 1.0 x 109/L complicated or not by fever or infection. 
 
• 
Platelets < 75.0 x 109/L. 
 
• 
Grade 3 or 4 non-hematologic toxicities. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
95 
 
 
Table 9. Dose Reductions for Carboplatin plus Gemcitabine. 
 
Dose Level 1 
Carboplatin 
Gemcitabine 
Starting dose 
AUC5 
1000 mg/m2 
First dose reduction 
AUC4 
750 mg/m2 
Second dose reduction 
Not permitted 
500 mg/m2 
Third dose reduction 
Not permitted 
Not permitted 
1 If the patient continues to experience specified drug-related adverse events after the second 
reduction, the treatment should be discontinued. 
 
 
The administration of carboplatin or gemcitabine should be delayed on Day 1 of each cycle for 
any of the following: 
• 
ANC < 1.5 x 109/L complicated or not by fever or infection. 
 
• 
Platelets < 100.0 x 109/L. 
 
• 
Grade 3 or 4 non-hematologic toxicities. 
 
 
 
Day 8 of gemcitabine treatment may be given according to the Table 10 
 
 
 
Table 10. Gemcitabine Dose on Day 8. 
 
ANC 
 
Platelets 
Gemcitabine 
≥ 1.0 x 109/L 
And 
> 100.0 x 109/L 
1000 mg/m2 
0.5-0.9 x 109/L 
Or 
75.0-100.0 x 109/L 
750 mg/m2 
< 0.5 x 109/L 
Or 
< 75.0 x 109/L 
Not permitted 
 
ANC = absolute neutrophil count. 
 
 
7.4 
General concomitant medication and additional assistance guidelines 
 
Concomitant treatment and prior medication are defined as non-IMP. Concomitant treatment 
includes any prescribed medication or phytotherapy between the 28 days prior to the 
administration of the first treatment dose and the last safety visit during treatment period. All 
concomitant treatments will be recorded. After this time, information will only be collected on any 
anti-cancer drugs taken by the patient until end of study. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
96 
 
 
Information on concomitant medication will include start date, end date, brand or generic name, 
route of administration, dose, and treatment indication. 
The following concomitant treatments are permitted during the study: 
 
1. Oral contraceptives, as allowed per local guidelines. 
 
2. Pre-medication with steroids, antihistamines, antipyretics, and/or analgesics (e.g., prior to 
scans or chemotherapy administration), and steroids used on a single day to manage 
infusion-related reactions or allergic reactions. 
3. Prophylactic loperamide is recommended for all patients during at least the first initial cycle 
of treatment and may be extended to the next cycle (if necessary and if allowed by local 
guidance, except when the Medical Monitor approves omission). Patients who experience 
diarrhea should be on treatment doses of loperamide per the management guidelines 
provided in Section 8.4.1; please refer to that section for additional details. Patients should 
be educated/reminded to be cognizant of the onset, duration, severity, and frequency of 
symptoms and the medications administered. 
4. Erythropoiesis-stimulating agents (ESA) are allowed (such as Procrit®, Aranesp®, Epogen®) 
for the supportive treatment of anemia. Blood transfusions are permitted during the study. 
5. The prophylactic use of granulocyte-colony stimulating factors (G-CSF; GM-CSF) is not 
allowed during the first treatment cycle but can be used for cases of neutropenia arising during 
treatment, in accordance with the National Comprehensive Cancer Network (NCCN) 
guidelines. 
6. Bisphosphonate therapy or RANKL inhibitor therapy (e.g., zoledronic acid and denosumab) 
used specifically to prevent skeletal events. 
7. Luteinizing hormone-releasing hormone or gonadotropin-releasing hormone agonists for 
ovarian function preservation are allowed. 
8. Prophylactic or therapeutic anticoagulation therapy according to Inclusion Criteria #14.d) 
(please refer to Section 5.2). 
9. Any medications deemed necessary to ensure patient safety and well-being may be 
administered at the discretion of the investigator with the exception of prohibited therapies 
described below. 
 
 
 
7.5 
Prohibited Concomitant Medication 
 
Use of the therapies described below is prohibited during the study treatment period: 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
97 
 
 
1. Investigational therapy (other than protocol-mandated study treatment) is prohibited within 14 
days prior to initiation of study treatment and during study treatment. Patients are not allowed 
to participate in other clinical trials while they are participating in the PATHFINDER trial. 
2. Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, and radiotherapy) is prohibited for various 
time periods prior to starting study treatment, depending on the agent (See Section 7.4), and 
during study treatment, until disease progression is documented and the patient has 
discontinued study treatment, with the exception of palliative radiotherapy under certain 
circumstances (See Section 7.8 for details). 
3. Any cancer related surgery is prohibited throughout the duration of the active treatment phase 
of the study. 
4. Chronic use of a strong CYP3A inhibitor or inducer, or sensitive CYP3A substrates with a 
narrow therapeutic window that are deemed not permissible by the Medical Monitor after 
enrollment (refer to the guidance in Section 7.6). 
5. Vaccination with a live vaccine. 
 
 
 
7.6 
Medications Given with Precaution 
 
Although not prohibited, the following drugs should be avoided or temporarily used with 
precaution. 
Please, 
refer 
to 
the 
following 
webpage 
(https://drug- 
interactions.medicine.iu.edu/Main-Table.aspx) for a more exhaustive list. 
1. Strong CYP3A inhibitors, such as, but not limited to, atazanavir, clarithromycin, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandamycin, and/or voriconazole. 
2. Strong CYP3A inducers, such as, but not limited to, rifampin, carbamazepine, rifapentine, 
phenytoin, and/or phenobarbital. 
3. CYP3A substrates with a narrow therapeutic index, such as, but not limited to, alfentanil, 
astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, ergot alkaloids ergotamine, and/or dihydroergotamine. 
4. Patients who require short-term use of a strong CYP3A inhibitor or inducer or use of sensitive 
CYP3A substrates with a narrow therapeutic window for medical treatment (e.g., an 
alternative treatment cannot be used) must exercise caution and all study treatment should 
be temporarily held until at least seven days after the last dose of these drugs. 
5. If daily systemic steroids are initiated for treatment of any toxicity or other condition, they must 
be tapered to ≤ 10 mg/day oral prednisone or equivalent before ipatasertib (GDC-0068) can 
be resumed. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
98 
 
 
6. Patients using drugs known to cause QTc prolongation should be monitored closely with 
ECGs performed at a frequency no less than every 12 weeks. 
 
 
 
7.7 
Herbal Therapies and Prohibited Food 
 
1. Concomitant use of herbal therapies is not recommended because their pharmacokinetics, 
safety profiles, and potential drug−drug interactions are generally unknown. However, herbal 
therapies not intended for the treatment of cancer may be used during the study at the 
discretion of the investigator. 
2. Consumption of grapefruit juice, a potent CYP3A4 enzyme inhibitor, is prohibited during the 
study treatment period and for 10 days after the last dose of study treatment. 
3. Consumption of St. John’s wort (hyperforin), a potent CYP3A4 enzyme inducer, is prohibited 
for up to 14 days prior to and during the study treatment period, and for 10 days after the last 
dose of study treatment. 
 
 
 
7.8 
Cautionary Therapy 
 
1. Palliative radiotherapy (e.g., treatment of known bone metastases or symptomatic relief of 
pain) as outlined below: 
• 
Palliative radiotherapy is permitted for a preexisting lesion, provided it does not interfere 
with the assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
a site of measurable disease). 
• 
All study treatment during palliative radiotherapy should be temporarily held for at least 
seven days before and after the procedure. For single-day radiotherapy, this hold may be 
shorter, if discussed by the investigator with, and approved in advance by, the Medical 
Monitor. 
2. Surgery as part of medical treatment in the absence of radiographic disease progression must 
exercise with caution. All study treatment should be temporarily held for at least seven days 
before and after the procedure. For minor surgeries, this hold may be shorter, if discussed by 
the investigator with, and approved in advance by, the Medical Monitor. 
 
 
 
7.9 
Medication Errors and Overdose 
 
Medication errors may result in this study from the administration or consumption of the wrong 
drug, by the wrong patient, at the wrong time, or at the wrong dosage strength, drug misuse or 
drug abuse. Patient medication errors should be recorded in the relevant section in the CRF. In 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
99 
 
 
the event of an error in the administration of the medication, the Sponsor should be informed 
immediately. 
Medication errors must be reported irrespective of the presence of an associated AE, including: 
 
• 
Medication errors involving patient exposure to the IMP. 
 
• 
Drug misuse or drug abuse 
 
• 
Any possible medication errors or use of the medication not defined in the protocol that 
do or do not involve the participating patient. 
 
 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, 
the medication error should be captured on the AE page and should be reported immediately to 
the Sponsor as a SAE. 
Regarding ipatasertib (GDC-0068), in Study PAM4743g (single-agent, dose-escalation study in 
patients with advanced solid tumors), MTD was exceeded at 800 mg with two DLTs of grade 3 
asthenia and grade 3 nausea. Cases of overdosing should be managed in accordance with best 
medical practice. 
 
 
7.10 Compliance 
 
At the beginning of each cycle patients will be required to return the used package of ipatasertib 
(GDC-0068) and capecitabine. 
Investigator should check compliance for chemotherapy as well as the completed patient diary 
for ipatasertib (GDC-0068) and capecitabine accountability. 
Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for 
the next cycle. 
To be considered compliant, each study patient must have received at least 80% of the planned 
number of doses of primary therapy based on the number of days of actual dose administration. 
Dose adjustments must follow instructions provided in the Section 7.3. 
 
 
 
7.11 Drug Storage and Drug Accountability 
 
Storage conditions stated in the Study Reference Safety Document (e.g., SmPC, or Local Product 
Document) may be superseded by the label storage information. 
Investigators and site staff are reminded to continuously monitor room storage temperatures and 
ensure that thermometers are working correctly as required for proper storage of IMP. These 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
100 
 
 
include thermometers for both the room storage and refrigerator storage. Any temperature 
excursions must be reported immediately to the Sponsor and documented. Once a deviation is 
identified, the IMP must be quarantined and not used until the Sponsor provides documentation 
of permission to use the IMP. 
At the end of the trial, the Sponsor will provide instructions as to disposition of any unused IMP. If 
the Sponsor authorizes destruction at the trial site, the investigator must ensure that the materials 
are destroyed in compliance with applicable environmental regulations, institutional policy, and 
any special instructions provided by the Sponsor. Destruction must be adequately documented. 
Ipatasertib (GDC-0068) tablets must be stored in their original container according to labelled 
storage conditions. 
Medication should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Returned medication should be stored separately from medication that 
needs to be dispensed. 
Accurate records of all study drugs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Accountability Log. In particular, to ensure adequate 
records, ipatasertib (GDC-0068) tablets will be accounted for as instructed by the Sponsor/Roche. 
Patients are requested to return previously dispensed containers as well as their completed 
patient diary to the clinic at each visit for accountability purposes even if they will not be issued 
with new medication at that visit. 
 
 
 
8 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
 
Safety assessments will consist of monitoring and recording protocol-defined AEs, adverse 
events of special interest (AESIs), and SAEs; measurement of protocol-specified hematology, 
clinical chemistry, measurement of protocol-specified vital signs; and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to competent authorities, 
other applicable regulatory authorities, and participating investigators, in accordance with 
International Conference on Harmonization (ICH) guidelines, European Clinical Trials Regulation 
(Regulation (EU) No 536/2014), and/or local regulatory requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the study drug to the regulatory agencies and competent 
authorities within seven calendar days after being notified of the event. The Sponsor or its 
designee will report other relevant SAEs associated with the use of the study medication to the 
appropriate competent authorities (according to local guidelines), investigators, and central 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
101 
 
 
Institutional Review Boards (IRBs)/ECs by a written safety report within 15 calendar days of 
notification. 
 
 
 
8.1 
AEs Definitions 
 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporarily associated with the 
use of an IMP, regardless of whether it is considered related to the IMP or not. 
An abnormal test finding should only be reported as an AE if meets any of the following criteria: 
 
• 
Is associated with accompanying symptoms and a general diagnostic term, including the 
symptoms and the abnormal test finding, cannot be defined. 
• 
Requires additional diagnostic testing or medical/surgical intervention, leads to a change in 
study drug(s) dosing or discontinuation from the study. 
• 
Needs additional concomitant drug treatment. 
 
• 
Is considered to be an AE by the investigator or by the Sponsor. 
 
 
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
The causal relationship between an AE and the IMP will be defined as follows: 
 
• 
Unrelated: The temporal association between the AE and the administration of the IMP makes 
a causal relationship unlikely, or the patient’s clinical state or the study procedure/conditions 
provide a sufficient explanation for the AE. 
• 
Related: The temporal association between the AE and the administration of the IMP makes 
a causal relationship possible, and the patient’s clinical state or the study 
procedure/conditions do not provide a sufficient explanation for the AE. 
 
 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the IMP. If the investigator does not know whether or not the 
IMP caused the event, then the event will be handled as “related to IMP” for reporting purposes. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
102 
 
 
The descriptions and grading scales found in the revised NCI-CTCAE v.5.0 will be utilized for all 
toxicity reporting. A copy of the NCI-CTCAE v.5.0 can be downloaded from the CTEP website: 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_ 
Reference_8.5x11.pdf). 
- 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
- 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental activities of daily living (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. 
* 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. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it meets one of the criteria 
for SAEs, listed below. Seriousness rather than severity serves as a guide for defining regulatory 
reporting obligations. 
 
 
 
8.2 
SAEs 
 
Per definition, a SAE is defined as any AE that either: 
 
• 
Results in death (e.g., the AE actually causes or leads to death). 
 
• 
Is life-threatening (e.g., the AE, in the view of the investigator, places the patient at immediate 
risk of death when it occurs). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
• 
Results in persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person ability to conduct normal life functions). 
• 
Constitutes a congenital anomaly/birth defect (in a neonate/infant born to a mother exposed 
to the IMP. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
103 
 
 
 
 
Definition of life-threatening: An AE is life-threatening if the patient was at immediate risk of death 
from the event as it occurred, e.g., does not include an event that might have caused death if it 
had occurred in a more serious form. For instance, drug induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though drug induced 
hepatitis can be fatal. 
Definition of hospitalization: AEs requiring hospitalization should be considered serious. In 
general, hospitalization means that the patient has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment which would not have 
been appropriate at the study site. When in doubt as to whether hospitalization occurred or was 
necessary, the AE should be considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of an 
AE, need not to be notified according to immediate reporting criteria. If anything untoward is 
reported during any procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ 
attributed according to the usual criteria. 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE not 
to be notified according to immediate reporting criteria. Examples include: 
• 
Admission for treatment of a pre-existing condition not associated with the development of a 
new AE or with a worsening of the pre-existing condition (e.g., for work-up of persistent pre- 
treatment lab abnormality). 
• 
Social admission (e.g., patient has no place to sleep). 
• 
Administrative admission (e.g., for yearly physical examination). 
• 
Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol). 
• 
Optional admission not associated with a precipitating clinical AE (e.g., for elective cosmetic 
surgery). 
• 
Hospitalization for observation without a medical AE. 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation and/or for the individual patient. 
• 
Admission exclusively for the administration of blood products. 
 
 
Definition of clinically/medically significant event: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
104 
 
 
the development of drug dependency or drug abuse. Clinically/medically significant events MUST 
be reported as SAEs. 
In this clinical trial and as defined in this protocol, SAEs and hospitalizations unequivocally and 
solely related to established tumor disease progression will NOT be treated as SAEs for reporting 
obligations. 
 
 
 
8.3 
AESIs to Report Immediately 
 
AESIs are required to be reported by the Investigator to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event). Please, refer to Section 8.6, for reporting instructions. 
AESIs for this study include: 
 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
 
o 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product. This term applies only when a contamination of the study drug is suspected. 
• 
Cases of potential drug-induced liver injury (DILI) as follows: 
 
o 
AST and/or ALT elevations >3 times the ULN with concurrent elevation of total bilirubin 
(TBL) > 2 times the ULN as defined by Hy's Law (see Appendix 3) (or clinical jaundice 
if TBL measures are not available), except in patients with documented Gilbert’s 
syndrome. For patients with Gilbert’s syndrome, elevation of direct bilirubin >2 times the 
ULN should be used instead. 
• 
Grade ≥ 3 Hyperglycemia. 
 
• 
Grade ≥ 3 ALT/AST elevations. 
 
• 
Grade ≥ 2 colitis/enterocolitis. 
 
• 
Grade ≥ 3 diarrhea. 
 
• 
Grade ≥ 3 rash. 
 
• 
Grade ≥ 2 pneumonitis. 
 
 
 
All SAEs/AESIs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient's participation in the study, must be followed until any of the 
following occurs: 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
105 
 
 
• 
The event resolves. 
 
• 
The event stabilizes. 
 
• 
The event returns to baseline, if a baseline value/status is available. 
 
• 
The event can be attributed to agents other than the IMP or to factors unrelated to study 
conduct. 
It becomes unlikely that any additional information can be obtained (patient or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of due 
diligence with follow-up efforts). 
 
 
8.4 
AEs Management Guidelines 
 
8.4.1 
Diarrhea Management Guidelines 
 
Treatment modifications for diarrhea (any grade), when it occurs, should be instituted as early as 
possible. As shown in Table 11, guidelines for treatment of diarrhea following the prophylactic 
dose of loperamide (where allowed) includes use of loperamide 2 mg every 4 hours or after each 
loose, watery stool, up to the maximum total dose of 16 mg/day or per institutional guidelines and 
standard of care, including, but not limited to, additional therapy with Lomotil® (diphenoxylate and 
atropine), codeine, or octreotide. Duration of diarrhea may be minimized by taking ipatasertib 
(GDC-0068) with food, avoiding lactose-containing foods, and hydrating with 8−10 glasses per 
day (~355 mL/glass) of electrolyte-containing clear liquid, such as broth or low-calorie drinks. 
For diarrhea grade ≥ 2 that persists for more than five days, despite treatment with anti-diarrheal 
agent(s) and/or withholding dosing of ipatasertib (GDC-0068), gastroenterologists should be 
consulted to rule out the risk of colitis and infection (e.g., obtaining CT images or a stool culture 
for infectious workup [Clostridium difficile, enteric bacteria, cytomegalovirus, etc.]). Patients 
should be educated on the symptoms and importance of early reporting of diarrhea to receive 
instructions of treatment and prevention of dehydration so that patients can be promptly and 
appropriately managed. Educational materials will be provided to investigators and patients 
outlining these guidelines. 
Dose intensity of chemotherapy agents should be maintained as tolerated. Dose reductions of 
ipatasertib (GDC-0068) will be by one level at a time (e.g., 400 mg to 300 mg; 300 mg to 200 mg) 
as outlined in Section 7.3.3. If grade ≥ 2 diarrhea persists following dose reductions of ipatasertib 
(GDC-0068) to 200 mg daily and with maximum treatment for diarrhea, ipatasertib (GDC-0068) 
should be discontinued. Chemotherapy dose reduction or discontinuation should be considered 
for diarrhea grade ≥ 3 and when diarrhea persists even after ipatasertib (GDC-0068) 
discontinuation. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
106 
 
 
 
Table 11. Diarrhea Management Guidelines. 
 
Severity of Diarrhea 1 
Management Guideline 
Prevention 
• 
All patients are mandated to receive loperamide (2 mg 
twice a day or 4 mg once a day) as prophylaxis for 
diarrhea during at least the first initial cycle of treatment 
and may be extended to the next cycle if necessary (if 
necessary and if allowed by local guidance). If there are 
clinical concerns that preclude the use of loperamide 
prophylaxis in Cycle 1, discussion with the Medical 
Monitor is required. Loperamide dose adjustment may 
be made per investigator discretion after discussion with 
the Medical Monitor. 
• 
After the first cycle, investigators are encouraged to 
continue this dosing for the remainder of the study using 
their discretion as clinically indicated. 
Grade 1 
Increase of < 4 stools per day 
over baseline; mild increase in 
ostomy output compared with 
baseline 
• 
Continue study drugs at the current dose level. 
• 
Manage with loperamide as early as possible 4 mg 
initially and then 2 mg every four hours or after every 
unformed stool until after 12-hour diarrhea-free interval. 
• 
Dietary modifications, such as avoiding any lactose- 
containing foods and eating small meals. 
• 
Hydration with 8−10 glasses per day (~355 mL/glass) of 
clear liquid, such as broth or low-calorie drinks with 
electrolytes. 
• 
Upon resolution, loperamide prophylaxis can be 
considered and continues as clinically indicated, if 
allowed by local guidance. 
Grade 2 
Increase of 4−6 stools per day 
over baseline; moderate 
increase in ostomy output 
compared with baseline 
• 
Interrupt ipatasertib (GDC-0068) until diarrhea improves 
to grade 1 or better. Ipatasertib (GDC-0068) can be 
resumed at the same dose or one dose lower per 
investigator's evaluation upon improvement to grade 1 
or better. 
• 
For recurrent grade 2 diarrhea, reduce ipatasertib (GDC- 
0068) by one (or one additional) dose level. 
• 
Rule out infectious etiology. 
• 
Manage with loperamide as early as possible 4 mg 
initially and then 2 mg every four hours or after every 
unformed stool until after 12-hour diarrhea-free interval. 
• 
Dietary modifications, such as avoiding any lactose- 
containing foods and eating small meals. 
• 
Hydration with 8−10 glasses per day (~355 mL/glass) of 
clear liquid, such as broth or low-calorie drinks with 
electrolytes. 
• 
For non-infectious diarrhea lasting more than 48 hours 
despite optimal loperamide treatment, manage with 
second-line anti-diarrheal agents, including, but not 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
107 
 
 
 
Severity of Diarrhea 1 
Management Guideline 
 
limited to Lomotil®, codeine, or octreotide, or as per 
institutional guidelines. 
• 
Upon  resolution,  loperamide  prophylaxis  can  be 
considered and continues as clinically indicated, if 
allowed by local guidance. 
Grade 3 
Increase of ≥ 7 stools per day 
over baseline; incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to baseline; 
limiting self-care ADL 
• 
Interrupt ipatasertib (GDC-0068) and chemotherapy 
until diarrhea improves to grade 1 or better. Ipatasertib 
(GDC-0068) can be resumed at one dose lower. 
• 
For recurrent grade 3 diarrhea, reduce ipatasertib (GDC- 
0068) by one (or one additional) dose level. Consider 
reducing chemotherapy by one dose level when 
treatment is restarted. 
• 
Rule out infectious etiology. 
• 
Treat per grade 2 management guidelines and 
supportive care. 
• 
Upon resolution, loperamide prophylaxis can be 
considered and continues as clinically indicated, if 
allowed by local guidance. 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
• 
Permanently discontinue ipatasertib (GDC-0068). 
• 
Interrupt chemotherapy until diarrhea improves to grade 
1 or better. Consider resuming chemotherapy regimen 
by one dose level lower or discontinuing chemotherapy 
per investigator's discretion. 
• 
Rule out infectious etiology. 
• 
Treat per grade 2 management guidelines and 
supportive care. 
 
ADL = activities of daily living; BID= twice a day; NCI-CTCAE v.5.0 = National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0; QD = once a day. 
1 Diarrhea, as defined by NCI-CTCAE v.5.0, a disorder characterized by frequent and watery 
bowel movements. 
 
 
8.4.2 
Fasting Hyperglycemia 
 
Because the PI3K-AKT-mTOR pathway is involved in glucose metabolism, inhibition of this 
signaling network and its target mTOR can cause hyperglycemia, which is a toxicity common to 
the class of PI3K-AKT-mTOR inhibitors. Ipatasertib (GDC-0068)-induced hyperglycemia is 
associated with transient insulin concentration changes and is generally asymptomatic. 
Hyperglycemia, including cases of grade 3, grade 4, and a single case of grade 5 hyperglycemia, 
has been reported in patients receiving ipatasertib (GDC-0068) treatment. Isolated cases of 
hyperglycemia associated with ketoacidosis or hyperosmolar conditions resulting in dehydration 
and renal insufficiency have also been observed, particularly in diabetic patients. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
108 
 
 
Fasting is defined as abstaining from food and drink (with the exception of water) for at least eight 
hours. In general, patients with diabetes either requiring insulin therapy or with a baseline fasting 
glucose > 150 mg/dL (8.3 mmol/L) or high hemoglobin A1c as defined as > 7%, suggesting poorly 
controlled diabetes, should be excluded from studies with ipatasertib (GDC-0068). Fasting 
glucose levels should be carefully monitored per protocol guidelines. Patients should be 
instructed to report symptoms associated with hyperglycemia such as thirst, frequent urination, 
and blurred vision. Hyperglycemia should be managed per institutional standards of care, and per 
protocol guidelines. Use of oral anti-hyperglycemic agents (e.g., metformin) for patients 
experiencing grade ≥ 2 hyperglycemia should be considered. For grade ≥ 2 hyperglycemia, 
ipatasertib (GDC-0068) dosing may be interrupted or reduced per protocol guidelines. 
To diminish the risk of hypoglycemia, insulin should not be administered for asymptomatic 
hyperglycemia of any grade. Moreover, in the event of ipatasertib (GDC-0068) interruption, anti- 
diabetic medications may need to be held or reduced (per investigator judgement) and glucose 
should be monitored closely to minimize the risk of hypoglycemia. 
Dose modification guidelines for fasting hyperglycemia attributable to study treatment are outlined 
below (See Table12) and are intended to provide guidance for fasting glucose measurements 
assessed in the clinic. Decisions regarding study treatment should be made on fasting levels 
drawn in the clinic whenever possible. 
Home glucose measurements may be used to trigger contact between patient and investigative 
site team and may lead to an unscheduled clinic visit to assess fasting glucose. Guidance for 
when to call the investigator/site staff (or designated endocrinologist, if applicable) should be 
provided to patients for hypoglycemia (e.g., glucose value under 70 mg/dL) and hyperglycemia 
(e.g., glucose value over 300 mg/dL). Alternative thresholds may be selected as clinically 
indicated per investigator discretion or institutional guidance and noted in the source documents. 
For any patients performing home glucose monitoring, the blood glucose log should be reviewed 
at each clinic visit (and source data retained), entry of results into the patient’s CRF will be limited 
to values which result in intervention. 
 
 
Table12. Fasting Hyperglycemia Management Guidelines. 
 
Fasting Glucose 
Values 
Management Guideline 
Fasting glucose value 
> ULN to 160 mg/dL 
(8.9 mmol/L) 1 
• 
Continue ipatasertib. 
• 
Provide patient with education on a diabetic diet and consider 
home glucose monitoring. 
• 
Consider oral anti-diabetic medications (e.g., metformin). 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
109 
 
 
 
Fasting Glucose 
Values 
Management Guideline 
Fasting glucose value 
>160 to 250 mg/dL (> 
8.9−13.9 mmol/L) 1 
• 
Interruption of ipatasertib until fasting glucose values return to ≤ 
160mg/dL (8.9 mmol/L). 
• 
Encourage a diabetic diet and initiate home glucose monitoring. 
• 
Start oral anti-diabetic medications (e.g., metformin). 
• 
If patient is already on an oral anti-diabetic medication, the dose 
of ipatasertib should be reduced by one dose level (see Section 
7.3.3 for further details). 
• 
If the patient previously has not been receiving any oral 
antidiabetic medication, ipatasertib may be resumed at the 
previous dose level with initiation of oral anti-diabetic 
medication. 
Fasting glucose value 
250 to 500 mg/dL (> 
13.9−27.8 mmol/L) 1 
• 
Interrupt ipatasertib until fasting glucose values return to ≤ 
160 mg/dL (8.9 mmol/L). 
• 
Encourage a diabetic diet and initiate home glucose monitoring. 
• 
Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used. 
• 
Start (or increase dose of) oral anti-diabetic medications 
(e.g., metformin). 
• 
If the patient is already on an oral anti-diabetic medication, 
ipatasertib should be reduced by one dose level when treatment 
is restarted. 
• 
If previously, the patient has not been receiving any oral anti- 
diabetic medication, ipatasertib may be resumed at the previous 
dose level with initiation of oral anti-diabetic medication. 
• 
If fasting glucose value exceeds 250 mg/dL (13.9 mmol/L) again, 
the dose of ipatasertib should be reduced by one dose level 
when treatment is restarted (see Section 7.3.3 for further 
details). 
Fasting glucose value 
> 500 mg/dL (> 27.8 
mmol/L) 1 
• 
Interrupt ipatasertib until fasting glucose values return to ≤ 160 
mg/dL (8.9 mmol/L). 
• 
Encourage a diabetic diet and initiate home glucose monitoring. 
• 
Treat hyperglycemia per standard of care, noting risk of 
hypoglycemia if insulin is used. 
• 
Start (or increase dose of) oral anti-diabetic medications 
(e.g., metformin). 
• 
Assess for volume depletion and appropriate intravenous or oral 
hydration. 
• 
Reduce ipatasertib by one dose level when treatment is 
restarted (see Section 7.3.3 for further details). 
• 
If fasting glucose value exceeds 500 mg/dL (27.8 mmol/L) again, 
permanently discontinue ipatasertib. 
ULN = upper limit of normal. 
1 Note: For all grades, the patient should receive education on a diabetic diet. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
110 
 
 
8.4.3 
Nausea and/or Vomiting 
 
Dose reductions for nausea and/or vomiting should occur only if the symptoms persist despite a 
minimum of two treatments with adequate (combination) anti-emetic treatment(s), including 
ondansetron and other anti-emetics (e.g., prochlorperazine or metoclopramide per institutional 
guidelines). Dose modification and symptom management guidelines for persistent nausea 
and/or vomiting attributable to ipatasertib (GDC-0068) are outlined in Table 13. 
 
 
 
Table 13. Nausea and vomiting management guidelines. 
 
Severity of Nausea and/or 
Vomiting 
Management Guideline 
Grade 1 
• 
Continue study drugs. 
• 
Provide supportive care as needed. 
Grade 2 
• 
Continue study drugs. 
• 
Provide maximum supportive care as needed per local 
guidelines, with a minimum of two anti-emetics, including 
ondansetron. 
Grade ≥ 3 
• 
Interrupt ipatasertib (GDC-0068) and chemotherapy 
until nausea or vomiting resolves to grade 2 or better. 
• 
Provide maximum supportive care per local guidelines, 
with a minimum of two anti-emetics, including 
ondansetron. 
• 
If grade ≥ 3 nausea or vomiting recurs, ipatasertib (GDC- 
0068) should be reduced by one dose level when 
treatment is restarted. Chemotherapy dose may also be 
reduced by one level if recurrent grade 3 nausea or 
vomiting occurs after dose reduction of ipatasertib 
(GDC-0068) has occurred. 
 
 
8.4.4 
Rash 
 
Ipatasertib (GDC-0068) should be permanently discontinued for rash associated with Stevens- 
Johnson syndrome, toxic epidermal necrolysis, or other suspected severe hypersensitivity or 
allergic reaction. Dose modification and symptom management guidelines for skin toxicity 
attributable to study treatment are shown in Table 14. 
 
 
 
Table 14. Rash Management Guidelines. 
 
Severity of Rash 
Management Guideline 
Grade 1 
• 
Continue study drugs. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
111 
 
 
 
 
• 
Consider topical steroids. 
Grade 2 
• 
Interrupt ipatasertib (GDC-0068) treatment until 
resolution to grade 1 or better or the toxicity is no 
longer clinically significant. 
• 
Treat rash with topical steroids. 
• 
Consider treatment of rash with oral steroids. 
Grade 3 
• 
Interrupt ipatasertib (GDC-0068) treatment until 
resolution to grade 1 or better or the toxicity is no 
longer clinically significant. 
• 
Treat rash with topical and systemic steroids. 
• 
Consider dermatological consultation and skin biopsy. 
 
• 
If the skin toxicity resolves to grade 1 or better or is no 
longer clinically significant within 21 days, following 
completion of the steroid taper, ipatasertib (GDC-0068) 
may be resumed at one dose level below the previous 
dose. 
• 
If recovery of the skin toxicity to grade 1 or better does 
not occur or skin toxicity remains clinically significant 
continuously for three weeks, or grade 3 rash recurs, 
permanently discontinue ipatasertib (GDC-0068). 
Grade 4 
• 
Ipatasertib 
(GDC-0068) 
should 
be 
permanently 
discontinued. 
• 
Administration of systemic steroids (oral or intravenous) 
is recommended. 
• 
Consider dermatological consultation and skin biopsy. 
 
 
8.4.5 
Pneumonitis 
 
Pneumonitis is not known to be causally related to any of the study drugs; however, it has been 
observed with other drugs treating pathways similar to ipatasertib (GDC-0068). Every effort 
should be made to determine the etiology of dyspnea and changes in pulmonary function (See 
Table 15). 
 
 
 
Table 15. Pneumonitis Management Guidelines. 
 
Severity of Pneumonitis 
Management Guideline 
Grade 1 
• 
Continue study drugs. 
• 
Perform CT scan and PFTs. Repeat CT scan every eight 
weeks until a return to baseline. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
112 
 
 
 
Severity of Pneumonitis 
Management Guideline 
Grade 2 
• 
Interrupt ipatasertib (GDC-0068) and chemotherapy 
treatments until improvement to grade 1 or better. 
Consider 
resuming 
ipatasertib 
(GDC-0068) 
and 
chemotherapy at same dose level or one dose level 
below the previous dose per investigator's assessment. 
• 
If infectious etiology is ruled out or if improvement is not 
evident with broad spectrum antibiotics, prescribe 
systemic steroids as clinically indicated. 
• 
Perform CT scan and PFTs. Repeat CT scan every four 
weeks until a return to baseline. 
• 
For recurrent non-infectious grade 2 pneumonitis, 
ipatasertib (GDC-0068) must be resumed at one dose 
level below the previous dose. Consider resuming 
chemotherapy at same dose or one dose below the 
previous per investigator's assessment. 
• 
Discontinue ipatasertib (GDC-0068) if recovery to grade 
1 or better is not evident within 21 days. Chemotherapy 
dose should be resumed at one dose level below the 
previous dose or discontinued per investigator's 
assessment. 
Grade 3 
• 
Interrupt ipatasertib (GDC-0068) and chemotherapy 
treatments until improvement to grade 1 or better. 
Resume ipatasertib (GDC-0068) and chemotherapy at 
or one dose level below the previous dose per 
investigator's assessment. 
• 
If infectious etiology is ruled out or if improvement is not 
evident with broad spectrum antibiotics, prescribe 
systemic steroids as clinically indicated. 
• 
Perform CT scan and PFTs. Repeat CT scan every four 
weeks until a return to baseline. Bronchoscopy is 
recommended. Bronchoscopy is recommended. 
• 
For recurrent non-infectious grade 3 pneumonitis 
events, ipatasertib (GDC-0068) and chemotherapy 
should be permanently discontinued. 
• 
Discontinue ipatasertib (GDC-0068) and chemotherapy 
if recovery to grade 1 or better is not evident within 21 
days. 
Grade 4 
• 
Permanently discontinue ipatasertib (GDC-0068) and 
chemotherapy. 
• 
If infectious etiology is ruled out or if improvement is not 
evident with broad spectrum antibiotics, prescribe 
systemic steroids as clinically indicated. 
• 
Perform CT scan and PFTs. Repeat CT scan every four 
weeks until a return to baseline. Bronchoscopy is 
recommended. 
 
CT = computed tomography; PFT = pulmonary function test. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
113 
 
 
8.4.6 
Mucositis 
 
Mouthwash such as magic mouth wash (if inaccessible, warm salt or bicarbonate water) should 
be used as supportive care per institution guidelines. Brushing teeth after meals, keeping lips 
moisturized with non-Vaseline® products, and avoiding alcohol, spicy food, and smoking have all 
been shown to reduce pain and infection related to mucositis. Ranitidine or omeprazole may be 
helpful if patients have epigastric pain. Dose modification guidelines for mucositis attributable to 
study treatment are outlined in Table 16. 
 
 
 
Table 16. Mucositis Management Guidelines. 
 
Severity of Mucositis 
Management Guideline 
Grade 1 or 2 
• 
Continue study drugs. 
• 
Manage with maximum supportive care. 
• 
If grade ≥ 2 mucositis recurs in subsequent 4-week 
cycles, despite maximal supportive care, the dose of 
ipatasertib (GDC-0068) should be reduced by one dose 
level. The dose of chemotherapy may be maintained or 
reduced by one level for subsequent cycles per 
investigator's discretion. 
Grade ≥ 3 
• 
Hold ipatasertib (GDC-0068) and chemotherapy until 
recovery to grade 2 or better. If the mucositis resolves to 
grade 2 or better during the current cycle, the dose of 
ipatasertib should be reduced by one dose. The dose of 
chemotherapy may be maintained or reduced by one 
dose level for subsequent cycles per investigator's 
discretion. 
• 
If recovery of mucositis to grade 2 or better does not 
occur within a maximum of three weeks, the patient will 
permanently discontinue chemotherapy and ipatasertib 
(GDC-0068). 
 
 
8.4.7 
Hepatotoxicity 
 
Permanently discontinue ipatasertib for any patients who develop a concurrent elevation of ALT 
and/or AST greater than 3 ´ ULN and total bilirubin greater than 2 ´ ULN and/or clinical jaundice 
in the absence of biliary obstruction or other causes responsible for the concurrent elevation, 
including patients having abnormal liver function tests that meet Hy’s law criteria. Dosage 
modification and symptom management guidelines for hepatotoxicity, attributable to study 
treatment are shown below (see Table 17) 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
114 
 
 
Table 17 
Hepatotoxicity Management Guidelines 
 
Severity of LFT Elevation 
Management Guideline 
Grade 1 
AST or ALT > baseline 
-3 ´ ULN or 
T bilirubin > baseline -1.5 ´ ULN 
Continue study drugs. 
Grade 2 
AST or ALT > 3–5 ´ ULN or 
T bilirubin > 1.5–3.0 ´ ULN 
Continue study drugs. 
The frequency of liver function test monitoring should be 
increased as clinically indicated if the investigator judges that 
the laboratory abnormalities are potentially related to study 
medication. 
Grade 3 
AST or ALT > 5–20 ´ ULN or 
T bilirubin > 3–10 ´ ULN 
Immediately interrupt ipatasertib. 
On return of LFTs to baseline or to AST and ALT £ 2.5 ´ ULN 
and total bilirubin £ 1.5 ´ ULN levels, restart ipatasertib/ at 
previous dose level (refer to Table 1) 
Following treatment resumption, monitor serum 
transaminases and bilirubin at a minimum every 2 weeks for 
3 months and monthly thereafter. 
If another Grade 3 event occurs, interrupt ipatasertib/. On 
return of LFTs to baseline or AST and ALT £ 2.5 x ULN and 
total bilirubin £ 1.5 x ULN levels, restart ipatasertib/, reducing 
the dose by one level 
Further Grade 3 occurrences must result in permanent 
discontinuation of ipatasertib. 
Grade 4 
AST or ALT > 20 ´ ULN or 
T bilirubin > 10 ´ ULN 
Permanently discontinue ipatasertib. 
LFT = liver function test; QD = once daily; ULN = upper limit of normal. 
 
 
 
8.4.8 
Other non-Hematologic Toxicities 
 
If other grade ≥ 3 non-hematologic toxicities not described above develop in patients, treatment 
with ipatasertib (GDC-0068) and/or chemotherapy regimen may be held, depending on the 
attribution of the toxicity, at the discretion of the investigator. During this time, treatment may 
continue with the other non-attributable treatment agent (e.g., either ipatasertib [GDC-0068] or 
chemotherapy agent). Grade ≥ 3 non-hematologic toxicity should be monitored at least weekly. 
If the toxicity resolves to grade 1 or better within two weeks, treatment may resume with the 
attributable agent. 
If the toxicity resolves to grade 1 or better after two weeks of treatment interruption, the dose of 
the attributable drug should be reduced by one level. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
115 
 
 
Depending on the nature and the severity of the adverse event, if recovery to grade 1 or better 
takes more than three weeks, the attributable agent may be permanently discontinued, at the 
discretion of the investigator and after discussion with the Medical Monitor. 
 
 
 
8.5 
AEs Reporting and Other Safety Related Issues Reporting 
 
For serious and non-serious AEs, the reporting period to the Sponsor (or its designated 
representative) begins from the time that the patient provides ICF. 
Reporting period for SAEs/AESIs that are NOT related with the study IMP and also all non-serious 
AEs is as follows: 
• 
If patient discontinues treatment during the study, until 30 calendar days after the last 
administration of the study IMP. 
• 
If patient still on treatment at the time of the EoS visit (See definition on Section 4.2.4) until 
the EoS visit. 
All study patients will be carefully monitored for the occurrence of AEs (including SAEs and 
AESIs) during the above specified adverse event reporting period. 
If the investigator becomes aware of a SAE/AESI at any time after the end of administration of 
study treatment and believes that it is possibly related to ipatasertib (GDC-0068)/chemotherapy 
(a serious adverse reaction to ipatasertib [GDC-0068]/chemotherapy), the investigator should 
notify the serious adverse reaction to the Sponsor immediately irrespective of the time elapsed 
since last administration of the study IMP. 
For all grade ≥ 3 AEs with causal relationship to the IMP, follow-up by the Investigator may be 
required until the event or its sequelae resolve or stabilize at the level acceptable to the 
Investigator, and the Sponsor concurs with that assessment. 
Clearly related signs, symptoms, and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. Any additional 
events that fall outside this definition should also be reported separately. 
All AEs must be recorded in the CRF. 
 
 
 
8.6 
SAE reporting and timeframe 
 
Reporting requirements will comply with all EU safety reporting requirements as detailed in 
Clinical Trials Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 
April 2014 on clinical trials on medicinal products for human use, repealing Directive 2001/20/EC 
and all applicable local regulations for safety reporting. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
116 
 
 
The investigator or investigator’s team will report all protocol defined SAEs and AESIs to the 
Sponsor (MEDSIR) no later than 24 hours of any site study team staff becoming aware of the 
event as follows: 
• 
The full details of the SAE and/or AESI should be collected and fully documented using the 
SAE form and sent to the Sponsor (MEDSIR). 
• 
Follow-up information, copies of any relevant test results, event outcome and the opinion of 
the investigator as to the relationship between the ipatasertib (GDC-0068)/chemotherapy and 
the SAE and AESI, accompanied by other applicable documentation when it is requested, will 
be sent along with the SAE form, if available on the day the event is reported or as soon as 
possible if it is not. 
• 
The original SAE reporting form and the confirmation from the Sponsor must be kept with the 
CRF documentation at the study site(s). 
All SAE forms will be sent by the investigator or investigator’s team to the Sponsor (MEDSIR) 
according to the reporting instructions provided by MEDSIR at the site initiation visit and filed in 
the Investigator’s File. 
SAEs and AESIS will be followed until resolved, a stable outcome is reached, patient is lost to 
follow-up, or dies. 
As sponsor, MEDSIR will be responsible for ensuring that events are reported within the 
mandated timeframe to the EMA, and other competent authorities, IRBs/ECs, and investigator(s), 
as necessary and in accordance with all applicable guidelines, approved directives and 
regulations. All safety reporting local regulatory requirements will be followed. 
 
 
 
8.7 
Expedited Reporting to Health Authorities, Investigators, IRBs, and ECs 
 
To determine reporting requirements for single SAE cases, MEDSIR (as Sponsor) or its designee, 
will assess the expectedness of these events using the following reference documents: 
- 
IB for ipatasertib (GDC-0068); 
- 
SmPC for capecitabine; 
- 
SmPC for eribulin; 
- 
SmPC for carboplatin and gemcitabine. 
 
 
MEDSIR (as Sponsor) or its designee will compare the severity of each event and the cumulative 
event frequency reported for the study with the severity and frequency reported in the applicable 
reference document. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
117 
 
 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
Within seven calendar days after being notified of the event, MEDSIR (as Sponsor) or its designee 
will report unexpected fatal or life-threatening events associated with the use of the study drug to 
the regulatory agencies and competent authorities, to the investigators and IRBs/ECs. MEDSIR 
(as Sponsor) or its designee will report other unexpected SAEs associated with the use of the 
study medication to the appropriate competent authorities (according to local guidelines), 
investigators, and central IRBs/ECs by a written safety report within 15 calendar days of 
notification. All safety expedited reports will be reported in accordance to all regulatory reporting 
obligations (including timelines) and local regulatory requirements. 
 
8.8 
Other Safety-Related Reports 
 
As Sponsor, MEDSIR will assess constantly the benefit/risk profile of the trial, that means a 
continuous evaluation of the safety profile of the drugs under investigation will be done using all 
available information. MEDSIR will provide the regulatory agencies and competent authorities 
and the investigators with any relevant information that may affect the benefit/risk profile of the 
trial. 
An 
annual 
Development 
Safety 
Update 
Report 
(DSUR) 
safety 
report 
for 
ipatasertib/chemotherapy will be prepared and distributed by MEDSIR or its designee in 
accordance to all regulatory reporting obligations and local regulatory requirements. 
MEDSIR or its designee will report any finding of noncompliance (as failure to follow any 
applicable regulation or institutional policies that govern human subjects’ research) and/or serious 
noncompliance (as noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants) 
according to any reporting obligation and local regulatory requirements. 
 
 
 
8.9 
Pregnancy Reporting 
 
Irrespective of the treatment received by the patient, any patient’s or patient’s partner pregnancy 
occurring during study treatment or within 30 days after completing therapy must be reported 
within 24 hours of investigator’s knowledge of the event. 
Pregnancies will be treated as SAEs and the investigator will complete a pregnancy form and 
forward it to the Sponsor according to the reporting instructions provided by MEDSIR at the site 
initiation visit and filed in the investigator’s File. 
The patient will be asked to provide follow-up information on the outcome of the pregnancy, 
including premature termination should the case arise. Spontaneous miscarriage and congenital 
abnormalities will also be reported as SAEs. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
118 
 
 
The follow-up period will be deemed to have ended when the health status of the child has been 
determined at 12 months of the infant’s life. 
Additional follow-up information on any ipatasertib/chemotherapy-exposed pregnancy and infant 
will be requested at specific time points (e.g., after having received the initial report, at the end of 
the second trimester, two weeks after the expected date of delivery, and at three, six, and 12 
months of the infant’s life). 
Follow-up queries may be sent, asking for further information, if required for a comprehensive 
assessment of the case. 
 
 
 
9 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
 
9.1 
Determination of Sample Size 
 
A total sample of 54 evaluable taxane-pretreated patients (safety run-in phase + non-comparative 
phase) with unresectable locally advanced or metastatic TNBC will be allocated based on 
investigator’s criteria, in accordance with previous patient’s treatments and slots availability, to 
one of the following treatment arms: 
• 
Arm A: Ipatasertib (GDC-0068) plus capecitabine. 
• 
Arm B: Ipatasertib (GDC-0068) plus eribulin. 
• 
Arm C: Ipatasertib (GDC-0068) and carboplatin plus gemcitabine. 
 
We expected to recruit 18 patients per arm. However, patients could be assigned to one of the 
other open treatments if one arm was stopped due to feasibility or safety reasons. At the end of 
the study all 54 patients will be recruited, unless all arms were discontinued. 
 
 
 
9.2 
Justification of Total Sample Size 
 
This is a pilot study to determine the safety and tolerability of three different study combinations 
with non-taxane chemotherapy agents and ipatasertib (GDC-0068). The analysis will be 
exploratory without hypothesis testing. However, The Sponsor has estimated the precision for the 
incidence of adverse events rate in ipatasertib combinations. Based on Lotus clinical trial (59) the 
Sponsor assumes a 100% incidence of all grades and 50% grade≥3 adverse events, respectively. 
Therefore, a sample size of 18 patients in one arm will provide the following precisions: 
 
• 
18.5% to 0% (9.25% half width of confidence interval) assuming an observed AEs 
incidence of 100% (i.e. 95% Clopper-Pearson confidence interval of 81.5 to 100%), and 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
119 
 
 
• 
24 to 24% (24% half width of confidence interval) assuming an observed AEs incidence 
of 50% (i.e. 95% Clopper-Pearson confidence interval of 26 to 74%). 
 
9.3 
Statistical Plan 
 
No hypothesis testing is planned for this study. 
 
9.4 
Analysis Sets 
 
9.4.1 
Full Analysis and Safety Analysis Set 
 
All patients who meet selection criteria and receive at least one drug exposure. The full analysis 
set will be considered the primary population for the analysis. 
 
9.4.2 
Safety run-in Set 
 
All patients in safety run-in phase who complete the first two cycles of treatment or who stop 
treatment during this time because of significant toxicities. 
 
9.4.3 
Exploratory Analysis Set 
 
All patients with evaluable samples for biomarker analysis who meet selection criteria and receive 
at least one drug exposure. 
 
9.5 
Safety Analysis (primary objective) 
 
9.5.1 
Safety Run-In Analysis 
 
The number and the proportion of patients with significant toxicities in each arm and dosing 
schedule will be described. The definition of significant toxicities has been presented in Section 
6.3. Confidence intervals (CIs) will be calculated, according to Clopper-Pearson (exact binomial 
intervals). The safety run-in analysis will be developed in safety run-in set. 
 
9.5.2 
Analysis of Safety-Related Data 
 
Safety endpoints will be analyzed in full analysis set and separately in the three study arms. We 
will summarize AEs, AEs grade ≥ 3, SAEs (as described in Section 8), premature withdrawal 
from study medication, laboratory parameters, exposure to study medication, concomitant 
medications, vital signs, ECOG performance status, and physical examination. 
The incidence of AEs and SAEs will be summarized according to the primary system-organ class 
(SOC) and within each SOC, by the Medical Dictionary for Regulatory Activities (MedDRA) 
preferred term. Additional summaries by frequency tables will also be provided for the AEs. 
Patients who died will be listed together with the cause of death. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
120 
 
 
Laboratory parameters, hematology and biochemistry, will be presented in shift tables of NCI- 
CTCAE grade at baseline versus worst grade during treatment. 
Other safety variables, such as exposure to study medication, concomitant medications, vital 
signs, and physical examination, will be analyzed in a similar way. Frequency tables will 
summarize the exposure of study medication. 
ECOG performance status will be summarized over time and the percentage of patients in 
different categories will be presented by bar charts at different time points. 
 
9.6 
Secondary Efficacy Analysis 
 
9.6.1 
Response Assessment 
 
The response assessment of the tumor is defined as best response, in terms of complete CR, 
PR, SD, and progressive disease (PD) according the following list: 
• 
CR: Complete disappearance of all target lesions. Any pathological lymph nodes (target or 
non-target) must have reduction in short axis to < 10 millimeter (mm). 
• 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. 
• 
SD: Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
• 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum diameters while on study. The development of new, previously undetected 
lesions is also considered progression. 
ORR is defined as the number of patients with CR and PR divided by the number of patients in 
the analysis set. Tumor response will be defined as best response, based on local investigator’s 
assessment according to RECIST criteria guidelines v.1.1. 
CBR is defined as the number of patients with CR, PR, or SD (for at least 24 weeks) divided by 
the number of patients in the analysis set. Tumor response will be defined as best response, 
based on local investigator’s assessment according to RECIST criteria guidelines v.1.1. 
 
 
 
9.6.2 
Time-to-Event Measures Definitions 
 
• 
PFS is defined as the period of time from treatment initiation to the first occurrence of disease 
progression or death from any cause, whichever occurs first, as determined locally by the 
investigator through the use of RECIST v.1.1. Patients with no progression or no death will 
be censored at the date of their last evaluable imaging. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
121 
 
 
• 
TTR is defined as the time from the treatment initiation to time of the first objective tumor 
response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, as 
determined locally by the investigator through the use of RECIST v.1.1. 
• 
DoR is defined as the time from the first occurrence of a documented objective response to 
disease progression or death from any cause, whichever occurs first, as determined locally 
by the investigator through use of RECIST v.1.1. In case of the patient first reaching PR and 
later CR, the duration of CR will be measured and reported separately, starting from the date 
when first documented, and ending when a progressive disease is diagnosed, or the patient 
dies. 
• 
OS is defined as the time from treatment initiation to death from any cause, as determined 
locally by the investigator through use of RECIST v.1.1. Patients without documented death 
at the time of the final analysis will be censored at the date of the last follow-up. We will 
analyze 1- and 2-year survival probability. These are defined as the probability of survival at 
1 and 2 years after the date of treatment initiation based on the Kaplan-Meier estimate. 
• 
Best percentage of change from baseline in the size of target tumor lesions, defined as the 
biggest decrease, or smallest increase if no decrease will be observed, as determined locally 
by the investigator through use of RECIST v.1.1. 
 
 
 
9.7 
Secondary Efficacy Analysis 
 
All the efficacy analysis will be reported in the full analysis set and separately in the three study 
arms. The number and proportion of patients with an objective response and CBR with the 95% 
Pearson-Clopper CI will be calculated. 
The best percentage of change from baseline in the size of target tumor lesions will be described 
with the median, range, mean, standard deviation, and interquartile range. Waterfall plots 
describing the percentage of change in target tumor lesions according to RECIST v.1.1 criteria 
will be provided. 
Kaplan-Meier plots and swimmer plots for time-to-event endpoints (PFS, TTR, DoR, and OS) will 
be provided. Finally, number and proportion of events, median survival time, as well as the 1- and 
2-year survival rates with corresponding 95% Cl, will be calculated. 
 
 
9.8 
Exploratory Endpoints 
 
Biomarkers will be evaluated on a univariate level regarding their potential for prediction of the 
clinical endpoints (PFS, TTR, ORR, DoR, CBR, OS, and best percentage of change in target 
tumor lesions). Biomarker and response correlations with clinical covariates will be investigated. 
It will be checked whether covariates can improve the prediction and whether there is an 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
122 
 
 
interaction with the biomarkers. Relevant covariates could become a part of the statistical 
prediction model. Further multivariate techniques (e.g., Multiple Logistic Regression, Cox 
regression, Principal Component Analysis with Rotation, or Cluster Analysis) will be considered 
in order to study combinations of markers. Techniques to control false discovery rate and 
overfitting (Lasso, or ridge and elastic net methods) will be adopted. The biomarker analysis will 
be analyzed in biomarker set. 
 
 
 
9.9 
Missing Data Management 
 
For PFS, patients without a date of disease progression will be analyzed as censored 
observations on the date of last tumor assessment. If no post-baseline tumor assessment is 
available, patients will be censored at the date of treatment initiation + 1 day. Data for patients 
with an event who missed two or more scheduled assessments immediately prior to the event will 
be censored at the last tumor assessment prior to the missed visits. 
For OS, patients who are not reported as having died will be analyzed as censored observations 
on the date they were last known to be alive. If no post-baseline data are available, OS will be 
censored at the date of treatment initiation + 1 day. 
For responders and patients with clinical benefit, patients without any post-baseline assessment 
will be considered as non-responders or without clinical benefit. For the analysis of best 
percentage of change in tumor lesion we will analyze only observed cases. 
 
9.10 Interim Analysis 
 
The interim analysis will be performed independently in each arm after the last evaluable patient 
in the run-in phase has completed the two first cycles of study treatment in orden to assess the 
toxicity profile of each regimen. 
The data will be submitted to relevant local health authorities for approval, if/as required, before 
continuing to Phase IIa stage. 
This data will be shared with F. Hoffmann-La Roche Ltd. 
 
9.11 Steering Committee Review 
 
A Steering Committee will be established for this study. It will be composed by the Sponsor’s 
Medical Monitor, Scientific Global Coordinator, Principal investigator/, and additional physicians 
with experience in experimental therapy management. 
During the safety run-in period, the Steering Committee will meet to assess the safety and 
tolerability of the selected combined treatment regimens used in the study. This meeting will take 
place after the 3 or 6 first subjects of each Arm have completed the 2 first cycles. This data will 
be shared with F. Hoffmann-La Roche Ltd. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
123 
 
 
After this period, data from the interim analysis will be evaluated by the Steering Committee. 
During this meeting, the decision to continue to Phase IIa or increase the number of patients in 
the safety run-in phase will be made. The data will be submitted to relevant local 
health authorities for approval, if/as required, before continuing to Phase IIa stage. This data will 
be shared with F. Hoffmann-La Roche Ltd. 
 
During phase IIa, the Steering Committee and the study site investigators will meet on demand 
to review, discuss, and evaluate all of the gathered safety data. In case of any arising safety 
concern, these meetings can also be called at any time at request of a participating investigator. 
At these meetings, the Sponsor and the participating investigators must reach a consensus on 
safety data. The Sponsor will prepare minutes from these meetings and circulate them to each 
investigator for comments prior to finalization. 
Study site investigators and the Sponsor will review patient data at least every six months. Each 
study site investigator will monitor patient’s data for serious toxicities on an ongoing basis. 
 
 
 
10 ETHICAL CONSIDERATIONS 
 
10.1 Regulatory and Ethics Compliance 
 
The study will be performed and reported in accordance with the guidelines of the ICH, and the 
ethical principles laid down in the Declaration of Helsinki. The study will be also compliance with 
2001 EU Clinical Trial Directive and any applicable local regulations. 
 
 
 
10.2 IRB/EC 
 
Conduct of the study must be approved by an appropriately constituted IRB/EC. Approval is 
required for the study protocol, protocol amendments, ICFs, study patient information sheets, and 
advertising materials. The IRB/EC may also be contacted in the event of any major protocol 
violation (or serious breach if applicable), or any SAE or any urgent safety measures to protect 
the subjects against any immediate hazard. 
The investigator and/or the Sponsor when required, must communicate with the IRB/EC to ensure 
accurate and timely information is provided at all phases during the study. 
The principal investigator, and/or the Sponsor when required, is responsible for providing written 
summaries of the status of the study to the IRB/EC annually or more frequently in accordance 
with the requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
124 
 
 
In addition to the requirements to report protocol-defined AEs to the Sponsor, investigators are 
required to promptly report to their respective IRB/EC all unanticipated problems involving risk to 
human patients. Some IRBs/ECs may want prompt notification of all SAEs, whereas others 
require notification only about events that are serious, assessed to be related to study treatment, 
and are unexpected. Investigators may receive written safety reports or other safety-related 
communications from the Sponsor. Safety reports should be made available to IRB/EC to be 
reviewed and processed in accordance with regulatory requirements and with the policies and 
procedures established by their IRB/EC and archived in the site’s study file. 
 
 
 
10.3 ICF 
 
For each study patient, signed ICF will be obtained prior to any protocol-related activities. As part 
of this procedure, the study site investigator or designee (if in line with local regulation) must 
explain orally and in writing the nature, duration, and purpose of the study, and the action of the 
drugs in such a manner that the study patient is aware of the potential risks, inconveniences, or 
AEs that may occur. The study patient should be informed that she is free to withdraw from the 
study at any time and with no obligation to specify her reasons. The patient will receive all 
information that is required by local regulations and ICH guidelines. 
After a failed screening attempt, one re-screening will be allowed to patients who did not meet 
one or more criteria required for participation in this study. A potential re-screened patient should 
sign a new ICF before any screening test or study related procedure is performed. 
The ICF must be signed and dated by the principal investigator or medical designees (if in line 
with local regulation) and the patient before any protocol-related activity. The case history or 
clinical records for each patient shall document the ICF process and that signed ICF was obtained 
prior to participation in the study. 
A copy of each signed ICF must be provided to the patient. 
 
All signed and dated ICFs must remain in each patient’s study file and must be available for 
verification by study monitors at any time. 
The ICF should be revised whenever there are changes to procedures outlined in the ICF or when 
new information becomes available that may affect the willingness of the patient to participate. 
For any updated or revised ICFs, the case history for each patient shall document the ICF process 
and that written ICF was obtained for the updated/revised ICF for continued participation in the 
study. The final revised IRB/EC-approved ICF must be provided to the Sponsor for regulatory 
purposes. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
125 
 
 
10.4 Data Protection 
 
The Sponsor will ensure the confidentiality of patient’s medical information in accordance with all 
applicable laws and regulations. 
The Sponsor as data controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of such data 
(95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of data management. 
Data generated by this study must be available for inspection upon request by representatives of 
national and local Health Authorities, the Sponsor monitors, representatives, and collaborators, 
and the IRB/EC for each study site, as appropriate. 
 
 
 
11 SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE 
 
11.1 Source Data Documentation 
 
Source data refers to all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in source documents (original records or 
certified copies). 
Source documents are original documents, data, and records (e.g., hospital records, clinical and 
office charts, laboratory notes, memoranda, patients' diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the laboratories, 
and at medico-technical departments involved in the clinical trial). 
Sponsor’s quality assurance group may assist in assessing whether electronic records generated 
from computerized medical record systems used at investigational sites can serve as source 
documents for the purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the purposes of 
clinical research (as opposed to general clinical practice), applicable hardcopy source documents 
must be maintained to ensure that critical protocol data entered into the CRFs can be verified. 
At a minimum, source documentation must be available to substantiate patient identification, 
eligibility, and participation; proper ICF procedures; dates of visits; adherence to protocol 
procedures; adequate reporting and follow-up of AEs; administration of concomitant medication; 
study drug receipt/dispensing/return records; study drug administration information; and date of 
completion and reason. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
126 
 
 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(e.g., all original records, laboratory reports, medical records) in order to ensure data 
completeness and accuracy as required by study protocol. The investigator and/or site staff must 
make CRFs and source documents of patients enrolled in this study available for inspection by 
the Sponsor or its representative at the time of each monitoring visit. 
The source documents must also be available for inspection, verification, and copying, as required 
by regulations, officials of the regulatory Health Authorities (e.g., FDA, EMA, and others), and/or 
IRBs/ECs. The investigator and study site staff must comply with applicable privacy, data 
protection, and medical confidentiality laws for use and disclosure of information related to the 
study and enrolled patients. 
The patient must also allow access to the patients’ medical records. Each patient should be 
informed of this requirement prior to the start of the study. 
 
 
 
11.2 Study Monitoring and Source Data Verification 
 
Study progress will be monitored by the Sponsor or its representative (e.g., a Clinical Research 
Organization [CRO]) as frequently as necessary to ensure that: 
• 
The rights and well-being of human patients are protected. 
 
• 
The reported trial data are accurate, complete, and verifiable from the source documents. 
 
• 
The conduct of the trial is in compliance with the current approved protocol/amendment(s), 
Good Clinical Practice (GCP) guidelines, and applicable regulatory requirements. 
 
 
Contact details for the team involved in study monitoring will be identified in a hand-out located in 
the investigator site file. 
Data recorded on the CRF will be verified by checking the CRF entries against source documents 
(e.g., all original records, laboratory reports, medical records, patient diaries) in order to ensure 
data completeness and accuracy as required by study protocol. The investigator and/or site staff 
must make CRFs and all source documents of patients enrolled in this study available for 
monitoring, auditing and/or inspection by the Sponsor/its representative or the regulatory 
authorities at the time of each monitoring visit, audit and/or inspection. 
 
 
 
11.3 Retention of Records 
 
Investigators must retain all study records required by the applicable regulations in a secure and 
safe facility. The investigator must consult a Sponsor representative before disposal of any study 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
127 
 
 
records and must notify the Sponsor of any change in the location, disposition, or custody of the 
study files. 
Essential documents must be retained until at least two years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least two years have elapsed since the formal discontinuation 
of clinical development of the IMP. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced. These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor (ICH E6[R2], 4.9.5). The 
sponsor should inform the investigator/institution in writing of the need for record retention and 
should notify the investigator/institution in writing when the trial related records are no longer 
needed (ICH E6[R2], 5.5.12). However, unless other Union law requires archiving for a longer 
period, the Sponsor and the Investigator shall archive the content of the clinical trial master file 
for at least 25 years after the end of the clinical trial. Moreover, the medical files of patients shall 
be archived in accordance with national law (Article 58 of the European Clinical Trials Regulation 
[EU] No 536/2014). 
The study site investigator must not dispose of any records relevant to this study without either 
(1) written permission from the Sponsor or (2) providing an opportunity for the Sponsor to collect 
such records. The study site investigator shall take responsibility for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated during 
this study. Such documentation is subject to inspection by the Sponsor and the FDA and/or EMA 
(or respective individual EU country regulatory authorities). 
These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 
 
 
 
11.4 Data Quality Assurance 
 
During and/or after completion of the study, quality assurance auditor(s) or inspector(s) named 
by the Sponsor or by the regulatory authorities may wish to perform on-site audits or inspections. 
The investigators will be expected to cooperate with any audit or inspection and provide 
assistance and documentation (including all source data) as requested. 
The Sponsor’s representatives are responsible for contacting and visiting the investigator for the 
purpose of inspecting the facilities and, upon request, monitoring the various records of the clinical 
study (e.g., CRFs and other pertinent data) provided that patient confidentiality is respected. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits, including delays in completing CRFs, are resolved. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
128 
 
 
In accordance with (ICH E6[R2] GCP) and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from the Sponsor’s (or designee’s) quality assurance department. 
Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study- 
related records will occur to evaluate the study conduct and compliance with the protocol, (ICH 
E6[R2] GCP), and applicable country regulatory requirements. 
 
 
 
12 DATA MANAGEMENT 
 
12.1 Data Entry and Management 
 
In this study, all data will be entered on to CRFs in a timely manner by the investigator and/or the 
investigator’s dedicated site staff. 
The investigator must review data recorded in the CRF to verify their accuracy. 
 
Reconciliation of the data will be performed by the designated CRO. At the conclusion of the 
study, the occurrence of any protocol violations will be identified and recorded as part of the 
clinical database. After these actions have been completed and the database has been declared 
to be complete and accurate, it will be locked and will become available for statistical data 
analysis. 
 
 
 
12.2 Data Clarification 
 
As part of the conduct of the trial, the Sponsor may have questions about the data entered by the 
site, referred to as queries. The monitors and the Sponsor are the only parties that can generate 
a query. 
 
 
 
12.3 Data Coding Procedures 
 
Coding of AEs, medical history, and prior and concomitant medications will be performed using 
standard dictionaries as described in the data management plan. 
 
 
 
13 STUDY MANAGEMENT 
 
13.1 Discontinuation of the Study 
 
The Sponsor reserves the right to discontinue the study for safety or administrative reasons at 
any time. If the study is discontinued and/or the site is closed for any reason, all investigational 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
129 
 
 
drugs pertaining to the study must be returned to the Sponsor. Any actions required to assess or 
maintain study patient safety will continue as required, in spite of termination of the study. 
 
 
 
13.2 Protocol Amendments 
 
Any change or addition to this protocol requires a written protocol amendment or administrative 
letter that must be approved by the Sponsor, the scientific global coordinator, the study site 
investigator, and the IRB/EC before implementation. This requirement for approval should in no 
way prevent any immediate action from being taken by the study site investigator or the Sponsor 
in the interests of preserving the safety of all patients included in the trial. If an immediate change 
to the protocol is felt to be necessary by the study site investigator and is implemented for safety 
reasons, the Sponsor should be notified as soon as possible (within 24 hours if possible) and the 
IRB/EC should be informed as necessary. 
 
 
 
13.3 Protocol Deviations 
 
The investigator should document and explain any protocol deviations. The investigator should 
promptly report any deviations that might have an impact on patient safety and data integrity to 
the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and procedures. 
The Sponsor will review all protocol deviations and assess whether any represent a serious 
breach of Good Clinical Practice guidelines and require reporting to health authorities. As per the 
Sponsor's standard operating procedures, prospective requests to deviate from the protocol, 
including requests to waive protocol eligibility criteria, are not allowed. 
 
 
 
13.4 Publication Policy Protection of Trade Secrets 
 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without prior written permission 
from the scientific global coordinator and the Sponsor. However, authorized regulatory officials, 
the scientific global coordinator, study site investigators, and the Sponsor (or their 
representatives) will be allowed full access to inspect and copy the records. All clinical 
investigational drugs, patient bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by scientific global coordinator 
or study site investigators and the Sponsor. 
The Sponsor will ensure that as far as possible results of this study will be published as 
scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such manuscripts 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
130 
 
 
will be made with full collaboration of principal investigators and in accordance with the current 
guidelines of Good Publication Practice. 
The Sponsor must be notified of any intent to publish data collected from the study and prior 
approval from Sponsor must be obtained prior to publication. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
131 
 
 
 
 
14 REFERENCES 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7– 
34. 
 
2. 
Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits 
of human breast tumours. Nature. 2000 Aug 17;406(6797):747–52. 
 
3. 
Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009 Feb 
19;360(8):790–800. 
 
4. 
Cheang MCU, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. Ki67 index, HER2 status, 
and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009 May 
20;101(10):736–50. 
 
5. 
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative 
paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007 Apr 
15;13(8):2329–34. 
 
6. 
Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, et al. Gene 
expression profiling and histopathological characterization of triple-negative/basal-like breast 
carcinomas. Breast Cancer Res. 2007;9(5):R65. 
 
7. 
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative 
breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007 Aug 1;13(15 
Pt 1):4429–34. 
 
8. 
Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant 
therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008 
Mar 10;26(8):1275–81. 
 
9. 
Hennessy BT, Gonzalez-Angulo A-M, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee 
J-S, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to- 
mesenchymal transition and stem cell characteristics. Cancer Res. 2009 May 15;69(10):4116– 
24. 
 
10. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, et al. Phenotypic and 
molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer 
Research [Internet]. 2010 Sep 2 [cited 2019 Feb 13];12(5):R68. Available from: 
https://doi.org/10.1186/bcr2635 
 
11. Cheang MCU, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast 
cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. 
Clin Cancer Res. 2008 Mar 1;14(5):1368–76. 
 
12. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification 
of human triple-negative breast cancer subtypes and preclinical models for selection of targeted 
therapies. J Clin Invest [Internet]. 2011 Jul 1 [cited 2019 Feb 5];121(7):2750–67. Available from: 
https://www.jci.org/articles/view/45014 
 
13. Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies 
for triple-negative breast cancer subtypes. J Pathol. 2014 Jan;232(2):142–50. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
132 
 
 
14. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of 
Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy 
Selection. PLoS ONE. 2016;11(6):e0157368. 
 
15. Adams TA, Vail PJ, Ruiz A, Mollaee M, McCue PA, Knudsen ES, et al. Composite analysis 
of immunological and metabolic markers defines novel subtypes of triple negative breast cancer. 
Mod Pathol. 2018;31(2):288–98. 
 
16. Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, et al. 
Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer 
molecular subtypes. Clin Cancer Res. 2013 Oct 1;19(19):5533–40. 
 
17. Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. Eribulin 
monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer 
(EMBRACE): a phase 3 open-label randomised study. The Lancet [Internet]. 2011 Mar 12 [cited 
2019 
Feb 
5];377(9769):914–23. 
Available 
from: 
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60070-6/abstract 
 
18. Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, et al. A randomized phase 
III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for 
metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat [Internet]. 2017 
[cited 
2019 
Feb 
5];161(1):63–72. 
Available 
from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222915/ 
 
19. Rugo HS, Roche H, Thomas E, Chung HC, Lerzo GL, Vasyutin I, et al. Efficacy and Safety 
of Ixabepilone and Capecitabine in Patients With Advanced Triple-negative Breast Cancer: a 
Pooled Analysis From Two Large Phase III, Randomized Clinical Trials. Clin Breast Cancer. 2018 
Dec;18(6):489–97. 
 
20. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 
Jan;1(1):27–31. 
 
21. Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, et al. Prognostic significance 
of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer 
Inst. 1997 Jan 15;89(2):139–47. 
 
22. Gasparini G, Toi M, Miceli R, Vermeulen PB, Dittadi R, Biganzoli E, et al. Clinical relevance 
of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive 
breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am. 
1999 Apr;5(2):101–11. 
 
23. Linderholm BK, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtiö J, et al. Significantly 
higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients 
with primary operable triple-negative breast cancer. Ann Oncol. 2009 Oct;20(10):1639–46. 
 
24. Foulkes WD, Stefansson IM, Chappuis PO, Bégin LR, Goffin JR, Wong N, et al. Germline 
BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2003 Oct 
1;95(19):1482–5. 
 
25. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus 
bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 
27;357(26):2666–76. 
 
26. Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, et al. Phase III study of 
bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
133 
 
 
human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 
Jul 10;28(20):3239–47. 
 
27. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: 
randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without 
bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally 
recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252–60. 
 
28. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al. 
Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in 
patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792–9. 
 
29. O’Shaughnessy JA, Brufsky AM. RiBBON 1 and RiBBON 2: phase III trials of bevacizumab 
with standard chemotherapy for metastatic breast cancer. Clin Breast Cancer. 2008 
Aug;8(4):370–3. 
 
30. Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O’Neill V, et al. RIBBON-2: a 
randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of 
bevacizumab in combination with chemotherapy for second-line treatment of human epidermal 
growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 
10;29(32):4286–93. 
 
31. O’Shaughnessy J, Dieras V, Glaspy J, Brufsky A, Miller K, Miles D, et al. Comparison of 
Subgroup Analyses of PFS from Three Phase III Studies of Bevacizumab in Combination with 
Chemotherapy in Patients with HER2-Negative Metastatic Breast Cancer (MBC). Cancer Res 
[Internet]. 2009 Dec 15 [cited 2019 Feb 13];69(24 Supplement):207–207. Available from: 
http://cancerres.aacrjournals.org/content/69/24_Supplement/207 
 
32. Brufsky A, Rivera RR, Hurvitz SA, Bondarenko IN, Smirnov V, Valero V, et al. Progression- 
free survival (PFS) in patient subgroups in RIBBON-2, a phase III trial of chemotherapy (chemo) 
plus or minus bevacizumab (BV) for second-line treatment of HER2-negative, locally recurrent or 
metastatic breast cancer (MBC). JCO [Internet]. 2010 May 20 [cited 2019 Feb 
13];28(15_suppl):1021–1021. 
Available 
from: 
http://ascopubs.org/doi/abs/10.1200/jco.2010.28.15_suppl.1021 
 
33. Gligorov J, Bines J, Alba E, Mustacchi G, Cinieri S, Gupta V, et al. Abstract P2-17-01: Overall 
survival (OS) in the IMELDA randomized phase III trial of maintenance bevacizumab (BEV) with 
or without capecitabine (CAP) for HER2-negative metastatic breast cancer (mBC). Cancer Res 
[Internet]. 2015 May 1 [cited 2019 Feb 13];75(9 Supplement):P2-17-01-P2-17–01. Available from: 
http://cancerres.aacrjournals.org/content/75/9_Supplement/P2-17-01 
 
34. Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic 
Breast Cancer in Patients with a Germline BRCA Mutation. New England Journal of Medicine 
[Internet]. 
2017 
Aug 
10 
[cited 
2019 
Feb 
6];377(6):523–33. 
Available 
from: 
https://doi.org/10.1056/NEJMoa1706450 
 
35. Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee K-H, et al. Talazoparib in Patients 
with Advanced Breast Cancer and a Germline BRCA Mutation. New England Journal of Medicine 
[Internet]. 
2018 
Aug 
23 
[cited 
2019 
Feb 
13];379(8):753–63. 
Available 
from: 
https://doi.org/10.1056/NEJMoa1802905 
 
36. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab 
and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018 
29;379(22):2108–21. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
134 
 
 
37. Bardia A, Mayer IA, Diamond JR, Moroose RL, Isakoff SJ, Starodub AN, et al. Efficacy and 
Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily 
Pretreated Patients With Metastatic Triple-Negative Breast Cancer. J Clin Oncol. 2017 Jul 
1;35(19):2141–8. 
 
38. Starodub AN, Ocean AJ, Shah MA, Guarino MJ, Picozzi, Jr. VJ, Vahdat LT, et al. First-in- 
Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the 
Treatment of Diverse Metastatic Solid Tumors. Clin Cancer Res [Internet]. 2015 Sep 1 [cited 2019 
Feb 13];21(17):3870–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558321/ 
 
39. Mina A, Yoder R, Sharma P. Targeting the androgen receptor in triple-negative breast 
cancer: current perspectives. Onco Targets Ther [Internet]. 2017 Sep 20 [cited 2019 Feb 
13];10:4675–85. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614778/ 
 
40. Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, et al. Phase II Trial of 
Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor–Negative 
Metastatic Breast Cancer. Clin Cancer Res [Internet]. 2013 Oct 1 [cited 2019 Feb 
13];19(19):5505–12. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086643/ 
 
41. Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, et al. 
Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast 
Cancer. J Clin Oncol. 2018 Mar 20;36(9):884–90. 
 
42. Parker JS, Peterson AC, Tudor IC, Hoffman J, Uppal H. A novel biomarker to predict 
sensitivity to enzalutamide (ENZA) in TNBC. JCO [Internet]. 2015 May 20 [cited 2019 Feb 
13];33(15_suppl):1083–1083. 
Available 
from: 
http://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.1083 
 
43. Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell. 2007 Apr;12(4):487–502. 
 
44. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007 Jun 
29;129(7):1261–74. 
 
45. LoRusso PM. Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors. J Clin Oncol. 2016 
01;34(31):3803–15. 
 
46. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: 
implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86. 
 
47. Brugge J, Hung M-C, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer 
Cell. 2007 Aug;12(2):104–7. 
 
48. Tokunaga E, Oki E, Egashira A, Sadanaga N, Morita M, Kakeji Y, et al. Deregulation of the 
Akt pathway in human cancer. Curr Cancer Drug Targets. 2008 Feb;8(1):27–36. 
 
49. Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes 
resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 
2002 Jul;1(9):707–17. 
 
50. Dummler B, Hemmings BA. Physiological roles of PKB/Akt isoforms in development and 
disease. Biochem Soc Trans. 2007 Apr;35(Pt 2):231–5. 
 
51. Sale EM, Sale GJ. Protein kinase B: signalling roles and therapeutic targeting. Cell Mol Life 
Sci. 2008 Jan;65(1):113–27. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
135 
 
 
52. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. 
Oncogene. 2005 Nov 14;24(50):7455–64. 
 
53. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast 
tumours. Nature. 2012 Oct 4;490(7418):61–70. 
 
54. Millis SZ, Gatalica Z, Winkler J, Vranic S, Kimbrough J, Reddy S, et al. Predictive Biomarker 
Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment 
Implications. Clin Breast Cancer. 2015 Dec;15(6):473-481.e3. 
 
55. Yang SX, Polley E, Lipkowitz S. New insights on PI3K/AKT pathway alterations and clinical 
outcomes in breast cancer. Cancer Treat Rev. 2016 Apr;45:87–96. 
 
56. Lin K, Lin J, Wu W-I, Ballard J, Lee BB, Gloor SL, et al. An ATP-site on-off switch that restricts 
phosphatase accessibility of Akt. Sci Signal. 2012 May 8;5(223):ra37. 
 
57. Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, et al. Targeting activated Akt 
with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin 
Cancer Res. 2013 Apr 1;19(7):1760–72. 
 
58. Saura C, Roda D, Roselló S, Oliveira M, Macarulla T, Pérez-Fidalgo JA, et al. A First-in- 
Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust 
and Safe Targeting of AKT in Patients with Solid Tumors. Cancer Discov. 2017;7(1):102–13. 
 
59. Isakoff SJ, Saura C, Calvo I, Gil Gil MJ, Patt DA, Morales Murillo S, et al. FAIRLANE: A 
phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (GDC-0068) in 
combination with paclitaxel as neoadjuvant treatment for early stage triple-negative breast cancer. 
JCO [Internet]. 2016 May 20 [cited 2019 Feb 13];34(15_suppl):TPS1105–TPS1105. Available 
from: http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.TPS1105 
 
60. Dent R, Im S-A, Espie M, Blau S, Tan AR, Isakoff SJ, et al. Overall survival (OS) update of 
the double-blind placebo (PBO)-controlled randomized phase 2 LOTUS trial of first-line ipatasertib 
(IPAT) + paclitaxel (PAC) for locally advanced/metastatic triple-negative breast cancer (mTNBC). 
JCO [Internet]. 2018 May 20 [cited 2019 Feb 13];36(15_suppl):1008–1008. Available from: 
http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.1008 
 
61. Oliveira M, Saura C, Calvo I, Andersen J, Coelho JLP, Gil MG, et al. Abstract CT041: Primary 
results from FAIRLANE (NCT02301988), a double-blind placebo (PBO)-controlled randomized 
phase II trial of neoadjuvant ipatasertib (IPAT) + paclitaxel (PAC) for early triple-negative breast 
cancer (eTNBC). Cancer Res [Internet]. 2018 Jul 1 [cited 2019 Feb 13];78(13 
Supplement):CT041–CT041. 
Available 
from: 
http://cancerres.aacrjournals.org/content/78/13_Supplement/CT041 
 
62. Kim S-B, Dent R, Im S-A, Espié M, Blau S, Tan AR, et al. Ipatasertib plus paclitaxel versus 
placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): 
a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 
2017;18(10):1360–72. 
 
63. U.S. Food and Drug Administration. Drug Interactions & Labeling - Drug Development and 
Drug Interactions: Table of Substrates, Inhibitors and Inducers [Internet]. 2016 [cited 2019 Jan 
25].  
Available 
from: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti 
onsLabeling/ucm093664.htm 
 
64. European Medicines Agency. Guideline on the investigation of drug interactions. 2012 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
136 
 
 
Jun;59. Available from: https://www.ema.europa.eu/documents/scientific-guideline/guideline- 
investigation-drug-interactions_en.pdf 
 
65. Morgillo F, Della Corte CM, Diana A, Mauro C di, Ciaramella V, Barra G, et al. 
Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances 
the efficacy of anti-microtubule drugs in human breast cancer cells. Oncotarget. 2017 
29;8(44):76479–91. 
 
66. Rajput S, Guo Z, Li S, Ma CX. PI3K inhibition enhances the anti-tumor effect of eribulin in 
triple negative breast cancer. Oncotarget [Internet]. 2019 Jun 4 [cited 2020 May 11];10(38):3667– 
80. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557212/ 
 
67. Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate 
suppresses experimental metastasis of breast cancer cells by reversing phenotype from 
epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br J 
Cancer. 2014 Mar 18;110(6):1497–505. 
 
68. Wang X, Wang Y, Gu J, Zhou D, He Z, Wang X, et al. ADAM12-L confers acquired 5- 
fluorouracil resistance in breast cancer cells. Scientific Reports [Internet]. 2017 Aug 29 [cited 2020 
May 11];7(1):9687. Available from: https://www.nature.com/articles/s41598-017-10468-x 
 
69. Gohr K, Hamacher A, Engelke LH, Kassack MU. Inhibition of PI3K/Akt/mTOR overcomes 
cisplatin resistance in the triple negative breast cancer cell line HCC38. BMC Cancer [Internet]. 
2017 
Nov 
3 
[cited 
2020 
May 
11];17. 
Available 
from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670521/ 
 
70. Lin F-M, Yost SE, Wen W, Frankel PH, Schmolze D, Chu P-G, et al. Differential gene 
expression and AKT targeting in triple negative breast cancer. Oncotarget [Internet]. 2019 Jul 9 
[cited 
2020 
May 
11];10(43):4356–68. 
Available 
from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633890/ 
 
71. Yang XL, Lin FJ, Guo YJ, Shao ZM, Ou ZL. Gemcitabine resistance in breast cancer cells 
regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the 
MEK/MAPK and mTOR pathways. Onco Targets Ther [Internet]. 2014 Jun 13 [cited 2020 May 
11];7:1033–42. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063800/ 
 
72. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009 Jan;45(2):228–47. 
 
73. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER). Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation [Internet]. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. 2019 [cited 2019 May 10]. Available from: /regulatory-information/search-fda- 
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
137 
 
 
 
Appendix 1. Schedule of Assessments and Study Procedures 
 
Study Period 
Screening 
Treatment period* 
Post-Treatment Follow-Up Period 
Treatment Arm 
Arms A + B + C 
Arm A 
Arms B + C 
Arms A + B + C 
Day 
 
-28 to 
-1 
 
-14 to 
-1 
 
-7 to - 
1 
Day 1 of 
each cycle 
(every 21 
days) 
Cycle 1 
day 8 
Day 1 of each 
cycle (every 21 
days) 
Day 8 of 
each 
cycle21 
Within 30 days after 
last dose of study 
treatment 
(end of treatment) 
Follow-up every 3 
months20 
(survival period) 
Informed Consent 
Form1 
X 
 
 
 
 
 
 
 
Local HR/HER2 
status2 
X 
 
 
 
 
 
 
 
Baseline 
signs/symptoms 
X 
 
 
 
 
 
 
 
Check of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
 
 
Complete physical 
examination and 
ECOG performance 
status 
X 
 
 
X 
 
X 
 
X 
Limited physical 
examination 
(diarrhea, nausea, 
vomiting, mucositis, 
dyspnea/cough, skin 
toxicity) 
 
 
 
 
X 
 
X 
 
Weight and vital 
signs4 
X 
 
 
X 
X 
X 
X 
X 
Body Surface Area 
(BSA) 
 
 
 
X 
 
X 
 
 
Concomitant 
medication reporting5 
X 
 
 
X 
X 
X 
X 
X 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
 
 
Review patient diary 
 
 
 
X 
 
X 
 
 
Study Period 
Screening 
Treatment period* 
Post-Treatment Follow-Up Period 
Treatment Arm 
Arms A + B + C 
Arm A 
Arms B + C 
Arms A + B + C 
 
Day 
 
 
-28 to 
-1 
 
 
-14 to 
-1 
 
 
-7 to - 
1 
Day 1 of 
each cycle 
(every 21 
days) 
 
Cycle 1 
day 8 
Day 1 of each 
cycle (every 21 
days) 
Day 8 of 
each 
cycle21 
Within 30 days after 
last dose of study 
treatment 
(end of treatment) 
Follow-up every 3 
months20 
(survival period) 
Home glucose 
monitoring 
 
 
 
If clinically indicated 
AE reporting6 
X 
 
 
X 
X 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
X 
X 
Post-study anticancer 
therapy 
 
 
 
 
 
 
 
X 
X 
12-lead ECG7 
X 
 
 
If clinically indicated 
 
ECHO or MUGA 
scan8 
X 
 
 
If clinically indicated 
 
Tumor assessments 
(chest, abdomen, 
pelvis)9 
X 
 
 
X9 
 
X9 
 
X19 
Bone scans10 
X10 
 
 
If clinically indicated10 
 
Brain MRI11 
 
If clinically indicated11 
 
Tumor samples12 
X 
 
 
 
 
 
 
At the time of 
progression 
(if feasible) 
Blood samples13 
X 
 
 
X13 
 
X13 
 
At the time of 
progression 
 
Standard Laboratory Procedures** 
Hematology14 
 
X 
 
X 
 
X 
X 
X19 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
 
 
Fasting Serum 
Biochemistry15 
 
X 
 
X 
X 
X 
X 
X19 
Study Period 
Screening 
Treatment period* 
Post-Treatment Follow-Up Period 
Treatment Arm 
Arms A + B + C 
Arm A 
Arms B + C 
Arms A + B + C 
 
Day 
 
 
-28 to 
-1 
 
 
-14 to 
-1 
 
 
-7 to - 
1 
Day 1 of 
each cycle 
(every 21 
days) 
 
Cycle 1 
day 8 
Day 1 of each 
cycle (every 21 
days) 
Day 8 of 
each 
cycle21 
Within 30 days after 
last dose of study 
treatment 
(end of treatment) 
Follow-up every 3 
months20 
(survival period) 
Glycated 
Hemoglobin HbA1c 
 
X 
 
 
 
 
 
 
INR and PTT (or 
aPTT) 
 
X 
 
 
 
 
 
 
Pregnancy test16 
 
 
X 
X 
 
X 
 
X19 
Viral serology17 
X 
 
 
 
 
 
 
 
Prophylaxis anti- 
diarrheal18 
 
 
 
X18 
 
X18 
 
 
Ipatasertib 
dispensing and 
accountability 
 
 
 
X 
 
X 
 
 
Chemotherapy 
administration 
 
 
 
X 
 
X 
X 
 
 
 
Abbreviations: Arm A = Ipatasertib plus capecitabine; Arm B = Ipatasertib and eribulin; Arm C = Ipatasertib plus carboplatin plus gemcitabine. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
 
 
AE = Adverse events; aPTT = activated partial thromboplastin time; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; HER2 = Human Epidermal Growth Factor Receptor 2; HR = Hormone Receptor; INR = International normalized ratio; MUGA = Multiple-Gated 
Acquisition; PTT = Partial thromboplastin time. 
* All visits must occur within ± 2 working days (± 1 working day in Day 8 of each cycle). Assessments scheduled for Days 1 and 8 of each cycle must be 
performed within 48 hours and 24 hours prior to study treatment administration, respectively, unless otherwise indicated in the schedule of assessments, in 
order to confirm to the patient if treatment can be followed up. 
** Laboratory tests will be performed at the study site's local laboratory within 48 hours prior to Day 1 of each cycle following ≥ 8-hour fast. Blood test at C1D1 
does not need to be repeated if it was performed at screening within 48 hours prior to start of study treatment. For patients included in Arms B or C, laboratory 
tests will be also performed within 24 hours prior to Day 8 of each cycle. 
1. 
Informed Consent Form: Signed written Informed Consent Form obtained prior to any trial-specific procedure. 
2. 
Local HR/HER2 status: Confirmation of histological diagnosis and specified estrogen receptor, progesterone receptor, and HER2 status based on local 
testing on the most recent analyzed biopsy. 
3. 
Medical history: Complete medical history and demographics (including age, gender, and ethnic origin). All medications taken in the last 28 days prior to 
enrolment will be collected. 
4. 
Weight and vital signs: Weight, height (only at screening), respiratory rate, blood pressure measurements (systolic and diastolic), pulse rate, and body 
temperature (oral, axillary, or tympanic temperature). 
5. 
Concomitant medication reporting: Relevant concomitant medication will be recorded at screening and on an ongoing basis. 
6. 
AE reporting: All Adverse Events occurring during the trial and until 30 days after treatment discontinuation visit (end of treatment visit) have to be recorded 
with grading according to the NCI-CTCAE v.5.0. 
7. 
12-lead ECG: One mandatory ECG at screening. Thereafter, additional ECGs should be performed if clinically indicated (symptoms, use of drugs known to 
prolong QTc, etc.). 
8. 
ECHO or MUGA scan: LVEF assessment must be done within 12 weeks prior to C1D1. Afterwards, cardiac function evaluation should be repeated if 
clinically indicated. 
9. 
Tumor assessments (chest, abdomen, pelvis): Baseline assessments of the chest, abdomen, and pelvis (preferably CT or MRI in case of contrast allergy) 
must be performed no more than 28 days before the first dose of study treatment. Post-baseline assessments will be performed every 6 weeks (± 3 days) 
for first 6 months of treatment and every 9 weeks (± 7 days) thereafter using the same imaging method and where possible obtained at the same institution

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
 
 
10. Bone scans: Bone imaging is mandatory at baseline and thereafter will be performed every 24 weeks (± 7 days) only for patients with bone lesions identified 
at baseline, unless clinically or biochemically suspected bone progression. If a bone scan was performed > 28 days but ≤ 60 days prior to start of study 
treatment, the bone scan does not need to be repeated. 
11. Brain imaging (MRI): Brain imaging during the trial should be performed only in subjects with known brain metastases (every 6 weeks [± 3 days] for first 6 
months and thereafter every 9 weeks [± 7 days]) and those with worsening and/or new neurological symptoms. 
12. Tumor samples: A tumor tissue sample from a metastatic site or the primary breast tumor must be collected at the time of study entry (mandatory), with 
the exception of patients for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or subject safety concern) that may submit an archived 
metastatic tumor specimen only upon agreement from the Sponsor. If feasible, patients will also be given the option of providing a tumor tissue sample 
from metastasis or primary breast tumor obtained at disease progression or study termination. 
13. Blood samples: Blood samples are required for all patients at the time of inclusion, after two cycles of study treatment, and upon progression or study 
termination. 
14. Hematology: Hemoglobin, hematocrit, red blood cell count, platelet count, WBC with differential count (ANC, lymphocytes, monocytes, eosinophils and 
basophils. 
15. Fasting (≥ 8-hour fast) serum biochemistry: Renal function analysis (serum creatinine, creatinine clearance according to the Cockcroft-Gault formula), 
liver function [AST, ALT, ALP, gamma-glutamyl transferase (GGT), total and direct bilirubin], amylase, lipase, glucose, total cholesterol, high-density 
lipoprotein, low-density lipoprotein, triglycerides, sodium, potassium, calcium, chloride, magnesium, uric acid, total protein, albumin, and lactate 
dehydrogenase. 
16. Pregnancy test: A negative serum pregnancy test must be obtained for women with childbearing potential either within 96 hours prior to C1D1 study 
treatment administration, or within 7 days of C1D1 (in this case, confirmed by a negative urine pregnancy test prior to C1D1 dosing). In addition, pregnancy 
tests (serum or urine) are to be performed within 48 hours of Day 1 of each following treatment cycle prior to dosing. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. In case an additional pregnancy test is indicated during the trial, a serum test should be performed. 
17. Viral serology: Human Immunodeficiency Virus, Hepatitis B surface Antigen (HBsAg), total Hepatitis B core Antibody (HBcAb), Hepatitis C Virus antibody; 
additional tests for Hepatitis B Virus DNA or Hepatitis C Virus RNA will be required to confirm eligibility. 
18. Prophylaxis anti-diarrheal: Prophylactic loperamide dose of 2 mg twice a day or 4 mg once a day will be administered daily as prophylaxis for diarrhea 
during at least the first initial cycle of treatment and may be extended to the next cycle if necessary and if allowed by local guidance. Refer to Section 8.4.1 
for further diarrhea management guidance. 
19. These assessments do not need to be completed if they have been performed within 1 week before study withdrawal (within 4 weeks for imaging studies). 
20
Follow up every 3 months: After study treatment discontinuation post treatment follow up (including survival status and post study anticancer therapy

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
 
 
discontinued treatment for any reason other than progression, tumor assessment will be included in the assessment. EoS will occur at 12 months after the 
last patient included in the study, unless premature termination of the study. 
21. Assessments scheduled for Days 1 and 8 of each cycle, must be performed within 48 hours and 24 hours prior to study treatment administration, respectively, 
unless otherwise indicated in the schedule of assessments, in order to confirm to the patient if treatment can be followed up. If a mandatory procedure 
described in the protocol falls on a bank holiday and/or weekend, this procedure should be performed on the day before or after the holiday (e.g., within a 
period of ± 2 working days). Day 8 visits can be omitted, at the Investigator’s discretion, for patients enrolled in Arms B or C that permanently discontinue 
chemotherapy and continue with ipatasertib (GDC-0068) as single agent. However, laboratory assessments and clinical visits could be scheduled as needed 
for follow-up of ipatasertib (GDC-0068)-related adverse events. A telephone call may be also acceptable. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
143 
 
 
Appendix 2. Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines V.1.1. 
 
 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247. 
 
 
RECIST v.1.1 (72) will be used in this study for assessment of tumor response. While either CT 
or MRI may be utilized, as per RECIST v.1.1, CT is the preferred imaging technique in this study. 
 
 
1. CATEGORIZING LESIONS AT BASELINE 
 
1.1 Measurable lesions 
 
• Lesions that can be accurately measured in at least one dimension. 
 
• Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when 
assessed by CT or MRI (slice thickness 5-8 mm). 
• Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
 
• Superficial lesions with longest diameter 10 mm or greater when assessed by caliper (e.g. skin 
nodules). For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be evaluated by 
both clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study. 
• Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
 
Note: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other measurable lesions. 
 
 
1.2 Non-measurable disease 
 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured with 
calipers, abdominal masses identified by physical exam that are not measurable by reproducible 
imaging techniques. 
• Bone disease: Bone disease is non-measurable with the exception of soft tissue components 
that can be evaluated by CT or MRI and meet the definition of measurability at baseline. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
144 
 
 
· Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
 
 
1.3 Normal sites 
 
• Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be 
recorded either as target or non-target disease. Cystic lesions thought to represent cystic 
metastases can be measurable lesions, if they meet the specific definition above. If non-cystic 
lesions are also present, these are preferred as target lesions. 
• Normal nodes: Nodes with short axis < 10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease 
 
 
1.4 Recording tumor assessments 
 
All sites of disease must be assessed at baseline. Baseline assessments should be done as close 
as possible prior to study start. For an adequate baseline assessment, all required scans must 
be done within 28 days prior to treatment and all disease must be documented appropriately. If 
baseline assessment is inadequate, subsequent statuses generally should be indeterminate. 
 
 
1.5 Target lesions 
 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative 
of all involved organs, should be identified as target lesions at baseline. Target lesions should be 
selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. 
Record the longest diameter for each lesion, except in the case of pathological lymph nodes for 
which the short axis should be recorded. The sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to 
assessments performed on study. 
• If two target lesions coalesce the measurement of the coalesced mass is used. If a large target 
lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be recorded. If a target 
lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to 
have disappeared; otherwise a default value of 5 mm should be recorded. 
Note: When nodal lesions decrease to <10 mm (normal), the actual measurement should still be 
recorded. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
145 
 
 
1.6 Non-target disease 
 
All non-measurable disease is non-target. All measurable lesions not identified as target lesions 
are also included as non-target disease. Measurements are not required but rather assessments 
will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, INCREASED. 
Multiple non-target lesions in one organ may be recorded as a single item on the CRF (e.g., 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
 
2. OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case must 
be discussed with the radiologist to determine if substitution is possible. If not, subsequent 
objective statuses are indeterminate. 
 
 
2.1 Target disease 
 
• Complete Response (CR): Complete disappearance of all target lesions with the exception of 
nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target 
lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of 
diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, 
while the longest diameter is used in the sum for all other target lesions. All target lesions must 
be assessed. 
• Stable disease (SD): Does not qualify for CR, PR or PD. All target lesions must be assessed. 
Stable can follow PR only in the rare case that the sum increases by less than 20% from the nadir, 
but enough that a previously documented 30% decrease no longer holds. 
• Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions 
above the smallest sum observed (over baseline if no decrease in the sum is observed during 
therapy), with a minimum absolute increase of 5 mm. 
• Indeterminate. Progression has not been documented, and 
 
o 
one or more target measurable lesions have not been assessed, 
o 
or assessment methods used were inconsistent with those used at baseline, 
o 
or one or more target lesions cannot be measured accurately (e.g., poorly visible unless 
due to being too small to measure), 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
146 
 
 
o 
or one or more target lesions were excised or irradiated and have not reappeared or 
increased. 
 
 
2.2 Non-target disease 
 
• CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph 
nodes must be ‘normal’ in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the 
normal limits. 
• PD: Unequivocal progression of pre-existing lesions. Generally, the overall tumor burden must 
increase sufficiently to merit discontinuation of therapy. In the presence of SD or PR in target 
disease, progression due to unequivocal increase in non-target disease should be rare. 
• Indeterminate: Progression has not been determined and one or more non-target sites were not 
assessed, or assessment methods were inconsistent with those used at baseline. 
 
 
2.3 New lesions 
 
The appearance of any unequivocal malignant lesion indicated PD. If a new lesion is equivocal, 
for example due to its small size, continued assessment will clarify the etiology. If repeat 
assessments confirm the lesion, then progression should be recorded on the date of the initial 
assessment. A lesion identified in an area not previously scanned will be considered a new lesion. 
 
 
2.4 Supplemental investigations 
 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate. If no disease is identified, objective status is CR. 
If progression determination depends on a lesion with an increase possibly due to necrosis, the 
lesion ay be investigated with biopsy or fine needle aspirate to clarify status. 
 
 
2.5 Subjective progression 
 
Patients requiring discontinuation of treatment without objective evidence of disease progression 
should not be reported as PD on tumor assessment CRFs. This should be indicated on the end 
of treatment CRF as off treatment due to Global Deterioration of Health Status. Every effort should 
be made to document objective progression even after discontinuation of treatment. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
147 
 
 
 
 
Table 18. Objective Response Status at Each Evaluation. 
 
Target 
Lesions 
Non-Target Disease 
New Lesions 
Objective Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Indeterminate or Missing 
No 
PR 
PR 
Non-CR/Non-PD, 
Indeterminate, or Missing 
No 
PR 
SD 
Non-CR/Non-PD, 
Indeterminate, or Missing 
No 
Stable 
Indeterminate 
or Missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
If the protocol allows enrollment of patients with only non-target disease, the following table will 
be used: 
 
 
Table 19. Objective Response Status at Each Evaluation for Patients with Non-Target 
Disease Only. 
 
Non-Target Disease 
New Lesions 
Objective Status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Indeterminate 
No 
Indeterminate 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
148 
 
 
Appendix 3. Actions Required in Cases of Increases in Liver Biochemistry and Evaluation 
of Hy’s Law. 
 
 
1. INTRODUCTION 
 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law (HL). It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates in reviewing and assessing of cases meeting PHL criteria to agree 
whether HL criteria are met. HL criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the IMP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
AE and SAE according to the outcome of the review and assessment in line with standard safety 
reporting processes. 
 
 
2. DEFINITIONS 
2.1 Potential Hy’s Law (PHL) 
 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal 
(ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study following the start 
of study medication irrespective of an increase in Alkaline Phosphatase (ALP). 
 
 
2.2 Hy’s Law (HL) 
 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the IMP, 
can be found to explain the combination of increases (e.g., elevated ALP indicating cholestasis, 
viral hepatitis, another drug). 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations in 
transaminases and TBL must occur. 
 
 
3. IDENTIFICATION OF POTENTIAL HY’S LAW CASES 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
149 
 
 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• 
ALT ≥ 3xULN; 
 
• 
AST ≥ 3xULN; 
 
• 
TBL ≥ 2xULN. 
 
Note: There are different processes for the identification of potential Hy’s law cases depending 
on whether central or local laboratories are being used. 
 
 
When a patient meets any of the identification criteria, in isolation or in combination, the 
Investigator will immediately: 
• 
Notify the Sponsor’s representative (or designee’s); 
 
• 
Request a repeat of the test (new blood draw) by the local laboratory; 
 
• 
Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result. 
 
 
When the identification criteria are met from local laboratory results the Investigator will without 
delay: 
• 
Determine whether the patient meets PHL criteria (see 2. Definition within this 
Appendix) by reviewing laboratory reports from all previous visits. 
 
 
 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the Sponsor’s representative (or designee’s); 
 
• 
Promptly enter the laboratory data into the laboratory CRF. 
 
 
 
4. FOLLOW-UP 
4.1 Potential Hy’s Law Criteria Not Met 
 
If the patient does not meet PHL criteria the Investigator will: 
 
• 
Inform the Sponsor’s representative (or designee’s) that the patient has not met PHL 
criteria. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
150 
 
 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol. 
 
 
4.2 Potential Hy’s Law Criteria Met 
 
If the patient does meet PHL criteria the Investigator will notify the Sponsor’s representative (or 
designee’s). 
The Sponsor’s Medical Scientist contacts the Investigator, to provide guidance, discuss and agree 
an approach for the study patients’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated; 
• 
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Sponsor’s Medical Scientist; 
• 
Complete the Liver CRF Modules as information becomes available 
 
• 
If at any time (in consultation with the Sponsor’s Medical Scientist) the PHL case meets 
serious criteria, report it as an SAE using standard reporting procedures. 
 
 
4.3 Review and Assessment of Potential Hy’s Law Cases 
 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Sponsor’s 
Medical Scientist contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP. 
The Scientific Global Coordinator and Principal Investigator will also be involved in this review 
together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF; 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
151 
 
 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the Sponsor’s standard processes. 
If it is agreed that there is NO explanation that would explain the ALT or AST and TBL elevations 
other than the IMP: 
• 
Report an SAE (report term ‘Hy’s Law’) according to Sponsor’s standard processes. 
 
- 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply; 
- 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above; 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review. 
 
 
4.4 Actions Required for Repeat Episodes of Potential Hy’s Law 
 
This section is applicable when a patient meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study? 
 
 
If No, follow the process described in 
 
Potential Hy’s Law Criteria Met of this Appendix. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
152 
 
 
If Yes, determine if there has been a significant change in the patient’s condition 1 compared with 
when PHL criteria were previously met: 
• 
If there is no significant change no action is required; 
 
• 
If there is a significant change, it is critical to initiate close observation immediately in order 
to determine as quickly as possible whether observed abnormal findings are transient and 
will resolve spontaneously or will progress: 
- 
Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of retesting can decrease to once a week or less if abnormalities stabilize or the trial drug 
has been discontinued and the subject is asymptomatic. - Obtaining a more detailed 
history of symptoms and prior or concurrent diseases; 
- 
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets; 
- 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
NASH; hypoxic/ischemic hepatopathy; and biliary tract disease; 
- 
Obtaining a history of exposure to environmental chemical agents; 
- 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin); 
- 
Considering gastroenterology or hepatology consultations. 
 
 
 
Discontinuation of treatment should be considered if: 
 
• 
ALT or AST >8xULN; 
• 
ALT or AST >5xULN for more than 2 weeks; 
• 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5); 
• 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
 
 
1 Note: A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Sponsor’s Medical Scientist if there is any uncertainty. 

EudraCT#: 2018-004648-44 
Protocol#: MEDOPP253 
Version: 5.0 
Version Date: 27-Apr-2023 
153 
 
 
References 
 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’ (73): 
https://www.fda.gov/media/116737/download