A Phase II Trial of Atezolizumab Plus CArboplatin Plus Nab-paclitaxel as First-line Therapy in Metastatic Triple-negative PD-L1 Positive Breast Cancer Patients - the GIM25-CAPT Trial
Phase: PHASE2
Conditions: Metastatic Breast Cancer, Triple Negative Breast Cancer, PD-L1 Gene Mutation
Sponsor: Consorzio Oncotech

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 1 / 115 
 
 
Clinical Protocol 
A Phase II Trial of atezolizumab plus CArboplatin plus Paclitaxel as first-line therapy in 
metastatic Triple-negative PD-L1 positive breast cancer patients – the GIM25-CAPT trial 
 
Investigational Drug Substance(s): 
Atezolizumab 
Coordinating Investigator (CI):  
Dott.ssa Claudia Bighin 
Protocol number/name:  
 
GIM25-CAPT 
Protocol version: 
 
 
1.0 
Protocol date:  
 
 
November 20th, 2019 
EudraCT number: 
 
 
2019-001388-55 
Sponsor: 
 
 
 
Consorzio Oncotech 
 
 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information belonging to Sponsor. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such 
information in confidence and not to disclose it to others (except where required by applicable 
law), nor to use it for unauthorized purposes. In the event of actual or suspected breach of this 
obligation Sponsor should be promptly notified. 
 
 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 3 / 115 
INVESTIGATOR PROTOCOL APPROVAL 
 
GIM25-CAPT 
“A Phase II trial of atezolizumab plus CArboplatin plus Paclitaxel as first-line Therapy in metastatic 
triple-negative PD-L1 positive breast cancer patients” 
 
 
I agree to the terms of this study protocol. I will conduct the study according to the procedures specified 
herein, and according to principles of Good Clinical Practices and local regulations and requirements. 
 
 
 
Investigator: 
 
Name:  
 
____________________________________ 
 
Signature:  
 
____________________________________ 
 
Date:   
 
_________________  
 
 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 4 / 115 
STUDY INSTITUTIONS 
Sponsor 
Consorzio Oncotech 
c/o Dipartimento di Medicina Clinica e Chirurgia 
Università degli Studi di Napoli “Federico II” 
Via Pansini, 5 – 80131 Napoli 
Tel.+39 081/7463660 
info@oncotech.org 
Principal Investigator and 
Medical Monitor/Emergency 
Contact 
Dott.ssa Claudia Bighin 
Department of Medical Oncology, Ospedale Policlinico San Martino 
Istituto di Ricovero e Cura a Carattere Scientifico,  
Largo Rosanna Benzi, 10 - 16132 Genova GE 
Tel. (+39) 010/5600898 
claudia.bighin@hsanmartino.it 
Steering Committee 
Prof.ssa Lucia Del Mastro 
Department of Medical Oncology, Ospedale Policlinico San Martino 
Istituto di Ricovero e Cura a Carattere Scientifico 
Largo Rosanna Benzi, 10, 16132 Genova (GE) 
Tel. (+39) 010/5600666 - 387 
lucia.delmastro@hsanmartino.it 
 
Prof. Fabio Puglisi 
Department of Medical Oncology 
IRCCS CRO Aviano National Cancer Institute 
Via Franco Gallini, 2, 33081 Aviano (PN) 
Tel (+39) 0434/659111 
fabio.puglisi@cro.it 
 
Dott. Lorenzo Gerratana 
Department of Medical Oncology 
IRCCS CRO Aviano National Cancer Institute 
Via Franco Gallini, 2, 33081 Aviano (PN) 
Tel (+39) 0434/659111 
lorenzo.gerratana@cro.it 
Safety Desk  
(SAE reporting) 
Clinical Research Technology Srl 
Pharmacovigilance Office 
Tel.: +39 089/301545 
Fax: +39 089/7724155 
pvg@cr-technology.com 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 5 / 115 
SYNOPSIS 
Study Title 
A Phase II trial of atezolizumab plus carboplatin plus paclitaxel as first-
line therapy in metastatic triple-negative PD-L1 positive breast cancer 
patients 
Study Phase 
II 
Protocol ID 
GIM25-CAPT 
Target Patients 
First-line therapy in metastatic triple-negative PD-L1 positive breast 
cancer patients 
Study objectives  
Primary objective: 
To  provide preliminary evidence on the efficacy of atezolizumab plus 
carboplatin plus paclitaxel as first-line therapy in metastatic triple-
negative PD-L1 positive breast cancer patients as evaluated by  % 2years 
OS. 
Secondary objective: 
 To  provide preliminary evidence on the efficacy of atezolizumab 
plus carboplatin plus paclitaxel as first-line therapy in metastatic 
triple-negative PD-L1 positive breast cancer patients in terms of 
% OS at 2.5 years 
 To  provide preliminary evidence on the efficacy of atezolizumab 
plus carboplatin plus paclitaxel as first-line therapy in metastatic 
triple-negative PD-L1 positive breast cancer patients in terms of 
% OS at 2 years in hormonal receptor (HR) between 1% and 
10% 
 To  provide preliminary evidence on the efficacy of atezolizumab 
plus carboplatin plus paclitaxel as first-line therapy in metastatic 
triple-negative PD-L1 positive breast cancer patients in terms of 
post-progression survival 
 To assess the activity of atezolizumab plus carboplatin plus 
paclitaxel as first-line therapy in metastatic triple-negative PD-
L1 positive breast cancer patients in terms of ORR, and time to 
treatment failure 
 To assess the safety of atezolizumab plus carboplatin plus 
paclitaxel as first-line therapy in metastatic triple-negative PD-
L1 positive breast cancer patients 
 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 6 / 115 
Exploratory Objectives: 
Exploratory objectives will be focused on the assessment of both tumor-
centered characteristics through the NGS analysis of circulating tumor 
DNA (ctDNA) and immune-centric features through the evaluation of a 
multiparametric Cancer agnostic circuLating ImmunOsignature (CLIO):  
 To assess the association between patients’ characteristics, 
treatment activity, efficacy and safety and through a CLIO in 
metastatic triple-negative breast cancer patients receiving 
atezolizumab plus carboplatin plus paclitaxel as first-line therapy 
 To explore the association between the CLIO and treatment 
activity, efficacy and safety 
 To explore the dynamics of circulating tumor DNA (ctDNA) 
levels and detectable aberrations with respect to treatment 
activity and efficacy 
Concomitant timepoints will not be used for cross-validations between 
the two methodologies. 
Endpoints 
Primary endpoints  
 % Overall survival at 2 years 
Secondary endpoints  
 % Overall survival at 2.5 years  
 2y OS in HR <1% and in HR 1-10% 
 Post-progression survival 
 Objective response rate 
 Time to treatment failure 
 Incidence and severity of adverse events and serious adverse 
events 
Exploratory end points  
 Variation of ctDNA levels from baseline to first evaluation 
through the multigene FoundationOne® Liquid NGS panel  
 Variation of ctDNA levels from the first evaluation to 
progression through the multigene FoundationOne® Liquid NGS 
panel  
 Association between archival PD-L1 levels and target genes 
expression levels through CLIO analysis 
 Variation of target genes expression levels through CLIO 
analysis from baseline to first evaluation 
 Variation of target genes expression levels through CLIO 
analysis from first evaluation to disease progression 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 7 / 115 
Number of Sites 
About 15 centers affiliated with the Gruppo Italiano Mammella (GIM) 
study group 
Number of patients 104 treated patients 
Countries 
1 – Italy 
Background and 
study rationale 
Breast cancer is the most common cancer among women worldwide. 
Triple-negative breast cancer, defined based on the lack of expression of 
estrogen 
and 
progesterone 
receptors 
as 
well 
as 
of 
HER2 
overexpression/amplification, represents 15% of all breast cancers. 
Patients with metastatic triple-negative breast cancer generally 
experience rapid progression and shorter overall survival as compared to 
those with other subtypes of breast cancer. Therefore, there is urgent 
need to improve the clinical outcomes of this subgroup of patients. 
Taxane-based chemotherapy represents the preferred standard first-line 
treatment in triple-negative breast cancer patients. Recent data from the 
TNT trial confirmed the activity of single agent taxane chemotherapy in 
this setting, although median progression-free survival was only 4.4 
months. 
The recently presented phase III IMpassion130 study has demonstrated 
that the combination of atezolizumab plus nab-paclitaxel significantly 
reduced the risk of disease worsening or death in the intention-to treat 
and PD-L1 positive population with metastatic triple-negative breast 
cancer showing also encouraging overall survival results. Therefore, the 
combination of atezolizumab plus nab-paclitaxel is likely to become 
soon the new standard of care as first-line treatment of patients with 
metastatic triple-negative breast cancer. 
The recent results of randomized phase II TNACITY trial showed that 
the association of nab-paclitaxel and carboplatin seems the best 
chemotherapy schedule in terms of median progression free survival as 
first-line treatment of patients with metastatic triple-negative breast 
cancer. 
Recent evidences in metastatic non-small cell lung cancer showed the 
efficacy of concomitant use of carboplatin, paclitaxel and atezolizumab 
without any detrimental interaction between atezolizumab and steroid 
premedication of paclitaxel. 
Therefore, based on these data, the combination of atezolizumab plus 
carboplatin and paclitaxel represents a promising combination to be 
tested as first-line therapy in patients with metastatic triple-negative 
breast cancer to enhance the clinical activity and efficacy of first-line 
therapy in this setting. 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 8 / 115 
Inclusion and 
exclusion criteria 
Inclusion Criteria 
1. Signed Informed Consent Form 
2. Women or men aged ≥18 years 
3. Histologically or cytologically confirmed adenocarcinoma of the 
breast with metastatic disease 
4. Hormone receptor-negative (ER and PgR < 10%) and HER2-
negative (IHC 0,1+ or 2+ ISH not amplified) breast cancer, based 
on the status of the primary tumor and/or the biopsy of metastatic 
disease before starting first-line therapy and assessed by local 
laboratory. 
5. PD-L1 positive defined as expression on tumor-infiltrating immune 
cells ≥1% (SP142 PD-L1 immunohistochemical assay, Ventana 
Medical Systems), based on the status of the primary tumor and/or 
the biopsy of metastatic disease before starting first-line therapy 
and assessed by local laboratory 
6. Availability of a representative tumor specimen for translational 
research 
7. Eligible for first-line taxane and carboplatin chemotherapy 
8. No prior chemotherapy or targeted systemic therapy (including 
endocrine therapy) for inoperable locally advanced or metastatic 
TNBC. Prior radiation therapy for metastatic disease is permitted. 
There is no required minimum washout period for radiation 
therapy; however, patients should have recovered from the effects 
of radiation before enrollment 
9. Previous chemotherapy with taxanes and/or carboplatin for early 
breast cancer (neoadjuvant or adjuvant setting) is permitted if 
completed ≥12 months before study entry 
10. Previous therapy with immune checkpoint inhibitors for early 
breast cancer (neoadjuvant or adjuvant setting) is permitted if 
completed ≥12 months before study entry 
11. ECOG performance status of 0 or 1 
12. Life expectancy ≥ 12 weeks 
13. Measurable or evaluable disease as defined by RECIST v1.1.  
14. Adequate hematologic and end-organ function, defined by 
laboratory results obtained within 2 weeks prior to the first study 
treatment (Cycle 1, Day 1) 
15. Negative human immunodeficiency virus (HIV) test at screening 
16. Negative hepatitis B surface antigen (HBsAg) test at screening 
17. Negative total hepatitis B core antibody (HBcAb) test at screening, 
or positive HBcAb test followed by a negative hepatitis B virus 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 9 / 115 
(HBV) DNA test at screening. The HBV DNA test will be 
performed only for patients who have a positive HBcAb test 
18. Negative hepatitis C virus (HCV) antibody test at screening, or 
positive HCV antibody test followed by a negative HCV RNA test 
at screening. The HCV RNA test will be performed only for 
patients who have a positive HCV antibody test 
19. Women of child bearing potential must agree to either use a 
contraceptive method with a failure rate of ≤ 1% per year or to 
remain abstinent (refrain from heterosexual intercourse) during the 
treatment period and for at least 5 months after the last dose of 
atezolizumab, or for at least 6 months after the last dose of 
paclitaxel. A woman is considered to be of childbearing potential if 
she is postmenarcheal, has not reached a postmenopausal state (≥ 
12 continuous months of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). Examples of contraceptive 
methods with a failure rate of ≤ 1% per year include bilateral tubal 
ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices. The reliability of sexual abstinence should be 
evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of 
contraception 
20. Women of child bearing potential must have a negative serum 
pregnancy test result within 7 days prior to initiation of study drug 
21. For men: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures and agreement to refrain 
from donating sperm 
Exclusion Criteria 
1. Spinal cord compression not definitively treated with surgery 
and/or radiation, or previously diagnosed and treated spinal cord 
compression without evidence that disease has been clinically 
stable for at least 2 weeks prior to enrollment. 
2. Known central nervous system (CNS) disease, except for treated 
asymptomatic CNS metastases, provided all of the following 
criteria are met: 
a) No ongoing requirement for corticosteroids as therapy for CNS 
disease (anticonvulsants at a stable dose are allowed) 
b) No stereotactic radiation within 7 days or whole-brain radiation 
within 14 days prior to enrollment 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 10 / 115 
c) No evidence of progression or hemorrhage after completion of 
CNS directed therapy 
Note: Patients with new asymptomatic CNS metastases detected at 
the screening scan must receive radiation therapy and/or surgery 
for CNS metastases. Following treatment, these patients may then 
be eligible, if all other criteria above are met. 
3. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: 
patients with indwelling catheters, such as PleurX® are allowed) 
4. Uncontrolled tumor-related pain 
a) Patients requiring narcotic pain medication must be on a stable 
regimen at study entry. 
b) Symptomatic lesions (e.g., bone metastases or metastases 
causing nerve impingement) amenable to palliative radiotherapy 
should be treated prior to enrollment. Patients should be 
recovered from the effects of radiation. There is no required 
minimum recovery period. 
c) Asymptomatic metastatic lesions whose further growth would 
likely cause functional deficits or intractable pain (e.g., epidural 
metastasis that is not presently associated with spinal cord 
compression) should be considered for loco-regional therapy if 
appropriate prior to enrollment. 
5. Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized 
calcium or serum calcium [uncorrected for albumin] >3 mmol/L 
[>12 mg/dL] or corrected serum calcium >ULN) or clinically 
significant (symptomatic) hypercalcemia 
a) Patients who are receiving bisphosphonate therapy or 
denosumab specifically to prevent skeletal events and who do 
not have a history of clinically significant (symptomatic) 
hypercalcemia are eligible. 
6. Malignancies other than TNBC within 5 years prior to enrollment, 
with the exception of those with a negligible risk of metastasis or 
death and treated with expected curative outcome (such as 
adequately treated carcinoma in situ of the cervix, non-melanoma 
skin carcinoma, or Stage I uterine cancer) 
7. Pregnant or lactating women, or intending to become pregnant 
during the study 
8. Evidence of significant uncontrolled concomitant disease that could 
affect compliance with the protocol or interpretation of results, 
including significant liver disease (such as cirrhosis, uncontrolled 
major seizure disorder, or superior vena cava syndrome) 
9. Significant cardiovascular disease, such as New York Heart 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 11 / 115 
Association (NYHA) cardiac disease (Class II or greater), 
myocardial infarction within 3 months prior to first dose, unstable 
arrhythmias, or unstable angina 
a) Patients with a known left ventricular ejection fraction (LVEF) < 
40% will be excluded 
b) Patients with known coronary artery disease, congestive heart 
failure not meeting the above criteria, or LVEF < 50% must be 
on a stable medical regimen that is optimized in the opinion of 
the treating physician, in consultation with a cardiologist if 
appropriate 
10. Presence of an abnormal electrocardiogram (ECG) that is clinically 
significant in the investigator’s opinion, including complete left 
bundle branch block, second- or third degree heart block, evidence 
of prior myocardial infarction, or QT interval corrected using 
Fridericia’s formula (QTcF) >470 ms demonstrated by at least two 
consecutive ECGs 
11. Serious infection requiring antibiotics within 2 weeks prior to 
enrollment, including but not limited to infections requiring 
hospitalisation or IV antibiotics, such as bacteremia, or severe 
pneumonia 
12. Major surgical procedure within 4 weeks prior to enrollment or 
anticipation of the need for a major surgical procedure during the 
study other than for diagnosis 
Note: Placement of central venous access catheter(s) (e.g., port or 
similar) is not considered a major surgical procedure and is therefore 
permitted 
13. Treatment with investigational therapy within 30 days prior to 
initiation of study treatment 
14. History of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric or humanized antibodies or fusion proteins 
15. Known hypersensitivity or allergy to biopharmaceuticals produced 
in Chinese hamster ovary (CHO) cells or any component of the 
atezolizumab formulation 
16. History of autoimmune disease, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus (SLE), rheumatoid arthritis (RA), inflammatory 
bowel 
disease, 
vascular 
thrombosis 
associated 
with 
antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Guillain-Barré syndrome, multiple sclerosis (MS), 
vasculitis, or glomerulonephritis 
(Note: Patients with a history of autoimmune-related hypothyroidism 
on a stable dose of thyroid replacement hormone and patients with 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 12 / 115 
controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible for this study) 
17. Prior allogeneic stem cell or solid organ transplantation 
18. History of idiopathic 
pulmonary 
fibrosis (IPF, 
including 
pneumonitis), drug-induced pneumonitis, organizing pneumonia 
(i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), 
or evidence of active pneumonitis on screening chest CT scan. 
(Note: History of radiation pneumonitis in the radiation field 
[fibrosis] is permitted) 
19. Positive test for human immunodeficiency virus (HIV) 
20. Active hepatitis B (positive hepatitis B surface antigen [HBsAg] 
test or hepatitis B virus [HBV] DNA polymerase chain reaction 
[PCR] test at screening) or hepatitis C (positive hepatitis C virus 
antibody test at screening). Note: 
 Patients with past HBV infection or resolved HBV infection 
(defined as having negative HBsAg and HBV DNA test but a 
positive hepatitis B core antibody [HBcAb] test) are eligible 
 Patients positive for hepatitis C virus (HCV) antibody are 
eligible only if PCR is negative for HCV ribonucleic acid (RNA) 
21. Current treatment with anti-viral therapy for HBV 
22. Active tuberculosis 
23. Receipt of a live, attenuated vaccine within 4 weeks prior to 
enrollment or anticipation that such a live, attenuated vaccine will 
be required during the study 
Note: Patients must agree not to receive live, attenuated influenza 
vaccine (e.g., FluMist®) within 28 days prior to enrollment, during 
treatment or within 5 months following the last dose of atezolizumab 
24. Treatment with systemic immunostimulatory agents (including but 
not limited to interferons or interleukin [IL]-2) within 4 weeks or 
five half-lives of the drug (whichever is longer) prior to enrollment 
25. Treatment 
with 
systemic 
immunosuppressive 
medications 
(including but not limited to corticosteroids, cyclophosphamide, 
azathioprine, 
cyclosporine, 
methotrexate, 
thalidomide, 
and 
antitumour necrosis factor [TNF] agents) within 2 weeks prior to 
enrollment, 
or 
anticipated 
requirement 
for 
systemic 
immunosuppressive medications during the trial 
a) Patients who have received acute, low-dose (≤ 10 mg oral 
prednisone or equivalent), systemic immunosuppressant 
medications may be enrolled in the study 
b) Patients with a history of allergic reaction to IV contrast 
requiring steroid pretreatment should have baseline and 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 13 / 115 
subsequent tumor assessments performed using MRI 
c) The use of corticosteroids (≤ 10 mg oral prednisone or 
equivalent) for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with 
orthostatic 
hypotension, 
and 
low 
dose 
supplemental 
corticosteroids for adrenocortical insufficiency are allowed 
d) Systemic 
corticosteroids 
are 
allowed 
as 
paclitaxel 
premedication during the trial at a dose ≤10 mg dexamethasone 
or equivalent in order to avoid severe hypersensitivity reactions 
26. Poor peripheral venous access 
27. Illicit drug or alcohol abuse within 12 months prior to screening, in 
the investigator’s judgment 
28. Any other serious medical condition or abnormality in clinical 
laboratory tests that, in the investigator’s judgment, precludes the 
patient’s safe participation in and completion of the study 
29. History of hypersensitivity reactions to paclitaxel or other drugs 
formulated in the same solvent as paclitaxel (polyoxyethylated 
castor oil) 
30. History of hypersensitivity reactions to carboplatin 
Study Design: 
All eligible patients will receive carboplatin Area Under the Curve 
(AUC) 2 dd 1,8,15 q 28 dd, paclitaxel 90 mg/m2 dd 1,8,15 q 28 dd and 
atezolizumab 840 mg dd 1,15 q 28 dd and they will continue this 
treatment until progression of disease, unacceptable toxicity, death, 
withdrawal of consent, loss to follow-up, or study termination by the 
Sponsor. In case of interruption of one of the three drugs for 
unacceptable toxicity and/or medical decision, the patient may continue 
to receive one or more of the remaining drugs until progression per 
RECIST v1.1. 
If the investigator decides to interrupt carboplatin and paclitaxel (for 
toxicity and/or medical decision), atezolizumab may be continued as 
maintenance therapy until disease progression or unacceptable toxicity. 
All patients who discontinue study treatment (including due to PD) will 
be followed for survival approximately every 3 months for 2 years from 
last patient enrolled or until death, withdrawal of consent, loss to follow-
up, or study termination by the Sponsor. 
Imaging tumor evaluation will be performed every 12 weeks. 
Study Treatment 
 Atezolizumab at a fixed dose of 840 milligrams via intravenous (IV) 
infusion on Days 1 and 15 of each 28-day cycle 
 Carboplatin area under the curve 2 via IV infusion on Days 1, 8, and 
15 of each 28-day cycle 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 14 / 115 
 Paclitaxel at a dose of 90 milligrams per square meter via IV 
infusion on Days 1, 8, and 15 of each 28-day cycle 
In the absence of disease progression or unacceptable toxicity, study 
treatments will continue until the end of the study (2 years from last 
patient enrolled or study termination by the Sponsor). 
Summary 
Statistical 
Statements 
This phase II, single-arm, study is designed to test the hypothesis that 
the addition of an anti-PDL1 to 1st line therapy in metastatic triple-
negative PD-L1 positive breast cancer is associated with a clinically 
relevant 2-year increase in OS over what expected based on historical 
data (54%). 
Statistical Considerations: 
The statistical design of this phase II trial is influenced by 2-factors: 
a) The addition of an immunotherapy agent to a polychemotherapy 
with a considerable activity in TNBC is unlikely to produce a 
substantial improvement in the Response Rate or in Progression 
Free Survival. Therefore, the only study endpoint capable of 
capturing any effect of this addition is Overall Survival. 
b) Although TNBC is possibly the biological variant of breast 
cancer which is least susceptible to medical treatments, short 
term survival of patients with mTNBC is still quite high, with a 
median OS in excess of 2 years (Tutt et al. 2018; Yardley et al. 
2018) 
As a consequence, the standard design of phase II trials, which is 
focused on short term markers of response and incorporates stopping 
rules for futility based on early interim analyses, cannot be used. Instead, 
this trial is designed as a single stage cohort study in which all patients 
will be followed til the end of the study,  which is set at two years after 
the enrolement of the last patient, thereby ensuring  a minimal potential 
follow-up of 2 years to all enrolled patients who did not die before 2 
years. 
The primary study endpoint will be the proportion of patient alive at two 
years (2ys OS%), but, OS% at 2.5 years will represent a important 
secondary endpoint, since, considering that no less than 1 year will be 
necessary to enroll all patients into the study, at the time of the final 
analysis (i.e. 2 years after the enrolment of the last patient), 50% of the 
enrolled patients will have a follow-up ≥2.5 years. 
Expected results and sample size:  
In order to reject with power 80% at the 0.05 (1-sided) significance level 
the null hypothesis that 2yrsOS in mTNBC treated with atezolizumab 
plus carboplatin and paclitaxel is 54%, under the alternative hypothesis 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 15 / 115 
that atezolizumab increases this porportion by 12% (i.e. to 66%), it is 
necessary to enroll into the study 104 patients. With 104 patients, the 
minimal observed 2yrsOS% allowing rejection of the null hypothesis at 
the 1-sided 5% significance level is 62.5% (=65  survivors at 2yrs /104 
enrolled patients)  and the estimated 2yrsOS will have a precision (= 
width of the exact 90% CI)  of approximately +/- 8% (e.g., for 65 
successess/104 patients)  0.5401 ≤ p ≤ 0.7044) 
Planned study 
timelines 
Enrollment period: 2 years approximately 
First Patient First Visit (FPFV): Feb 2020 
Last Patient First Visit (LPFV): Feb 2022 
Follow-up: 2 years (from the enrollment of the last patient) 
Total Study Duration: 4 years approximately 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 16 / 115 
STUDY SCHEDULE OF ASSESSMENTS AND PROCEDURES 
 
Screening Screening 
All Cycles [a1] 
(Q28 dd) 
End of 
Treatment  visit 
– EoT [b] 
Follow-up 
Every 3 months (± 
21 days) 
till 2 years from LP 
enrolled 
End of study (EoS): 
Last FU visit after 2 
years from LP 
enrolled 
 
Days -28  
to -1 
Days -7  
to -1 
Day 1 
(baseline) 
[a2] 
Day 8 
[a3] 
[a4] 
Day 15 
30 (+/-5) days 
after last dose 
 
Signed Informed Consent [c] 
x 
 
 
 
 
 
 
Review of eligibility criteria 
x 
x 
 
 
 
 
 
PD-L1 positivity [d] 
x 
 
 
 
 
 
 
Medical, surgical and cancer 
histories [e] 
x 
 
 
 
 
 
 
Head CT or MRI 
x 
 
 
 
 
 
 
HIV, HBV, HCV serology [f] 
x 
 
 
 
 
 
 
Tumor Assessment [g] 
x 
Every 12 weeks(± 1 week) starting from day 1, until PD, death, unacceptable 
toxicity, withdrawal of consent, or study termination by the Sponsor regardless 
of treatment delays, interruptions or discontinuations. 
Physical Examination [h] 
x 
(x) 
x 
 
 
x 
 
ECOG PS 
x 
(x) 
x 
 
 
x 
 
Vital signs [i] 
x 
 
x 
x 
x 
x 
 
Electrocardiogram [k] 
x 
Perform as clinically indicated 
Echocardiography 
x 
Perform as clinically indicated 
Hematology and Serum chemistry 
[l] 
x 
 
x 
x 
x 
x 
 
Coagulation Panel 
x 
 
 
 
 
x 
 
Urinalysis [m] 
x 
Perform as clinically indicated 
Pregnancy Test 
 
x[n] 
x[o] 
 
 
x[o] 
 
TSH, fT3, fT4 [p] 
x 
 
x[p] 
 
 
x 
 
Adverse events [q] 
x 
x 
x 
x 
x 
x 
(x) [q] 
Atezolizumab infusion [r] 
 
 
x 
 
x 
 
 
Paclitaxel and Carboplatin 
administration [a3, a4] 
 
 
x 
x 
x 
 
 
Survival and anti-cancer therapy 
follow-up [s] 
 
 
 
 
 
 
x 
Translational Assessments 
ctDNA blood sample collection 
(FoundationOne® Liquid) 
 
x 
An additional sample will be 
collected at first evaluation 
x 
 
CLIO blood sample collection 
 
x 
Every 12 weeks concomitantly 
to tumor assessments 
x 
 
[a1] If a scheduled treatment visit cannot be completed due to a holiday, dosing may be postponed to the earliest next date; subsequent dosing should continue 
according to the original schedule. However, paclitaxel and carboplatin should not be administered more frequently than every 7 days. After five cycles, one of 
three cycles may be delayed by one week to allow for vacations. 
[a2] Assessments scheduled on the day of study treatment administration (Day 1) of each cycle should be performed prior to study treatment infusion unless 
otherwise noted. 

Sponsor: Consorzio Oncotech 
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Date: November 20th, 2019 
 
Page 17 / 115 
[a3] Paclitaxel will be administered at the 90 mg/m2 dose via 1-hour IV infusion on Days 1, 8, and 15 of every 28-day cycle. Paclitaxel should not be 
administered more frequently than every 7 days. The Day 8 visits are not required for patients who have discontinued paclitaxel and are continuing treatment 
with atezolizumab only. 
[a4] Carboplatin will be administered at the AUC  dose via 1-hour IV infusion on Days 1, 8, and 15 of every 28-day cycle. Carboplatin should not be 
administered more frequently than every 7 days. The Day 8 visits are not required for patients who have discontinued carboplatin and are continuing treatment 
with atezolizumab only. 
[b] Patients will be asked to return to the clinic within 30 days after their last study drug dose for a treatment discontinuation visit. The visit at which the decision 
is made to discontinue treatment (e.g., due to PD) may be used as the treatment discontinuation visit. 
[c] Written informed consent is required before performing any study-specific tests or procedures. Signing of the Informed Consent Form can occur 
outside the 28-day screening period. All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility criteria before 
enrollment. Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to first dosing (except 
where otherwise specified) may be used for screening assessments rather than repeating such tests. 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. 
[d] PD-L1 positive defined as expression on tumor-infiltrating immune cells ≥1% (SP142 PD-L1 immunohistochemical assay, Ventana Medical Systems), based 
on the status of the primary tumor and/or the biopsy of metastatic disease before starting first-line therapy and assessed by local laboratory. The PD-L1 positivity 
may be evaluated in archival or fresh tumor tissue. An archived biopsy prior to therapy is acceptable if the fresh biopsy cannot be obtained and if the archived 
tissue meets the defined criteria as stated below: 
 
Obtained from primary or metastatic site 
 
An archived biopsy (block or slides) contains tumor tissue. 
 
If an archived block is not available, 10 or more slides containing tumor will be acceptable  
[e] Demographic information includes age, gender, and self-reported race/ethnicity. Reproductive status and smoking history should also be captured. Cancer 
history includes stage, date of diagnosis, and prior anti-tumour treatment. 
[f] All patients will be tested for HIV antibody, HBsAg, HBcAb, and HBsAb, and hepatitis C virus antibody (HCVAb) locally, prior to the inclusion into the 
study. HIV-positive patients will be excluded from the clinical trial. In patients with a negative HBsAg and positive HBcAb serology, HBV DNA must also be 
collected prior to enrollment. Patients positive for HCVAb require a negative PCR for HCV RNA to confirm eligibility. 
[g] Tumour assessments will be performed every 12 weeks starting from day 1, until PD, death, withdrawal of consent, or study termination by the Sponsor 
(whichever occurs first). All measurable and evaluable lesions should be assessed and documented at screening/baseline. Radiologic imaging performed during 
the screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis, 2) bone scan or PET scan, and 3) any other imaging studies (CT neck, 
plain films, etc.) as clinically indicated/determined by the treating physician. For each patient, the same radiographic procedures and technique must be used 
throughout the study, and results must be reviewed by the investigator before dosing at the next cycle. Tumour response will be evaluated using RECIST v1.1. 
During the post-treatment Follow-up period, only patients with no PD will undergo tumour assessments. For patients who discontinue study treatment before 
EOS for reasons other than PD, tumour assessments will continue until PD, death, withdrawal of consent, loss to follow-up, or study termination by the Sponsor. 
[h] Complete physical examination at Screening, and EOT, and symptom-driven physical examinations within 96 hours before Day 1 of each cycle, and as 
clinically indicated. Physical examinations will include a review of the main body organs and systems, with special attention to cardiovascular (e.g. abnormally 
low or irregular pulse, chest pain, tachycardia, swollen legs), respiratory (e.g. shortness of breath, crackling), gastrointestinal (e.g. abdominal pain, digestive 
disorders) systems, and a neurological exam focusing on signs and symptoms potentially indicative of disorders such as myasthenia gravis, motor and sensory 
neuropathy, meningitis, and encephalitis. 
[i] Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature. At all clinic visits where study treatment is administered, vital signs should be determined within 60 minutes before the first infusion. Vital signs 
will also be determined during and after the infusions if clinically indicated. 
[k] Standard 12-lead ECG, taken after resting in a supine position for at least 10 minutes. Additional cardiovascular monitoring (such as ECG and/or 
echocardiography) may be considered during the patient’s study participation, if clinically indicated by the appearance of symptoms or findings at regular vital 
sign checks or medical examinations suggestive of cardiovascular disease (e.g. abnormally low or irregular pulse, chest pain, tachycardia, swollen legs, shortness 
of breath, crackling) especially if these cannot be explained by thyroid or electrolyte abnormalities. 
[l] Haematology consists of RBC count, haemoglobin, haematocrit, WBC count with differential (if clinically indicated), and platelet count. Serum 
chemistry includes BUN, creatinine, sodium, potassium, chloride, bicarbonate, calcium, glucose, total bilirubin, ALT, AST, alkaline phosphatase, total 
protein, and albumin. Bicarbonates should only be tested at sites where this test is part of the standard safety laboratory panel. Magnesium and 
phosphorus should be collected at screening, and thereafter only if clinically indicated. Lipase and amylase levels should be determined if clinically 
indicated by the presence of abdominal symptoms suggestive of pancreatitis. 
[m] Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) will be performed at screening, and thereafter only if clinically indicated 
[n] Serum pregnancy test within 7 days before Cycle 1, Day 1. 
[o] Urine pregnancy test; if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
[p] TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on within 96 hours before Day 1 of Cycle 1, and 
within 96 hours before Day 1 of every second cycle thereafter, and at treatment discontinuation. 
[q] After informed consent has been obtained, throughout the treatment period and including the follow-up period,  adverse events and serious adverse events 
will be recorded. After initiation of study drug, all AEs will be reported until 30 days after the last dose of study treatment or until initiation of another anti-
cancer therapy, whichever occurs first. Serious adverse events and adverse events of special interest will continue to be reported until 90 days after the last dose 
of atezolizumab or until initiation of new systemic anti-cancer therapy, whichever occurs first. After this period, investigators should report any deaths, SAEs, or 
other AEs of concern that are considered related to prior treatment with the study drug. The investigator should follow each SAE and Grade ≥3 AE until the 
event has resolved to baseline grade, assessed as stable by the investigator, or until the patient withdraws consent or is lost to follow-up. 
[r] Patients should receive their first dose of study drug on the day 1of each cycle. The first dose of atezolizumab will be delivered over 60 ± 15 minutes; if well 
tolerated, all subsequent infusions may be delivered over 30 ± 10 minutes. 
[s] All patients will be followed for survival and new anti-cancer therapy (including targeted therapy and immunotherapy) information until death, 
withdrawal of consent, loss to follow-up, or until study termination by the Sponsor. Survival follow-up information will be collected via telephone calls, patient 
medical records, and/or clinic visits approximately every 3 months ± 21 days. Public information sources (e.g., county records) may also be used to obtain 
information about survival status only in case the patient withdrew from the study 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
Page 18 / 115 
TABLE OF CONTENTS 
 
PROTOCOL APPROVALS ........................................................................................................... 2 
INVESTIGATOR PROTOCOL APPROVAL ............................................................................... 3 
STUDY INSTITUTIONS ............................................................................................................... 4 
SYNOPSIS 5 
STUDY SCHEDULE OF ASSESSMENTS AND PROCEDURES ............................................ 16 
TABLE OF CONTENTS .............................................................................................................. 18 
ABBREVIATIONS AND DEFINITION OF TERMS ................................................................. 22 
1 
BACKGROUND........................................................................................................ 25 
1.1 
Background on Breast Cancer .................................................................................... 25 
1.1.1 
Triple-Negative Breast Cancer (TNBC) ..................................................................... 26 
1.1.2 
Taxanes and Paclitaxel in Metastatic Breast Cancer ................................................ 27 
1.1.3 
Platinum-based Regimens in Metastatic Breast Cancer ............................................ 27 
1.1.4 
PD-L1 Inhibitors in the Treatment of TNBC .............................................................. 29 
1.2 
BACKGROUND ON ATEZOLIZUMAB ................................................................ 29 
1.2.1 
Summary of Clinical Studies in Patients with TNBC ................................................. 30 
1.2.2 
Clinical Pharmacokinetics and Immunogenicity of Atezolizumab............................. 33 
1.3 
Study Rationale and Benefit-Risk Assessment .......................................................... 33 
1.3.1 
Atezolizumab .............................................................................................................. 33 
1.3.2 
Rationale for the Atezolizumab Dose and Schedule .................................................. 34 
1.3.3 
Rationale for Patient Population and Analysis Groups ............................................. 35 
1.3.4 
Rationale for Concomitant Carboplatin and Paclitaxel Treatment ........................... 35 
1.3.5 
Rationale for Atezolizumab in Combination with Carboplatin and Paclitaxel ......... 37 
1.3.6 
PD-L1-positive patients’ selection ............................................................................. 37 
1.3.7 
Rationale for the multiparametric cancer agnostic circulating immunosignature (CLIO)
 .................................................................................................................................... 38 
2 
STUDY DESIGN ....................................................................................................... 40 
2.1 
Description of the Study ............................................................................................. 40 
2.2 
Overview of the Study Design ................................................................................... 40 
3 
OBJECTIVES AND ENDPOINTS ........................................................................... 42 
3.1 
Objectives ................................................................................................................... 42 
3.1.1 
Primary objective: ...................................................................................................... 42 
3.1.2 
Secondary objectives: ................................................................................................. 42 
3.1.3 
Exploratory objectives: .............................................................................................. 42 
3.2 
Endpoints.................................................................................................................... 43 

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Page 19 / 115 
3.2.1 
Primary endpoint: ...................................................................................................... 43 
3.2.2 
Secondary endpoints: ................................................................................................. 43 
3.2.3 
Exploratory endpoints: ............................................................................................... 43 
4 
MATERIALS AND METHODS ............................................................................... 44 
4.1 
Patients ....................................................................................................................... 44 
4.1.1 
Inclusion Criteria ....................................................................................................... 44 
4.1.2 
Exclusion Criteria ...................................................................................................... 46 
4.2 
Study Treatment ......................................................................................................... 49 
4.2.1 
Formulation, Packaging, and Handling .................................................................... 49 
4.2.2 
Dosage, Administration, and Compliance ................................................................. 50 
4.2.3 
Investigational Medicinal Product accountability ..................................................... 52 
4.3 
Concomitant Therapy ................................................................................................. 52 
4.3.1 
Permitted Therapy ...................................................................................................... 53 
4.3.2 
Prohibited and Cautionary Therapy related to atezolizumab.................................... 54 
4.3.3 
Additional Restrictions Related to Chemotherapy ..................................................... 55 
4.4 
Study Assessments ..................................................................................................... 56 
4.4.1 
Informed Consent Forms and Screening Log ............................................................ 57 
4.4.2 
Medical History and Demographic Data ................................................................... 57 
4.4.3 
Physical Examinations ............................................................................................... 57 
4.4.4 
Vital Signs .................................................................................................................. 57 
4.4.5 
Tumor and Response Evaluations .............................................................................. 57 
4.4.6 
Laboratory, biomarker, and other biological samples .............................................. 59 
4.5 
Patient, Treatment, Study, and Site Discontinuation ................................................. 62 
4.5.1 
Patient Withdrawal .................................................................................................... 62 
4.5.2 
Study Drug Discontinuation ....................................................................................... 62 
4.5.3 
Study and Site Discontinuation .................................................................................. 63 
5 
ASSESSMENT OF SAFETY .................................................................................... 64 
5.1 
Safety Plan ................................................................................................................. 64 
5.1.1 
General Plan to Manage Safety Concerns ................................................................. 64 
5.1.2 
Risks Associated with Atezolizumab........................................................................... 64 
5.1.3 
Risks Associated with Paclitaxel ................................................................................ 65 
5.1.4 
Risks Associated with Carboplatin ............................................................................. 66 
5.1.5 
Management of Patients who experience specific Adverse Events ............................ 67 
5.1.6 
Dose Modifications and Interruptions due to Adverse Events ................................... 70 
5.2 
Safety Parameters and Definitions ............................................................................. 74 
5.2.1 
Adverse Events ........................................................................................................... 75 
5.2.2 
Serious Adverse Events (Immediately Reportable to the Sponsor) ............................ 75 

Sponsor: Consorzio Oncotech 
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Date: November 20th, 2019 
 
Page 20 / 115 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to the Sponsor) ........... 76 
5.2.4 
Product Complaints ................................................................................................... 76 
5.3 
Methods and timing for capturing and assessing safety parameters .......................... 77 
5.3.1 
Adverse Event Reporting Period ................................................................................ 77 
5.3.2 
Eliciting Adverse Event information .......................................................................... 77 
5.3.3 
Assessment of Severity of Adverse Events .................................................................. 77 
5.3.4 
Assessment of Causality of Adverse Events ............................................................... 78 
5.3.5 
Procedures for Recording Adverse Events ................................................................ 78 
5.4 
Immediate reporting requirements ............................................................................. 83 
5.4.1 
Reporting Requirements for Serious Adverse Events and Adverse Events of Special 
Interest ........................................................................................................................ 84 
5.4.2 
Reporting Requirements for Pregnancies .................................................................. 85 
5.4.3 
Reporting requirements for Product complaints ........................................................ 86 
5.5 
Follow-up of patients after adverse events................................................................. 86 
5.5.1 
Investigator Follow-Up .............................................................................................. 86 
5.5.2 
Sponsor Follow-Up .................................................................................................... 86 
5.6 
Adverse Events that occur after the adverse event reporting period .......................... 86 
5.7 
Expedited reporting to Health Authorities, Investigators, Institutional Review Boards, 
and Ethics Committees ............................................................................................... 87 
6 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ............................. 88 
6.1 
Statisitical Considerations .......................................................................................... 88 
6.2 
Expected results and sample size ............................................................................... 88 
6.3 
Efficacy Analyses ....................................................................................................... 88 
6.3.1 
Primary Efficacy Endpoint ......................................................................................... 88 
6.3.2 
Secondary Efficacy Endpoints .................................................................................... 89 
7 
ETHICAL AND REGULATORY REQUIREMENTS ............................................. 91 
7.1 
Regulatory and ethical compliance ............................................................................ 91 
7.2 
Study documentation, record keeping and retention of documents ........................... 91 
7.3 
Confidentiality of study documents and patient records .............................................. 92 
7.4 
Audits and inspections ............................................................................................... 92 
7.5 
Financial disclosures .................................................................................................. 92 
7.6 
Patient protection ....................................................................................................... 92 
7.7 
Subject identification – Personal Data Protection ...................................................... 92 
7.8 
Informed consent ........................................................................................................ 93 
7.9 
Conflict of Interest ..................................................................................................... 93 
7.10 
Data ownership ........................................................................................................... 93 
8 
STUDY MANAGEMENT......................................................................................... 94 

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Date: November 20th, 2019 
 
Page 21 / 115 
8.1 
Training of study site personnel ................................................................................. 94 
8.2 
Study timetable and end of study ............................................................................... 94 
9 
DATA MANAGEMENT ........................................................................................... 95 
9.1 
Data confidentiality .................................................................................................... 95 
9.2 
Site monitoring ........................................................................................................... 95 
9.3 
Data collection ........................................................................................................... 95 
9.4 
Database management and quality control ................................................................ 95 
10 
PROTOCOL ADHERENCE ..................................................................................... 97 
11 
PUBLICATION POLICY .......................................................................................... 98 
12 
REFERENCES ........................................................................................................... 99 
APPENDIX 1: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS: MODIFIED 
EXCERPT FROM ORIGINAL PUBLICATION .................................................... 109 
 
 
 
 

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Date: November 20th, 2019 
 
Page 22 / 115 
ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special term Explanation 
ADA  
Anti-drug antibody 
ADCC  
Antibody-dependent cell-mediated cytotoxicity  
AE 
 
Adverse event 
AESI  
Adverse event of special interest 
ALP 
 
Alkaline phosphatase 
ALT 
 
Alanine aminotransferase 
APC 
 
Antigen-presenting cells 
AST 
 
Aspartate aminotransferase 
AUC  
Area under the concentration-time curve 
CDC  
Complement-dependent cytotoxicity 
CI 
 
Confidence interval 
CL 
 
Clearance 
Cmax  
Peak concentration 
Cmax,ss 
Peak concentration at steady state 
Cmin  
Trough concentration 
Cmin,ss 
Trough concentration at steady state 
CNS 
 
Central nervous system 
CR 
 
Complete response 
CT 
 
Computed tomography 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
DC 
 
Disease control 
DCR  
Disease control rate 
DLT 
 
Dose-limiting toxicity 
DNA  
Deoxyribonucleic acid 
DoR 
 
Duration of response 
ECG  
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
EDTA  
Disodium edetate dihydrate 
Fc 
 
Fragment crystallizable 
FFPE  
Formalin fixed paraffin embedded 
FSH 
 
Follicle-stimulating hormone 
FTIH  
First-time-in-human 
GCP 
 
Good Clinical Practice 
GMP  
Good Manufacturing Practice 
GLP 
 
Good Laboratory Practice 
HCl 
 
Hydrochloride 
HIV 
 
Human immunodeficiency virus 
HR 
 
Hormonal Receptor 

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Page 23 / 115 
HUS  
Hemolytic-Uremic Syndrome 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonization 
IEC 
 
Independent Ethics Committee 
IFN 
 
Interferon 
IGF 
 
Insulin-like growth factor 
IgG1  
Immunoglobulin G1 
IgG2  
Immunoglobulin G2 
IGSF  
Immunoglobulin superfamily 
IHC 
 
Immunohistochemistry 
IL 
 
Interleukin 
irAE 
 
Immune-related adverse event 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous(ly) 
MAb  
Monoclonal antibody 
MDSC  
Myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
miRNA 
Micro ribonucleic acid 
MRI 
 
Magnetic resonance imaging 
mRNA  
Messenger ribonucleic acid 
MTD  
Maximum tolerated dose 
NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
 
Natural killer 
NOAEL 
No-observed-adverse-effect level 
NSCLC 
Non-small cell lung cancer 
OR 
 
Objective response 
ORR  
Objective response rate 
OS 
 
Overall survival 
PBMC  
Peripheral blood mononuclear cell 
PD 
 
Progressive disease 
PD-1  
Programmed cell death 1 
PD-L1  
Programmed cell death ligand 1 
PD-L2  
Programmed cell death ligand 2 
PFS 
 
Progression-free survival 
PK 
 
Pharmacokinetic(s) 
PR 
 
Partial response 
PRO 
 
Patient-reported outcome 
PVC 
 
Polyvinyl chloride 
Q2W  
Every 2 weeks 
Q3M  
Every 3 months 
Q3W  
Every 3 weeks 
Q4W  
Every 4 weeks 
Q12W  
Every 12 weeks 
QoL 
 
Quality of life 
QTc 
 
Time between the start of the Q wave and the end of the T wave corrected for heart rate 

Sponsor: Consorzio Oncotech 
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Date: November 20th, 2019 
 
Page 24 / 115 
QTcF  
QT interval on ECG corrected using the Frederica’s formula 
RCC  
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA  
Ribonucleic acid 
SAE 
 
Serious adverse event 
SD 
 
Stable disease 
SID 
 
Subject identification 
sPD-L1 
Soluble programmed cell death ligand 1 
SOCS3 
Suppressor of cytokine signaling 3 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
 
Half life 
TEAE  
Treatment-emergent adverse event 
TIL 
 
Tumor infiltrating lymphocyte 
Tmax  
Time to peak concentration 
Tmax,ss 
Time to peak concentration at steady state 
TNF-α  
Tumor necrosis factor alpha 
TSH 
 
Thyroid stimulating hormone 
ULN  
Upper limit of normal 
USA  
United States of America 
WFI 
 
Water for injection 
WHO  
World Health Organization 
BICR  
Blinded Independent Central Review 
PS 
 
Performance status 
 
 

Sponsor: Consorzio Oncotech 
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Page 25 / 115 
1  
BACKGROUND 
1.1 
Background on Breast Cancer 
Breast cancer is the second most common cancer in the world and, by far, the most frequent cancer among 
women both in more and less developed regions. There were an estimated 1.67 million new cancer cases 
diagnosed worldwide in 2012 (25% of all cancers) (Ferlay et al. 2013; Ferlay et al. 2015; Torre et al. 2015). 
Age-adjusted incidence rates (per 100,000 population) are highest in North America (91.6), followed by 
Europe (69.9), Latin America (47.2), and Eastern Asia (27.0) (Ferlay et al. 2013).  
It is estimated that in 2018 about 52,800 new cases of female breast carcinomas have been diagnosed in 
Italy. If cutaneous carcinomas are not considered, breast cancer is the most diagnosed neoplasia in women, 
in which about one malignant tumour out of three (29%) is a breast cancer. (I numeri del cancro in Italia, 
2018) 
The majority of patients are diagnosed with localized breast cancer, however, approximately 6% of patients 
present with de novo metastatic disease and between 10% and 40% of patients with localized breast cancer 
will relapse systemically (Zeichner et al. 2015a; Zeichner et al. 2015b). 
Breast cancer ranks as the fifth cause of death from cancer overall in the world (522,000 deaths; 6.4% of all 
cancer-related deaths), the leading cause of cancer-related deaths in women (14.7% of all cases), and the 
second cause of cancer death in women in more developed regions (198,000 deaths, 15.4% of total) after 
lung cancer (Ferlay et al. 2013; Ferlay et al. 2015; Torre et al. 2015). Age-adjusted mortality rates (per 
100,000 population) are highest in Europe (16.1), followed by North America (14.8), Latin America (13.0), 
and Eastern Asia (6.1) (Ferlay et al. 2013). In the USA, it is projected that there will be 40,450 deaths due 
to BC in 2016 (Siegel et al. 2016; Miller et al. 2016). Also in Italy, breast cancer is the first cause of death 
for cancer in women, with 12,274 deaths in 2015 (AIOM. 2018). 
The above statistics include all subtypes of BC (Ferlay et al. 2013; Collignon et al. 2016). However, BC is 
a heterogeneous disease encompassing about 15 different types of carcinomas, which are for therapeutic 
reasons, further classified according to their estrogen receptor (ER), progesterone receptor (PR), and 
human epidermal growth factor receptor 2 (HER2) status (Brouckaert et al. 2012). These subgroups have 
important implications for the choice of therapy, treatment outcomes, recurrence rate, and mortality risk. 
The lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth 
factor receptor 2 (HER2), is referred to as triple-negative BC (TNBC) (Trivers et al. 2009; Zeichner et al. 
2016). 
The prognosis of patients with metastatic breast cancer (mBC) varies from several months to many years 
depending upon multiple factors, including, but not limited to, ER/PR status and HER2 status (Zeichner et 
al. 2015a; Zeichner et al. 2015b). Most new treatment options for mBC are only effective for ER/PR-
positive or HER2-positive metastatic tumors (Zeichner et al. 2016). The 5-year survival rate following 
metastatic diagnosis is around 15% (Jemal et al. 2011; Ferlay et al. 2013). 

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1.1.1 Triple-Negative Breast Cancer (TNBC) 
The triple-negative subtype is a heterogeneous group of BCs, characterized by the lack of expression of 
hormonal receptors and the absence of HER2 overexpression (Collignon et al. 2016). According to the St. 
Gallen International Expert Consensus (Goldhirsch et al. 2009), and the recommendations of the American 
Society of Clinical Oncology and the American College of Pathology (Hammond et al. 2010), tumor 
specimens are ER or PR negative if less than 1% of tumor cells express the estrogen and progesterone 
receptors via immunohistochemistry (IHC), and HER2-negative if showing IHC 0 or 1+ or in situ 
hybridization (ISH) negative using single-probe ISH or dual-probe ISH (Wolff et al. 2013). 
Although 1% has been used as cut-off for ER positivity, several studies have reported that tumors with 
ER < 1% have characteristics similar to those with 1% ≤ ER < 10%. Recently an observational study 
showed that stage II or III HER2-negative primary breast cancer with ER < 10% behaves clinically like 
triple-negative breast cancer in terms of pCR and survival outcomes and patients with such tumors may 
have a limited benefit from adjuvant hormonal therapy. It may be more clinically relevant to define triple-
negative breast cancer as HER2-negative breast cancer with <10%, rather than <1%, of ER and/or 
progesterone receptor expression (Fujii T et al. 2017). However, all recent studies that evaluated first-line 
treatments in TNBC used cut-off of  <1% to define ER negativity but it could be extremely interesting and 
clinically useful to test new combinations also in the ER < 10% breast cancer patients. 
Approximately 15%-20% of all BCs belong to the triple-negative phenotype that has distinct risk factors, 
distinct molecular features, and a particular clinical presentation and outcome (Brouckaert et al. 2012; Lin 
et al. 2012; Penault-Llorca and Viale, 2012). The TNBC phenotype has been associated with younger age, 
and more advanced tumor stage at presentation (Millikan et al. 2008; Lund et al. 2009; Trivers et al. 2009; 
Lin et al. 2012; Danforth et al. 2013). TNBCs are more likely to have aggressive features, such as a high 
proliferative rate, and exhibit an invasive phenotype. Patients with metastatic TNBCs exhibit rapid 
progression and a poor clinical outcome (Mersin et al. 2008; Trivers et al. 2009; Wahba and El-Hadaad, 
2015). TNBC is associated with a higher risk of brain or lung metastases, and worse breast cancer specific 
and overall survival (OS) (Lin et al. 2012); median OS is generally between 12 months (Tutt et al. 2018) 
and 17 months in patients treated with various chemotherapy agents (Yardley et al. 2018). 
Large-scale comprehensive genomic analyses have characterized the heterogeneous nature of TNBCs and 
their diverse gene-expression patterns and underlying genomic changes, but these insights have not yet 
provided clear guidance for the identification of clinically effective targeted therapies (Hirshfield and 
Ganesan, 2014). Chemotherapy is the mainstay of treatment of TNBC, and current treatment strategies for 
triple-negative disease include anthracyclines, taxanes, platinum agents, and bevacizumab (Hudis and 
Gianni, 2011). However, although TNBC may respond to chemotherapy, including taxanes, relatively few 
new agents have been approved for the subset of patients with metastatic TNBC (mTNBC) (Carey et al. 
2012; O’Shaughnessy et al. 2014; Hirshfield and Ganesan, 2014; Zeichner et al. 2016) and there are no 
targeted therapies with widespread global approval available for patients with this specific subtype of 
breast cancer.  
Taxane-based chemotherapy represents the preferred standard first-line treatment in triple-negative breast 
cancer patients (Cardoso et al. 2018). Recent data from the TNT trial confirmed the activity of single agent 
taxane chemotherapy in this setting, although median progression-free survival (PFS) was only 4.4 months 

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(Tutt et al. 2018). 
The recent results of randomized phase II TNACITY trial showed that the association of nab-paclitaxel and 
carboplatin seems the best chemotherapy schedule as first-line treatment of patients with metastatic triple-
negative breast cancer with a median PFS of about 8 months (Yardley et al. 2018). 
Considering the improvement of PFS obtained with the combination compared to the monotherapy, the 
combination may represent a starting point for exploring new effective treatment regimens for mTNBC. 
1.1.2 Taxanes and Paclitaxel in Metastatic Breast Cancer 
Taxane-based regimens are considered a standard of care option in first-line therapy for patients with mBC, 
including TNBC (Cardoso et al. 2018). No standard approach exists for second- or further-line treatment, 
and options for cytotoxic chemotherapy are the same as those for other subtypes. Single-agent cytotoxic 
chemotherapeutic agents are generally regarded as the primary option for patients with metastatic TNBC, 
although combination chemotherapy may be used when there is aggressive disease and visceral 
involvement. The role of paclitaxel in the treatment of BC is well established. The response rates for 
paclitaxel administered as a single agent to patients with mBC are approximately 25% in first-line 
treatment (Wilson et al. 1994; Seidman et al. 1995; Nabholtz et al. 1996; Gradishar et al. 2005). Weekly 
paclitaxel (80–90mg/m2) is currently considered the most effective schedule for delivering paclitaxel 
(Swanton et al. 2011), and was found to be associated with higher overall survival (OS) and lower 
incidence of serious adverse events, neutropenia, neutropenic fever, and peripheral neuropathy compared 
with the three-weekly taxane schedules in advanced breast cancer (Seidman et al. 2008; Mauri et al. 2010). 
In addition, a regimen consisting of weekly paclitaxel administrations for three weeks, followed by one-
week break was reported to be associated with less neurotoxicity compared to continuous weekly 
administrations (Swanton 2011). 
1.1.3 Platinum-based Regimens in Metastatic Breast Cancer 
As predicted by their deoxyribonucleic acid (DNA)-damaging mechanism of action, platinum compounds 
are expected to be particularly active in tumors characterized by a defect in DNA double-strand break 
repair, such as those without active breast cancer susceptibility gene (BRCA1/2) proteins (Turner and Tutt 
2012; Cardoso et al. 2018; Isakoff et al. 2015). In recent years, substantial evidence has accumulated 
confirming the link between TNBC and BRCA1/2 mutations (Gerratana et al. 2016; González-Rivera et al. 
2016). Approximately 80% of breast cancers with BRCA1 mutation are TNBCs, and up to 20% of patients 
affected by TNBC are carriers of a BRCA germline mutation. Therefore, TNBCs had been postulated to be 
particularly sensitive to interstrand cross-linking agents, including platinum analogues (Turner and Tutt 
2012; Isakoff et al. 2015; Gerratana et al. 2016). 
The clinical activity of first- or second-line platinum monotherapy in mTNBC was demonstrated in a 
multicentre Phase II clinical trial (TBCRC009; N=86). In this study, objective response rate (ORR) was 
25.6% overall (cisplatin and carboplatin groups combined), and 54.5% in patients with germline BRCA1/2 
mutations (p=0.022) (Isakoff et al. 2015). In the recent phase III randomized TNT trial (N=376), treatment 
with carboplatin resulted in a significantly higher ORR versus docetaxel in patients with BRCA1/2 
mutations (68% versus 33.3%; P = 0.03) but no difference in terms of ORR and PFS were observed in the 

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wild-type population (Tutt et al. 2018). 
Platinum-containing chemotherapy combinations have demonstrated activity in patients with TNBC both 
in the neoadjuvant (Alba et al. 2012; von Minckwitz et al. 2014; Sikov et al. 2015; Loibl et al, 2018; 
Poggio et al. 2018) and metastatic settings (O’Shaughnessy et al. 2011; O’Shaughnessy et al. 2014; 
Yardley et al. 2018), particularly in TNBC patients with BRCA1/2 mutations (Tutt et al. 2018; Telli et al. 
2015).  
In the single-arm phase II PrECOG 0105 study, 80 patients with stage I to IIIA (T ≥ 1 cm) TNBC or 
BRCA1/2 mutation-associated breast cancer received neoadjuvant gemcitabine (1,000 mg/m2 
intravenously [IV] on days 1 and 8), carboplatin (area under curve [AUC] of 2 IV on days 1 and 8), and 
iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) every 21 days for initially four, and following a protocol 
amendment, every 6 cycles. In the intent to treat (ITT) population, pathological complete response (pCR) 
rates were higher in patients with BRCA1/2 mutation (47%), and even higher in patients with TNBC and 
BRCA1/2 mutations (56%) compared to those who were not carriers of these mutations (Telli et al. 2015). 
In a phase II randomized study (n = 123) evaluating the clinical benefits of gemcitabine and carboplatin 
with or without iniparib in patients with metastatic TNBC, gemcitabine 1000 mg/m2 IV plus carboplatin 
IV dosed at AUC2 on days 1 and 8 every 3 weeks (n = 62) resulted in a median progression-free survival 
(PFS) of 3.6 months, a median OS of 7.7 months, and ORR of 32% (O’Shaughnessy et al. 2011). In a 
subsequent confirmatory randomized phase III study comparing these two regimens in 519 women with 
metastatic TNBC, gemcitabine plus carboplatin demonstrated median PFS and OS of 4.1 and 11.1 months, 
respectively in the ITT population and 4.6 and 12.4 months based on an exploratory analysis in patients 
receiving first-line treatment (O’Shaughnessy et al. 2014). 
Other gemcitabine and carboplatin-containing regimens have also been evaluated in patients with advanced 
TNBC. The combination of carboplatin with eribulin (a mitotic inhibitor) as first-line therapy for locally 
recurrent or metastatic TNBC resulted in ORR of 57.9%, clinical benefit rate (CBR) of 68.1%, and a 
median PFS of 8.4 months (95% confidence interval [CI]: 4.6, 10.4) in a recently reported Phase 2 study 
(Michalaki et al. 2016). The results of phase II tnAcity study comparing weekly nab-paclitaxel 125 mg/m2 
plus gemcitabine IV 1000 mg/m2 or carboplatin IV AUC2 versus gemcitabine/carboplatin as first-line 
treatment of patients with metastatic TNBC have recently been published. Weekly nab-paclitaxel plus 
carboplatin was associated with significantly longer PFS (7.4 months) compared to weekly regimens of 
either nab-paclitaxel plus gemcitabine (5.4 months; P=0.02; HR 0.60, 95% CI, 0.39-0.93) or of carboplatin 
plus gemcitabine (6.0 months; P= 0.03; HR 0.61, 95% CI, 0.39-0.94). Nab-paclitaxel plus carboplatin also 
prolonged OS (16.4 months) compared to either nab-paclitaxel plus gemcitabine (12.1 months; P=0.07; HR 
0.66, 95% CI, 0.42-1.04) or of carboplatin plus gemcitabine (12.6 months; P= 0.18; HR 0.74, 95% CI, 
0.48-1.16), however the between-group differences were not statistically significant (Yardley et al. 2018).  
A recent systematic review and meta-analysis of 23 randomized trials involving 4625 patients assessed the 
efficacy and safety of platinum therapy (11 with cisplatin, 11 with carboplatin, and 1 with either agents 
respectively) in patients with locally advanced or metastatic breast cancer. Although at the expense of 
significantly increased fatigue, haematological and gastrointestinal toxicity, compared with non-platinum 
regimens, cisplatin, and carboplatin prolonged OS (HR 0.91; 95% CI 0.83-1.00, p = 0.04), PFS (HR 0.84; 
95% CI 0.73-0.97, p = 0.01), and RR (HR 1.27; 95% CI 1.03-1.57, p = 0.03) (Petrelli et al. 2016). 

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According to the latest (3rd) revision of the European School of Oncology (ESO)- European Society of 
Medical Oncology (ESMO) international consensus guidelines for advanced breast cancer, in triple-
negative ABC patients (regardless of BRCA status), previously treated with anthracyclines with or without 
taxanes in the (neo)adjuvant setting, carboplatin demonstrated comparable efficacy and a more favorable 
toxicity profile, compared to docetaxel, and is therefore an important treatment option. (Cardoso et al. 
2018). 
1.1.4 PD-L1 Inhibitors in the Treatment of TNBC 
Recent investigations of targeted therapy for advanced TNBC includes immune checkpoint inhibitors 
targeting the programmed death receptor 1 (PD-1)/ programmed death ligand 1 (PD-L1; also called B7-H1 
or cluster of differentiation [CD]274). PD-L1 is expressed on many cancer and immune cells (e.g., 
macrophages), and plays an important part in blocking the 'cancer immunity cycle' by binding and 
stimulating PD-1 and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. PD-
1 is an inhibitory receptor expressed on T cells following T-cell activation, which is sustained in states of 
chronic stimulation such as in chronic infection or cancer (Blank et al. 2005; Keir et al. 2008; Herbst et al. 
2014). B7.1 is a molecule expressed on presenting cells and activated T cells. Binding of PD-L1 to its 
receptors suppresses T cells migration, proliferation and secretion of cytotoxic mediators, and restricts 
tumor cell killing, leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et 
al. 2011; Herbst et al. 2014). The PD-1/PD-L1 pathway has been implicated in tumors evading immune 
surveillance. Blockage of the PD-1/PD-L1 interaction enables the rapid restoration of the effector function 
of preexisting anticancer T cells (Chen and Mellman, 2013; Saha and Nanda, 2016). Blocking PD-L1 
should therefore enhance anticancer immunity (Herbst et al. 2014). 
Based on results of early clinical studies, blockade of the PD-1/PD-L1 axis with atezolizumab (Emens et al. 
2015; Adams et al. 2015; Schmid et al. 2017), pembrolizumab (Nanda et al. 2016; Adams et al. 2017a; 
Adams et al. 2017b), or avelumab (Dirix et al. 2016) has demonstrated promising efficacy and durable 
responses in patients with advanced TNBC. 
1.2 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese hamster ovary 
(CHO) cells. Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution (asparagine to alanine) at position 298 on the heavy chain, which results in a non-glycosylated 
antibody that has minimal binding to Fc receptors and prevents Fc-effector function at expected 
concentrations in humans. Atezolizumab targets human PD-L1 and inhibits its interaction with its 
receptors, PD-1 and B7.1 (CD80, B7-1). Both interactions are reported to provide inhibitory signals to T 
cells. 
Atezolizumab is being investigated as a potential therapy against solid tumors and haematologic 
malignancies in humans. Atezolizumab has been approved in the USA for the treatment of locally 
advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer (NSCLC). 

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1.2.1 Summary of Clinical Studies in Patients with TNBC 
Atezolizumab is being investigated in multiple Phase I, II, and III clinical studies, both as monotherapy and 
in combination with several anti-cancer therapies against solid tumors and hematologic malignancies (see 
the atezolizumab Investigator’s Brochure for study descriptions). 
Anti-tumor activity, as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
responses, has been observed across multiple advanced tumor types for both atezolizumab monotherapy 
(Phase 1a study PCD4989g) as well as in combination with bevacizumab and/or chemotherapy (Phase 1b 
study GP28328). In patients with mTNBC, atezolizumab has shown activity as monotherapy (Emens et al. 
2015; Schmid et al. 2017), and in combination with nab-paclitaxel (Adams et al. 2016). 
Combining atezolizumab with chemotherapy is hypothesized to enhance tumor-specific T-cell immunity 
by exposing the immune system to high levels of chemotherapy-induced tumor antigens and modulating T-
cell and NK cell functions (Adams et al. 2016). 
1.2.1.1 Efficacy of Atezolizumab Monotherapy in Patients with TNBC 
Atezolizumab monotherapy has been evaluated in a mTNBC expansion cohort as part of a multicentre 
Phase Ia study PCD4989g (clinicaltrials.gov identifier: NCT01375842). 
PCD4989g is a first-in-human, ongoing open-label, dose-escalation trial evaluating the safety, tolerability, 
immunogenicity, PK, exploratory pharmacodynamics, and preliminary evidence of biologic activity of 
atezolizumab administered as a single agent to patients with locally advanced or metastatic solid 
malignancies or hematologic malignancies. 
Atezolizumab is administered at 15 mg/kg, 20 mg/kg or 1200 mg flat dose IV every three weeks (Q3W). 
Preliminary results based on the first 21 efficacy-evaluable patients (13 PD-L1 IHC2, and eight PDL-1 
IHC3) indicated an unconfirmed RECIST objective response rate (ORR) of 24% (95% confidence interval 
[CI], 8% to 47%); the confirmed ORR was 19% (95% CI 5.5% to 42%). Of the four patients with 
confirmed objective response, there were two partial responses (PRs) and two complete responses (CRs) 
(Emens et al. 2015; Atezolizumab Investigator’s Brochure, 2016). Response duration ranged from 0.1 to 
41.6 weeks, with the median not reached at the time of reporting. 
Overall, the 24-week progression-free survival (PFS) rate was 33% (95% CI, 12% to 53%). Biomarker 
analysis revealed transient elevation of plasma cytokines and proliferating CD8+ T-cells following 
atezolizumab treatment (Emens et al. 2015). Among 115 ORR-evaluable patients, investigator-assessed 
confirmed ORR was 10% (95% CI, 5-16) with 3 complete responses (CRs) and 8 partial responses (PRs). 
Median duration of objective response (DoR) was 21 months (range 3 to >38 weeks) and all-patient median 
OS was 8.9 months (95% CI, 7.0-12.6), with a median follow-up duration of 25.3 months. Median PFS was 
1.4 months (95% CI, 1.3–1.6). These data suggest a similarity to or advantage over standard of care (SOC) 
treatment. Higher PD-L1 expression (IC2/3) compared to lower PD-L1 expression (IC0/1) was associated 
with better clinical outcomes, as evidenced by higher ORR (12% vs. 5% in the two subgroups, 
respectively), and longer median OS (10.5 months [95% CI, 7.1–14.7] vs 7.0 [95% CI, 5.1–12.6], 
respectively). Greater treatment benefit was also observed in patients receiving first-line (1L) compared to 

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subsequent lines (2L+) atezolizumab, as evidenced by higher ORR (24% among 1L patients vs. 6% among 
2L+ patients), and longer median OS (17.6 months [95% CI, 10.2–NE], vs. 7.3 months [95% CI, 6.1–10.8], 
respectively). Median PFS was consistent (approximately 1.4 months) regardless of PDL1 expression or 
line of therapy (Atezolizumab Investigator’s Brochure, 2017). Atezolizumab increased intratumoural tumor 
infiltrating lymphocytes (TILs), CD8, macrophages and IC PD-L1 expression, but no response association 
was observed (Schmid et al. 2017). 
1.2.1.2 Efficacy of Atezolizumab Combined with Chemotherapy in Patients with TNBC 
Building on the promising results of atezolizumab as a single agent, an open-label Phase 1b trial 
(GP28328; clinicaltrials.gov identifier: NCT01633970) was initiated to evaluate atezolizumab in 
combination with chemotherapy and/or bevacizumab in locally advanced or metastatic solid tumors. One 
of the arms (Arm F) is evaluating 4-week cycles consisting of atezolizumab 800 mg Q2W (days 1 and 15) 
in combination with nab-paclitaxel 125 mg/m2 Q1W (days 1, 8, and 15) in patients with mTNBC, treated 
with ≤2 prior lines of therapy for metastatic disease. After nab-paclitaxel discontinuation, maintenance 
atezolizumab is allowed until loss of clinical benefit. Primary endpoints are safety and tolerability; 
secondary endpoints include clinical activity. Preliminary results are available for the 32 enrolled female 
patients aged 32 to 84 years (median 56 years). The majority of patients (87%) received prior taxane 
therapy (Adams et al. 2015; Adams et al. 2016). As of the data cut-off of 14 January 2016, the investigator-
assessed ORR per RECIST v1.1 was 37.5% (95% CI, 21.1, 56.3; confirmed responses only); these 
included one complete CR and 11 PRs. Clinical benefit was observed across all lines of therapy, with 
ORRs being comparable between patients with one vs three or more previous lines of treatment (46.2% and 
40.0%, respectively); refer to the atezolizumab Investigator's Brochure for further details. 
1.2.1.3 Efficacy and Safety of Atezolizumab Combined with Nab-paclitaxel in Patients with TNBC 
In phase III randomized trial Impassion 130, patients with untreated mTNBC cancer were randomized to 
receive atezolizumab 840 mg day 1 and 15 every 28 days plus nab-paclitaxel 100 mg/m2 day 1, 8 and 15 
every 28 days or placebo plus nab-paclitaxel; patients continued the intervention until disease progression 
or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or non-receipt of 
neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and PD-L1 
expression at baseline (positive vs. negative). The two primary end points were PFS (in the intention-to-
treat population and PD-L1–positive subgroup) and OS (tested in the intention-to-treat population; if the 
finding was significant, then it would be tested in the PD-L1–positive subgroup). 
Each group included 451 patients (median follow-up, 12.9 months). In the intention to-treat analysis, the 
median PFS was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with 
placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 
to 0.92; P = 0.002); among patients with PD-L1–positive tumors, the median PFS was 7.5 months and 5.0 
months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, 
the median OS was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus 
nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P = 0.08); among patients with PD-L1–
positive tumors, the median OS was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% 
CI, 0.45 to 0.86). Combination therapy with atezolizumab  plus nab-paclitaxel had a safety profile that was  

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consistent with the known toxic effects of each  agent. Consistent with observations from other  
atezolizumab–chemotherapy combination trials, no new adverse-event signals were.  
Among patients in the safety population, adverse events, regardless of attribution, occurred in 99.3% of 
452 patients in the atezolizumab–nab-paclitaxel group and in 97.9% of 438 patients in the placebo–nab-
paclitaxel group. The most common adverse events were similar in the two groups,  with no new adverse 
events identified. Alopecia was the most common event in each group. The frequencies of nausea, cough, 
neutropenia, pyrexia, and hypothyroidism were at least 5 percentage points greater in the atezolizumab–
nab-paclitaxel group than in the placebo–nab-paclitaxel group. The rate of adverse events of grade 3 or 4 
was 48.7% in the atezolizumab–nab-paclitaxel group and 42.2% in the placebo–nab-paclitaxel group, and 
the most common events in these groups (as assessed by the investigator) were neutropenia, decreased 
neutrophil count, peripheral neuropathy, fatigue, and anemia. The frequency of peripheral neuropathy of 
grade 3 or 4 was higher in the atezolizumab–nab-paclitaxel group (25 patients [5.5%]) than in the placebo–
nab-paclitaxel group (12 patients [2.7%]). Serious adverse events occurred in 103 patients (22.8%) in the 
atezolizumab–nab-paclitaxel group and in 80 (18.3%) in the placebo–nab-paclitaxel group. 
A total of 259 patients (57.3%) in the atezolizumab–nab-paclitaxel group and 183 (41.8%) in the placebo–
nab-paclitaxel group had an adverse event of special interest, which was suggestive of a potential immune-
related cause. Grade 3 or 4 adverse events of special interest occurred in 34 patients (7.5%) in the 
atezolizumab–nabpaclitaxel group and in 19 (4.3%) in the placebo–nab-paclitaxel group. Two grade 5 
adverse events of special interest occurred (autoimmune hepatitis in 1 patient in the atezolizumab–nab-
paclitaxel group and hepatic failure in 1 patient in the placebo–nab-paclitaxel group). Immune-related 
hypothyroidism occurred at a higher frequency in the atezolizumab–nab-paclitaxel group than in the 
placebo–nab-paclitaxel group (17.3% vs. 4.3%); all the events were of grade 1 or 2, and none led to the 
discontinuation of the trial regimen. Pneumonitis was infrequent, occurring in 3.1% of the patients in the 
atezolizumab–nab-paclitaxel group and in 0.2% of those in the placebo–nab-paclitaxel group; only 1 
patient (in the atezolizumab–nab-paclitaxel group) had an event of grade 3 or 4.  Fatal adverse events 
occurred in 6 patients (1.3%) in the atezolizumab–nab-paclitaxel group and in 3 (0.7%) in the placebo–nab-
paclitaxel group; three deaths in the atezolizumab–nab-paclitaxel group (from autoimmune hepatitis, 
mucosal inflammation, and septic shock, in 1 patient each) and one death in the placebo–nab-paclitaxel 
group (from hepatic failure) were considered by the investigators to be related to the trial regimen). 
Adverse events that led to withdrawal of any agent occurred in 15.9% of the patients who received 
atezolizumab–nab-paclitaxel group and in 8.2% of those who received placebo–nab-paclitaxel group. A 
total of 29 patients (6.4%) had adverse events that led to the discontinuation of atezolizumab, and 6 (1.4%) 
had adverse events that led to the discontinuation of placebo. 
This phase III study showed that Atezolizumab plus nab-paclitaxel prolonged PFS among patients with 
metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1–positive 
subgroup. In the PD-L1-positive patients, despite the limits of the statistical design, the median OS 
observed was very interesting and it has never been reached before (Schmid et al. 2018). 
1.2.1.4 Safety of Atezolizumab Combined with Carboplatin and Paclitaxel in Patients with NSCLC 
In phase III randomized trial IMPower150 patients with metastatic NSCLC were randomized to receive 
atezolizumab 1200 mg every three weeks plus 21-day carboplatin plus paclitaxel (ACP), bevacizumab plus 

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carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, 
followed by maintenance therapy with atezolizumab, bevacizumab, or both. 
In terms of efficacy this trial showed that the addition of atezolizumab to bevacizumab plus chemotherapy 
significantly improved PFS and OS among patients with metastatic nonsquamous NSCLC without any 
detrimental interaction between atezolizumab and steroid premedication of paclitaxel. 
The safety profile of atezolizumab in combination with other agents was consistent with safety profiles of 
the individual medicines, including the rate of hemorrhagic events caused by bevacizumab; no new safety 
signals were identified with the combination. The frequency of treatment-related serious adverse events 
was similar to that in previously reported studies of chemotherapy combined with checkpoint inhibitors. 
The incidence and nature of immune-related adverse events in the ABCP group were similar to those with 
atezolizumab monotherapy (Socinski et al. 2018). 
1.2.2 Clinical Pharmacokinetics and Immunogenicity of Atezolizumab 
Based on available PK data exposure to atezolizumab increased dose proportionally over the dose range of 
1 mg/kg to 20 mg/kg, including the fixed dose of 1200 mg administered Q3W. Based on a population PK 
analysis that included 472 patients in the dose range of 1 mg/kg to 20 mg/kg, the typical population 
clearance (CL) was 0.20 L/day, the volume of distribution at steady state (Vss) was 6.9 L, and the terminal 
half-life (t1/2) was 27 days. The population PK analysis suggested that steady state was obtained after 6 to 
9 weeks (2 to 3 cycles) of repeated dosing. The systemic accumulation in area under the concentration-time 
curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin) was 1.91, 1.46, and 2.75-
fold, respectively. Based on an analysis of exposure-safety, and exposure-efficacy data, the following 
factors had no clinically relevant effect: age (21 to 89 years), body weight, gender, positive ATA status, 
albumin levels, tumour burden, region or ethnicity, renal impairment, mild hepatic impairment, level of 
PD-L1 expression, or Eastern Cooperative Oncology Group (ECOG) status. The effect of moderate or 
severe hepatic impairment (bilirubin > upper limit of normal [ULN] and AST > ULN or bilirubin ≥ 1.0 to 
1.5 x ULN and any AST elevation) on the PK of atezolizumab is unknown. 
The development of anti-therapeutic antibodies (ADAsATAs) has been observed in patients at all dose 
levels. ADAATA positivity had no major effect on atezolizumab concentrations and PK although there was 
a trend for lower Cmin values in the ADAATA positive subgroup. The presence of ADAsATAs did not 
appear to have a clinically significant impact on PK, safety, or efficacy of atezolizumab. 
1.3 
Study Rationale and Benefit-Risk Assessment 
1.3.1 Atezolizumab 
Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies 
focused on enhancing T-cell responses against cancer can result in a significant survival benefit in patients 
with advanced malignancies (Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
As detailed in Section 1.2, PD-L1 is an extracellular protein that downregulates immune responses 
primarily in peripheral tissues through binding to its two receptors: PD-1 and B7.1. PD-L1 is expressed on 
many cancer and immune cells, and overexpression of PD-L1 on tumor cells has been reported to impede 

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anti-tumor immunity (Blank and Mackensen 2007; Herbst et al. 2014). Binding of PD-L1 to its receptors 
suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumor cell 
killing (Herbst et al. 2014). The PD-1/PD-L1 pathway has been implicated in tumors evading immune 
surveillance. Therefore, interruption of the PDL1/ PD-1 and the PD-L1/B7.1 pathways represents an 
attractive strategy to reinvigorate tumor-specific T-cell immunity (Blank and Mackensen 2007; Chen and 
Mellman, 2013; Herbst et al. 2014; Saha and Nanda, 2016). 
The rationale for investigating PD-L1 inhibitors in TNBC stems from a number of key clinical 
observations. ER-negative breast cancers have a higher density of tumor infiltrating lymphocytes (TILs) 
than their ER-positive counterparts (Loi et al. 2014), and greater numbers of TILs have been associated 
with better clinical outcomes in patients with TNBC (Cancer Discov. 2015). PD-L1 expression is also more 
prevalent in TNBC than in other breast cancer subtypes (Emens et al. 2014). TNBCs have a higher 
mutational burden compared with their ER-positive counterparts, and have been linked with increased 
immunogenicity (Wang et al. 2014). Gene expression profiling of TNBCs has identified an 
immunomodulatory subtype that is characterized by increased expression of genes involved in T-cell 
function (Lehmann et al. 2011; Saha and Nanda, 2016). Due to the higher mutation rate and a higher 
number of TILs relative to other breast cancer subtypes, TNBC may be particularly susceptible to 
immunotherapy (Cancer Discov. 2015). 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients with advanced 
malignancies, including patients with TNBC, who have failed standard-of care therapies. The observation 
that high CD8+ T-cell density in primary breast tumors is correlated with improved OS, and that mTNBC 
tumors have fewer TILs than their matched primary tumors, suggests that the immune system is able to 
partially restrain human breast cancer but that immune suppression becomes more prevalent with 
increasing growth and metastasis (Cimino-Mathews et al. 2013; Adams et al. 2014; Loi 2014). The 
identification of immune-enriched subtypes of TNBC underscores the potential to harness pre-existing host 
anti-tumor immunity in this disease (Lehmann et al. 2011). In this setting, re-invigorating T-cell activity 
with atezolizumab may be an effective treatment strategy. 
Atezolizumab has been generally well tolerated in clinical trials (see Section 1.2.1); adverse events with 
potentially immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
hypothyroidism, hepatitis/elevated transaminases, colitis, and myasthenia gravis, have been observed in 
ongoing studies of atezolizumab. To date, the majority of these events have been manageable without 
requiring treatment discontinuation. 
1.3.2 Rationale for the Atezolizumab Dose and Schedule 
Atezolizumab will be administered IV at a flat dose of 840 mg every two weeks (Q2W) to align with the 
chemotherapy schedule. 
The fixed dose of 840 mg administered Q2W was selected with the intent of selecting a dose that is the 
exposure equivalent of the fixed dose of 1200 mg Q3W (weight-based equivalent of 15 mg/kg), which has 
been approved for treating patients with urothelial carcinoma and NSCLC (refer to the TECENTRIQTM 
prescribing information). Of note, the exact equivalent dose is 800 mg; however, because atezolizumab is 
formulated at a concentration of 60 mg/mL, 800 mg corresponds to a volume of 13.33 mL, and in the 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
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interest of simplifying administration, the exact dose used in this study will be 840 mg, corresponding to a 
volume of 14 mL, which can be accurately administered with a single syringe. The 840 mg dose is not 
expected to result in meaningfully different exposure compared with the 800 mg dose. 
In the Phase Ia Study PCD4989g, patients were treated with doses ranging from 0.1 to 20 mg/kg. Anti-
therapeutic antibodies (ADAsATAs) to atezolizumab were associated with changes in PK for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg), but not for patients treated at 10, 15, and 20 mg/kg, 
including the approved dose of 1200 mg. To date, no relationship has been observed between the 
development of measurable ADAsATAs and safety or efficacy. 
1.3.3 Rationale for Patient Population and Analysis Groups 
The target population will include patients with previously untreated inoperable locally advanced or 
metastatic PD-L1 positive TNBC. Patients will be either newly diagnosed or have disease progression after 
completing treatment for early breast cancer at least 12 months prior to enrollment. 
As detailed in Section 1.1.1, TNBC is more likely to have aggressive features, such as a high proliferative 
rate, and exhibit an invasive phenotype. Patients with metastatic TNBC are characterized by a more 
aggressive course compared to other subtypes (Wahba and El-Hadaad, 2015) and a poor clinical outcome 
(Mersin et al. 2008; Trivers et al. 2009), including worse breast cancer-specific survival and OS (Lin et al. 
2012), generally with rapid progression and a median OS generally between 13 months (Kassam et al. 
2009) and 17.5 months in patients treated with various chemotherapy agents (Yardley 2018). Although 
TNBC may respond to chemotherapy, including taxanes, there are no targeted therapies with widespread 
global approval available for patients with this subtype of breast cancer, and relatively few new agents 
have been approved for mTNBC (Carey et al. 2012; O’Shaughnessy et al. 2014; Hirshfield and Ganesan, 
2014; Zeichner et al. 2016). Therefore, there is a pressing need for clinically active targeted therapy for 
mTNBC. 
Regarding its immunologic properties, TNBC is characterized by high DNA mutational rates (TCGAN, 
2012) which have been postulated as a source of immunogenic tumour specific neoantigens. Consistent 
with this, a significant proportion of TNBC patients display CD8+ tumour infiltrating lymphocytes at 
diagnosis, which has been correlated with a better prognosis (Ali et al. 2014) and suggests that activation of 
the immune system in TNBC patients could be utilized to modify the course of the disease. 
Atezolizumab showed promising anti-tumor activity, as determined by RECIST v1.1 response, across 
multiple advanced tumor types (including TNBC) both as monotherapy (Phase 1a study PCD4989g) as 
well as in combination with bevacizumab and/or chemotherapy (Phase 1b study GP28328). In patients with 
mTNBC, atezolizumab has shown activity as monotherapy (Emens et al. 2015), and most notably in 
combination with nab-paclitaxel (Adams et al. 2016). 
1.3.4 Rationale for Concomitant Carboplatin and Paclitaxel Treatment 
The taxane class of cytotoxic agents (paclitaxel, docetaxel, nab-paclitaxel) have significant antitumor 
activity in breast cancer. Despite the expansion of the therapeutic landscape for mBC over the last three 
decades, including the increasing availability of targeted therapies for various BC subtypes, cytotoxic 
taxane-based regimens remain standard of care in first-line therapy for patients with mBC, including 

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TNBC (Cardoso et al. 2018; Greene and Hennessy 2015; Hernandez-Aya and Ma 2016; Fukada et al. 
2016).  
Several studies and meta-analyses support the benefit of taxanes on clinical outcomes in mBC (Piccart-
Gebhart et al. 2008; Qi et al. 2013; Ghersi et al. 2015), and these benefits were generally comparable to 
those of anthracyclines in randomized controlled clinical studies. However, in a recent meta-analysis of 28 
studies (N= 6871 randomized women), the combined hazard ratio (HR) for OS and time to progression 
(TTP) favored the taxane-containing compared to the anthracycline regimens (HR 0.93, 95% CI 0.88 to 
0.99, P = 0.002, deaths = 4477; and HR 0.92, 95% CI 0.87 to 0.97, P = 0.002, estimated 5122 events, 
respectively). When the analyses were restricted to first-line treatments, this effect persisted for OS (HR 
0.93, 95% CI 0.87 to 0.99, P = 0.03) but not for TTP. 
Tumor response rates were higher with taxane-containing chemotherapy in assessable women (RR 1.20, 
95% CI 1.14 to 1.27, P < 0.00001). Taxanes were also associated with an increased risk of neurotoxicity 
but less nausea and vomiting compared to non-taxane containing regimens (Ghersi et al. 2015). 
Paclitaxel, docetaxel, and nab-paclitaxel are approved drugs for the treatment of recurrent and metastatic 
BC in many countries. Paclitaxel is administered weekly (80-90 mg/m2) (Swanton 2011) or every three 
weeks (175 mg/m2 dose recommended by the current Prescribing Information for Taxol® IV injection), 
with weekly paclitaxel (80–90mg/m2) currently considered the most effective schedule for delivering 
paclitaxel (Swanton 2011). A meta-analysis of 11 randomized clinical trials (n=2,540 patients) comparing 
weekly- and three-weekly taxanes in patients with advanced BC found that weekly administration of 
paclitaxel resulted in higher OS compared to the three-weekly schedule (HR 0.78; 95% CI, 0.67–0.89 
P=0.001); PFS was similar between the two schedules. The incidence of serious adverse events, 
neutropenia, neutropenic fever, and peripheral neuropathy were also significantly lower with the weekly 
compared to the three-weekly taxane schedules (Mauri et al. 2010). In addition, a regimen consisting of 
weekly paclitaxel administrations for three weeks, followed by one-week break was reported to be 
associated with less neurotoxicity compared to continuous weekly administrations (Swanton 2011). This 
finding is consistent with the lower neurotoxicity rate observed in the HER2-negative mBC population of 
the studies E2100 (Miller et al. 2007) and MERIDIAN (Miles et al. 2017), both using a 90 mg/m2 3-week 
on/1-week off weekly paclitaxel schedule, compared to study CALGB9840 (Seidman et al. 2008) using 
continuous 80 mg/m2 weekly paclitaxel dosing without interruption. Taken together, these findings support 
the selected regimen for paclitaxel (90 mg/m2 on days 1, 8, and 15 of every 28-day cycle) in the current 
study. 
The solvents used to enhance the solubility of taxanes have been associated with allergic reactions and 
peripheral neuropathy (ten Tije et al. 2003). Therefore, to reduce the risk of severe hypersensitivity 
reactions, study patients should be premedicated as described in Section 4.3.1.1. 
In most circumstances, single agents are currently preferred over chemotherapy combinations for the 
treatment of recurrent/metastatic breast cancer; however, this recommendation is based on a lack of 
compelling evidence demonstrating superiority of combination chemotherapy over treatment with 
sequential single agents in terms of survival [12, 14]. However, features that often accompany TNBC 
relapses such as short disease-free intervals (DFIs), high tumor burdens, significant visceral disease, and/or 
symptomatic disease warrant the consideration of combination chemotherapy in these settings. Treatment 

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guidelines specifically addressing patients with mTNBC are limited, and no specific standard of care exists 
for this patient population [12, 13]. 
The recent results of randomized phase II TNACITY trial showed a median PFS significantly longer with 
nab-paclitaxel 125 mg/m2 plus carboplatin AUC 2 on days 1 and 8 every 3 weeks versus nab-paclitaxel 
plus gemcitabine [8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38-0.92]; P = 0.02] or 
carboplatin plus gemcitabine (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37-0.90]; P = 0.02). OS 
was numerically longer with nab-paclitaxel/carboplatin versus nab-paclitaxel/gemcitabine (median, 16.8 
versus 12.1 months; HR, 0.73 [95% CI, 0.47-1.13]; P = 0.16) or carboplatin/gemcitabine (median, 16.8 
versus 12.6 months; HR, 0.80 [95% CI, 0.52-1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. 
Grade ≥3 adverse events were mainly hematologic (Yardley et al. 2018). 
On hese bases, a taxane in combination with carboplatin seem to be the best first-line treatment for 
mTNBC. 
1.3.5 Rationale for Atezolizumab in Combination with Carboplatin and Paclitaxel 
The recently published phase III IMpassion130 study has demonstrated that the combination of 
atezolizumab plus nab-paclitaxel significantly reduced the risk of disease worsening or death in the 
intention-to treat and PD-L1 positive population with metastatic triple-negative breast cancer showing also 
encouraging overall survival results (Schmid et al. 2018).  Therefore, the combination of atezolizumab plus 
nab-paclitaxel is likely to become soon the new standard of care as first-line treatment of patients with 
metastatic triple-negative PD-L1 positive breast cancer. 
Recent evidences in metastatic non-small cell lung cancer showed the efficacy and the safety of 
concomitant use of carboplatin, paclitaxel and atezolizumab without any detrimental interaction between 
atezolizumab and steroid premedication of paclitaxel (Socinski et al. 2018). 
Therefore, based on these data, the combination of atezolizumab plus carboplatin and paclitaxel represents 
a promising combination to be tested as first-line therapy in patients with metastatic triple-negative breast 
cancer to enhance the clinical activity and efficacy of first-line therapy in this setting. 
The selection of PD-L1 positive patients could lead to further evidence of increased efficacy of this first-
line treatment as evidenced by the results of Impassion130 study. 
1.3.6 PD-L1-positive patients’ selection 
Administered as first-line treatment, the combination of atezolizumab with nab-paclitaxel as part of the 
IMpassion130 study led to significantly longer progression-free survival than was seen with placebo plus 
nab-paclitaxel in both the intention-to-treat population and the subgroup of patients with PD-L1–positive 
tumors. 
Although the boundary for declaring a statistical advantage for atezolizumab–nab-paclitaxel in the 
intention-to-treat population at the first interim analysis of overall survival was not crossed, and formal 
testing was not performed in the PD-L1–positive subgroup, numerical increases in median overall survival 
were observed in both the intention-to-treat population and the PD-L1–positive subgroup. A clinical benefit 

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with atezolizumab–nab-paclitaxel was particularly notable in the PD-L1–positive subgroup, as shown by a 
median progression-free survival that was significantly longer by 2.5 months, by a median overall survival 
that was 10 months longer and a numerically higher objective response rate. (Schmid P. et al., NEJM 2018) 
These data confirm phase I observations of improved outcomes in patients with high PD-L1 expression 
who were receiving treatment with atezolizumab, pembrolizumab or avelumab. As has been found 
regarding existing chemoimmunotherapy data from patients with other solid tumors who received 
atezolizumab plus chemotherapy or pembrolizumab plus chemotherapy, IMpassion130 trial established the 
benefit of adding a checkpoint inhibitor to standard chemotherapy for the first-line treatment of metastatic 
triple-negative breast cancer, with most of the benefit realized in the PD-L1–positive subgroup. It is 
important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into 
consideration to inform treatment choices for patients with metastatic triple-negative breast cancer. 
According to the data of exploratory analyses subsequently presented at the 2018 San Antonio Breast 
Cancer Symposium in Texas, it was confirmed that PD-L1 IC positivity was predictive of PFS and OS 
benefit with atezolizumab + nab-paclitaxel (Emens LA et al., SABCS 2018 abstract #GS1-04). 
For the moment PD-L1 IC is the most robust predictive biomarker for selecting untreated metastatic TNBC 
patients who benefit from atezolizumab and nab-paclitaxel, and for this reason we would like to test the 
promising combination of atezolizumab plus carboplatin and paclitaxel as first-line therapy in metastatic 
triple-negative breast cancer really in the subgroup of patients with PD-L1‒positive tumors (defined as 
expression on tumor-infiltrating immune cells ≥1% by VENTANA SP142 IHC assay). 
1.3.7 Rationale for the multiparametric cancer agnostic circulating immunosignature (CLIO) 
It has been observed that the tumor-associated immune microenvironment can affect the efficacy of both 
chemotherapy and target therapies and therefore impact on the clinical outcome of cancer patients (Mittal 
D et al, Voron T, et al). Notably, a key role in this context is played by tumor associated macrophages 
(TAM), that are recruited by specific chemokines and polarized in populations with immune stimulating 
(M1) or tumor supportive properties (M2) (Heusinkveld M, et al). M2 macrophages are capable to 
negatively affect immune activation by expressing immunomodulatory cytokines and by suppressing T 
cells and the presence of M2 cells is a predictor of metastasis and poor outcome. 
Although it is well established that PD-1/PD-L1 blockade activates T cell, PD-1 expression impacts on 
numerous immune cell subsets, including tumor-associated macrophages, in which it has been shown to 
influence the polarization towards M1 or M2 phenotype.  
EMILIN2 is an extracellular matrix molecule that plays multifaceted functions in the tumor 
microenvironment, mainly in a tumor suppressive manner. Preliminary data indicate, however, that 
EMILIN2 may play a role in the modulation of tumor associated inflammation also through PD-1 and PD-
L1, that are found to be increased in Emilin2 knock-out mice (Emilin2-/-). Interestingly, ex vivo analysis 
confirmed that macrophages isolated from Emilin2-/- mice expressed higher levels of PD-L1 but were also 
more prone to acquire an M2 phenotype (i.e. immunosuppressive) compared to their wt counterpart.  
In breast cancer, M2 TAMs promote angiogenesis and extracellular matrix breakdown and remodeling, 
thus enabling breast tumor cells to intravasate into the peripheral blood. Furthermore, by communicating 

Sponsor: Consorzio Oncotech 
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and cooperating with breast tumor cells, M2 cells also migrate into peripheral circulation by intravasating 
across intratumor capillary barriers. Thus, circulating M2-like monocytes might be a subset of 
disseminated TAMs that derived from breast cancer tissue. 
Taking into consideration just PD-L1 could be, therefore, misleading and should be integrated with 
additional parameters and, since the immune system is highly dynamic, there is the need to optimize a 
liquid biopsy technique capable to capture its adaptations in real-time. 
Notably, tumor cells may escape immune surveillance by acquiring different genetic alterations. A higher 
expression of mesenchymal transition genes (e.g. AXL, ROR2, WNT5A, LOXL2, TWIST2), 
immunosuppressive genes (e.g. IL10, VEGFA, VEGFC) and chemokines that recruit immunosuppressive 
cells (e.g. CCL2, CCL7, CCL8, CCL13) may be associated with innate anti-PD-1 resistance. It has been 
observed that the evaluation of mesenchymal transition, angiogenesis, hypoxia and wound healing-related 
genes (IPRES) was able stratify metastatic melanoma patients according to anti-PD-1 resistance (OR = 4.6; 
p = 0.013 for IPRES-enriched tumors). Conversely, the IPRES signature showed no similar association 
with respect to anti-CTLA-4 treatment (Hugo W et al). By contrast, a subset of patients quickly develop 
resistance, even after an initial benefit, suggesting the rapid proliferation of a resistant clone.  
A pivotal role in decreased antigen presentation and immune escape has been observed for mutations in 
IFN receptor pathway genes (e.g. JAK1, JAK2) and for MHC-I structure genes (e.g B2M) (Ribas et al). 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
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Page 40 / 115 
2  
STUDY DESIGN 
2.1 
Description of the Study 
2.2 
Overview of the Study Design 
This is a Phase II single-arm multicenter study designed to evaluate the efficacy and safety of atezolizumab 
administered in combination with paclitaxel and carboplatin in patients with previously untreated, 
inoperable locally advanced or metastatic, PD-L1 positive TNBC. 
A biomarker discovery translational analysis was moreover built-in to better dissect tumor and immune-
related characteristics that could be further evaluated for treatment response stratification. 
A total of approximately 104 patients will be enrolled and treated in approximately 15 centers affiliated 
with the Gruppo Italiano Mammella (GIM) study group. 
All eligible patients will receive carboplatin, paclitaxel and atezolizumab and they will continue this 
treatment until progression of disease. In case of interruption of one of the three drugs for unacceptable 
toxicity and/or medical decision, the patient may continue to receive one or more of the remaining drugs 
until progression.  
Tumor assessments will be performed at screening/baseline and approximately every 12 weeks (± 1 week) 
until disease progression (PD), withdrawal of consent, death, unacceptable toxicity or study termination by 
the Sponsor, whichever occurs first.  
Tumor assessments performed as part of standard of care prior to obtaining informed consent and within 28 
days of Cycle 1, Day 1 may be used as baseline assessments rather than repeating the tests. Tumor 
assessments will be performed on the specified schedule regardless of treatment delays, interruptions or 
discontinuations. Radiologic imaging performed during the screening period should consist of 1) 
computerized tomography (CT) and/or magnetic resonance imaging (MRI) of the chest/abdomen/pelvis, 2) 
bone scan or PET scan, and 3) any other imaging studies (CT neck, plain films, etc.) as clinically 
indicated/determined by the treating physician. For each patient, the same radiographic procedures and 
technique must be used for disease evaluation throughout the study (e.g., the same contrast protocol for CT 
scans and/or MRI). Evaluation of tumor response (e.g., for estimation of PFS, PFS rate, ORR, DoR and 
CBR) will be completed per RECIST v1.1.  
Patients enrolled must discontinue all study treatment upon determination of PD per RECIST v1.1. For 
equivocal findings of progression (e.g., very small or uncertain new lesions or lymph nodes; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next 
scheduled assessment progression is confirmed, the date of progression should be the earlier date when 
progression was suspected. 
All patients who discontinued study treatment before End Of Study (including due to PD) will be followed 
for survival approximately every 3 months for 2 years from last patient enrolled or until death, withdrawal 
of consent, loss to follow-up, or study termination by the Sponsor. Information regarding PFS2 and the use 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
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Page 41 / 115 
of subsequent anti-cancer agents for metastatic TNBC will also be collected during the survival follow-up 
period. In addition, for patients who discontinue study treatment before EOS for reasons other than PD, 
tumor assessments will continue until PD, death, withdrawal of consent, loss to follow-up, or study 
termination by the Sponsor. 
The study Steering Committee (SC) will provide scientific oversight for the trial.  
A schedule of assessments is provided in section Study schedule of Assessments and Procedures. 
A study design schema is presented in Figure 1. 
Figure 1. Study design 
 
 
 
 
 
 
* In case of interruption of one of the three drugs for unacceptable toxicity and/or medical decision, the 
patient may continue to receive one or more of the remaining drugs until disease progression.  
Metastatic Triple-
Negative PD-L1 positive 
Breast Cancer 
N=104 
1) Not previously 
treated for metastatic 
disease 
2) Eligible for 
chemotherapy 
Carboplatin AUC 2 dd 1,8,15 q 28 dd 
+ 
Paclitaxel 90 mg/m2 dd 1,8,15 q 28 dd  
+ 
Atezolizumab 840 mg dd 1,15 q 28 dd 
 
(until PD or unacceptable toxicity)* 
 

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3  
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 Primary objective: 
To provide preliminary evidence on the efficacy of atezolizumab plus carboplatin plus paclitaxel as first-
line therapy in metastatic triple-negative PD-L1 positive breast cancer patients in terms of % Overall 
Survival at 2 years. 
3.1.2 Secondary objectives: 
 
To provide preliminary evidence on the efficacy of atezolizumab plus carboplatin plus 
paclitaxel as first-line therapy in metastatic triple-negative PD-L1 positive breast cancer patients 
in terms of % Overall Survival at 2.5 years. 
 
To  provide preliminary evidence on the efficacy of atezolizumab plus carboplatin plus 
paclitaxel as first-line therapy in metastatic triple-negative PD-L1 positive breast cancer 
patients in terms of % OS at 2 years in hormonal receptor (HR) between 1% and 10%. 
 
To  provide preliminary evidence on the efficacy of atezolizumab plus carboplatin plus 
paclitaxel as first-line therapy in metastatic triple-negative PD-L1 positive breast cancer 
patients in terms of post-progression survival 
 
To assess the activity of atezolizumab plus carboplatin plus paclitaxel as first-line therapy in 
metastatic triple-negative PD-L1 positive breast cancer patients in terms of ORR and time to 
treatment failure. 
 
To assess the safety of atezolizumab plus carboplatin plus paclitaxel as first-line therapy in 
metastatic triple-negative PD-L1 positive breast cancer patients. 
3.1.3 Exploratory objectives: 
Exploratory objectives will be focused on the assessment of both tumor-centered characteristics through 
the NGS analysis of ctDNA and immune-centric features through the evaluation of a multiparametric 
Cancer agnostic circuLating ImmunOsignature (CLIO):  
 To assess the association between patients’ characteristics, treatment activity, efficacy and safety 
and through a CLIO in metastatic triple-negative breast cancer patients receiving atezolizumab plus 
carboplatin plus paclitaxel as first-line therapy 
 To explore the association between the CLIO and treatment activity, efficacy and safety 
 To explore the dynamics of ctDNA levels and detectable aberrations with respect to treatment 
activity and efficacy 
Concomitant timepoints will not be used for cross-validations between the two methodologies. 

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3.2 
Endpoints 
3.2.1 Primary endpoint: 
 
% Overall Survival at 2 years 
3.2.2 Secondary endpoints: 
 
% Overall survival at 2.5 years  
 
Overall Survival at 2 years in HR <1% and in HR 1-10% 
 
Post-progression survival 
 
Objective response rate 
 
Time to treatment failure 
 
Incidence and severity of adverse events and seious adverse events 
3.2.3 Exploratory endpoints: 
 Variation of ctDNA levels from baseline to first evaluation through the multigene 
FoundationOne® Liquid NGS panel  
 Variation of ctDNA levels from the first evaluation to progression through the multigene 
FoundationOne® Liquid NGS panel  
 Association of CLIO and ctDNA with Objective response rate and survivalAssociation between 
archival PD-L1 levels and target genes expression levels through CLIO analysis 
 Variation of target genes expression levels through CLIO analysis from baseline to first 
evaluation 
Variation of target genes expression levels through CLIO analysis from first evaluation to disease 
progression 

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4  
MATERIALS AND METHODS 
4.1 
Patients 
The target population will include patients with previously untreated inoperable locally advanced or 
metastatic PD-L1 positive TNBC. Patients will be either newly diagnosed or have disease progression after 
completing treatment for early breast cancer at least 12 months prior to enrollment, 
4.1.1 Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Signed Informed Consent Form 
2. 
Women or men aged ≥18 years 
3. 
Histologically or cytologically confirmed adenocarcinoma of the breast with metastatic disease 
4. 
Hormone receptor-negative (ER and PgR < 10%) and HER2-negative (IHC 0,1+ or 2+ ISH not 
amplified) breast cancer, based on the status of the primary tumor and/or the biopsy of metastatic 
disease before starting first-line therapy and assessed by local laboratory 
5. 
PD-L1 positive defined as expression on tumor-infiltrating immune cells ≥1% (SP142 PD-L1 
immunohistochemical assay, Ventana Medical Systems), based on the status of the primary tumor 
and/or the biopsy of metastatic disease before starting first-line therapy and assessed by local 
laboratory 
6. 
Availability of a representative tumor specimen for translational research 
7. 
Eligible for first-line taxane and carboplatin chemotherapy 
8. 
No prior chemotherapy or targeted systemic therapy (including endocrine therapy) for inoperable 
locally advanced or metastatic TNBC. Prior radiation therapy for metastatic disease is permitted. 
There is no required minimum washout period for radiation therapy; however, patients should 
have recovered from the effects of radiation before enrollment 
9. 
Previous chemotherapy with taxanes and/or carboplatin for early breast cancer (neoadjuvant or 
adjuvant setting) is permitted if completed ≥12 months before study entry 
10. 
Previous therapy with immune checkpoint inhibitors for early breast cancer (neoadjuvant or 
adjuvant setting) is permitted if completed ≥12 months before study entry 
11. 
ECOG performance status of 0 or 1 
12. 
Life expectancy ≥ 12 weeks 
13. 
Measurable or evaluable disease as defined by RECIST v1.1 
14. 
Adequate hematologic and end-organ function, defined by laboratory results obtained within 2 
weeks prior to the first study treatment (Cycle 1, Day 1): 
a) Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony stimulating 
factor [G-CSF] support within 2 weeks prior to Cycle 1, Day 1) 
b) Lymphocyte count ≥ 500/μL 
c) Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1) 
d) Haemoglobin ≥ 9.0 g/dL 
Patients may be transfused or receive erythropoietic treatment to meet this criterion 
e) Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase ≤ 

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2.5× the upper limit of normal (ULN), with the following exceptions: 
i. 
Patients with documented liver metastases: AST and ALT ≤ 5× ULN 
ii. 
Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5× 
ULN 
f) Serum bilirubin ≤ 1.25× ULN 
Patients with known Gilbert’s disease who have serum bilirubin level ≤ 3× ULN may be 
enrolled. 
g) International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 
1.5× ULN 
This applies only to patients who are not receiving an anticoagulant medicinal product; 
patients receiving an anticoagulant medicinal product should be on a stable dose and have 
an INR which is not above the target therapeutic range. 
h) Calculated creatinine clearance (CrCl) ≥ 30 mL/min (Cockcroft-Gault). 
15. 
Negative human immunodeficiency virus (HIV) test at screening 
16. 
Negative hepatitis B surface antigen (HBsAg) test at screening 
17. 
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb test 
followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNA test will be 
performed only for patients who have a positive HBcAb test 
18. 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only 
for patients who have a positive HCV antibody test 
19. 
Women of child bearing potential must agree to either use a contraceptive method with a failure 
rate of ≤ 1% per year or to remain abstinent (refrain from heterosexual intercourse) during the 
treatment period and for at least 5 months after the last dose of atezolizumab, or for at least 6 
months after the last dose of paclitaxel. A woman is considered to be of childbearing potential if 
she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure 
rate of ≤ 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods 
of contraception 
20. 
Women of child bearing potential must have a negative serum pregnancy test result within 7 days 
prior to initiation of study drug 
21. 
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined below: 
a. With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 6 months 
after the last dose of paclitaxel. Men must refrain from donating sperm during this same 
period. 
b. The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 

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are not acceptable methods of contraception. 
4.1.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
Spinal cord compression not definitively treated with surgery and/or radiation, or previously 
diagnosed and treated spinal cord compression without evidence that disease has been clinically 
stable for at least 2 weeks prior to enrollment 
2. 
Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases, 
provided all of the following criteria are met: 
a) No ongoing requirement for corticosteroids as therapy for CNS disease (anticonvulsants at a 
stable dose are allowed) 
b) No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
enrollment 
c) No evidence of progression or hemorrhage after completion of CNS directed therapy 
Note: Patients with new asymptomatic CNS metastases detected at the screening scan must receive 
radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may then be 
eligible, if all other criteria above are met. 
3. 
Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with indwelling 
catheters, such as PleurX® are allowed) 
4. 
Uncontrolled tumor-related pain 
a) Patients requiring narcotic pain medication must be on a stable regimen at study entry. 
b) Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be 
recovered from the effects of radiation. There is no required minimum recovery period. 
c) Asymptomatic metastatic lesions whose further growth would likely cause functional deficits 
or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord 
compression) should be considered for loco-regional therapy if appropriate prior to enrollment. 
5. 
Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum calcium 
[uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium >ULN) or 
clinically significant (symptomatic) hypercalcemia 
a) Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent 
skeletal events and who do not have a history of clinically significant (symptomatic) 
hypercalcemia are eligible. 
6. 
Malignancies other than TNBC within 5 years prior to enrollment, with the exception of those 
with a negligible risk of metastasis or death and treated with expected curative outcome (such as 
adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I 
uterine cancer) 
7. 
Pregnant or lactating women, or intending to become pregnant during the study 
8. 
Evidence of significant uncontrolled concomitant disease that could affect compliance with the 

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protocol or interpretation of results, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome) 
9. 
Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to enrollment, unstable 
arrhythmias, or unstable angina 
a) Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded 
b) Patients with known coronary artery disease, congestive heart failure not meeting the above 
criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion 
of the treating physician, in consultation with a cardiologist if appropriate 
10. 
Presence of an abnormal electrocardiogram (ECG) that is clinically significant in the 
investigator’s opinion, including complete left bundle branch block, second- or third degree heart 
block, evidence of prior myocardial infarction, or QT interval corrected using Fridericia’s formula 
(QTcF) >470 ms demonstrated by at least two consecutive ECGs 
11. 
Serious infection requiring antibiotics within 2 weeks prior to enrollment, including but not 
limited to infections requiring hospitalisation or IV antibiotics, such as bacteremia, or severe 
pneumonia 
12. 
Major surgical procedure within 4 weeks prior to enrollment or anticipation of the need for a 
major surgical procedure during the study other than for diagnosis 
Note: Placement of central venous access catheter(s) (e.g., port or similar) is not considered a 
major surgical procedure and is therefore permitted 
13. 
Treatment with investigational therapy within 30 days prior to initiation of study treatment 
Exclusion Criteria Related to Atezolizumab 
14. 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
15. 
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
(CHO) cells or any component of the atezolizumab formulation 
16. 
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, 
Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis 
(MS), vasculitis, or glomerulonephritis 
(Note: Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone and patients with controlled Type 1 diabetes mellitus on a stable insulin 
regimen may be eligible for this study) 
17. 
Prior allogeneic stem cell or solid organ transplantation 
18. 
History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest CT scan. (Note: History of radiation 
pneumonitis in the radiation field [fibrosis] is permitted) 
19. 
Positive test for human immunodeficiency virus (HIV) 
20. 
Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test or hepatitis B virus [HBV] 
DNA polymerase chain reaction [PCR] test at screening) or hepatitis C (positive hepatitis C virus 

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antibody test at screening) 
Note: 
 
Patients with past HBV infection or resolved HBV infection (defined as having negative 
HBsAg and HBV DNA test but a positive hepatitis B core antibody [HBcAb] test) are eligible 
 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for 
HCV ribonucleic acid (RNA) 
21. 
Current treatment with anti-viral therapy for HBV 
22. 
Active tuberculosis 
23. 
Receipt of a live, attenuated vaccine within 4 weeks prior to enrollment or anticipation that such a 
live, attenuated vaccine will be required during the study 
Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days 
prior to enrollment, during treatment or within 5 months following the last dose of atezolizumab 
24. 
Treatment with systemic immunostimulatory agents (including but not limited to interferons or 
interleukin [IL]-2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to 
enrollment 
25. 
Treatment with systemic immunosuppressive medications (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate, thalidomide, and 
antitumour necrosis factor [TNF] agents) within 2 weeks prior to enrollment, or anticipated 
requirement for systemic immunosuppressive medications during the trial 
a) Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), systemic 
immunosuppressant medications may be enrolled in the study 
b) Patients with a history of allergic reaction to IV contrast requiring steroid pretreatment should 
have baseline and subsequent tumor assessments performed using MRI 
c) The use of corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronic obstructive 
pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low dose supplemental corticosteroids for adrenocortical insufficiency are 
allowed 
d) Systemic corticosteroids are allowed as paclitaxel premedication during the trial at a dose ≤10 
mg dexamethasone or equivalent in order to avoid severe hypersensitivity reactions 
26. 
Poor peripheral venous access 
27. 
Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment 
28. 
Any other serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the study 
Exclusion Criteria Related to Paclitaxel and Carboplatin 
29. 
History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same solvent as 
paclitaxel (polyoxyethylated castor oil) 
30. 
History of hypersensitivity reactions to carboplatin 

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4.2 
Study Treatment 
Atezolizumab, paclitaxel and carboplatin are considered investigational medicinal products (IMPs) in this 
study. Non-investigational medicinal products (NIMPs) used in the study include premedication (see 
Section 4.3.1.1), medications that may be administered to manage adverse events (see Section 4.3.1.2), and 
other permitted concomitant medications (see Section 4.3.1.3). 
The term "study drug" is used throughout this protocol to refer to all protocol-mandated treatment 
(atezolizumab, paclitaxel and carboplatin). 
4.2.1 Formulation, Packaging, and Handling 
4.2.1.1 Atezolizumab 
Atezolizumab will be supplied by Roche already relabeled for the study and released. 
The atezolizumab drug product is provided in a single-use, glass vial as a colourless-to-slightly-yellow, 
sterile, preservative-free clear liquid solution intended for IV administration. 
Atezolizumab could be supplied in 2 different formulations, detailed in the following table: 
 
Formulation A – 840 mg 
Formulation B – 1200 mg 
Nominal atezolizumab amount 
per vial 
840 mg 
1200 mg 
Concentration of atezolizumab 
60 mg/mL 
60 mg/mL 
Primary packaging 
15 mL glass vial 
20 mL glass vial 
Extractable volume 
14 mL 
20 mL 
Important note: Regardless of the formulation provided, 14 mL of atezolizumab concentrate should be 
withdrawn from the vial in order to have the right dose of atezolizumab. 
Both of the formulations contain histidine acetate, buffered at pH 5.8, sucroseand polysorbate 
20.Atezolizumab (both of the formulations, A and B) will be administered in 250 mL 0.9% NaCl IV 
infusion bags and infusion lines equipped with 0.2 or 0.22 μm in-line filters. The IV bag may be 
constructed of polyvinylchloride (PVC), polyethylene or polyolefin; the IV infusion line may be 
constructed of PVC or polyethylene, polybutadiene, or polyurethane; and the 0.2 or 0.22 μm in-line filter 
may be constructed of polyethersulfone or polysulfone. No incompatibilities have been observed between 
atezolizumab and these infusion materials (bags and infusion lines). 
Atezolizumab vials must be refrigerated at 2°C-8°C (36°F-46°F) upon receipt until use. 
Vials should not be used beyond the expiration date provided by the manufacturer. 
Atezolizumab must be prepared/diluted under appropriate aseptic conditions as it does not contain 
antimicrobial preservatives. The solution for infusion should be used immediately to limit microbial growth 
in case of potential accidental contamination. Any unused portion of drug left in a vial should be discarded. 

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Vial contents should not be frozen or shaken and should be protected from direct sunlight. 
Further details on the storage and preparation of atezolizumab are provided in the most updated 
Investigator’s Brochure of atezolizumab . 
4.2.1.2 Paclitaxel and Carboplatin 
Specific details for the carboplatin and paclitaxel regimen are given below. It is the responsibility of the 
investigator to ensure that recommendations in the Italian SmPCs for administration of the carboplatin and 
paclitaxel are followed. The SmPC is updated from time to time, up-to-date SmPCs are posted on the AIFA 
Website https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci  
For information on the formulation, packaging, and handling of paclitaxel and carboplatin, refer to the local 
prescribing information for paclitaxel and carboplatin. 
4.2.2 Dosage, Administration, and Compliance 
4.2.2.1 Atezolizumab 
Patients will receive atezolizumab 840 mg (in 250 mL 0.9% sodium chloride [NaCl]) by IV infusion 
administered on Day 1 and Day 15 (± 3 days) of every 28-day cycle. The first dose (Cycle 1, Day 1) will be 
administered over 60 (± 15) minutes. If the first infusion is well tolerated, all subsequent infusions may be 
delivered over 30 (±10) minutes. 
For the first infusion of atezolizumab, no premedication will be administered. 
However, should the patient experience infusion-related reaction(s) during any infusion, premedication 
with antihistamines will be administered for subsequent infusions at the discretion of the treating physician. 
Administration of atezolizumab will be performed in a setting with emergency medical facilities and staff 
who are trained to monitor for and respond to medical emergencies. Atezolizumab infusions will be 
administered per the instructions outlined in Table 1. 
Table 1. Administration of First and Subsequent Infusions of Atezolizumab 
First Infusion 
Subsequent Infusions 
 
No premedication is administered. 
 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 
starting infusion 
 
Infuse 840 mg of  atezolizumab in 250 mL 
0.9% NaCl over 60 (15) minutes. 
 
Record patient’s vital signs (heart rate, 
 
If patient experienced infusion-related 
reaction during any previous infusion, 
premedication with antihistamines may be 
administered at subsequent infusions at the 
discretion of the treating physician. 
 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before 

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respiratory rate, blood pressure, and 
temperature) during and after the infusion 
if clinically indicated 
 
Patients will be informed about the 
possibility of delayed symptoms following 
infusion and instructed to contact their 
study physician if they develop such 
symptoms. 
starting infusion. 
 
If the patient tolerated the first infusion 
well without infusion-associated adverse 
events, the second infusion may be 
administered over 30 (10) minutes. 
 
If no reaction occurs, subsequent infusions 
may be administered over 30 (10) 
minutes Continue to record vital signs 
within 60 minutes before starting infusion 
and during and after the infusion if 
clinically indicated. 
 
If the patient had an infusion-related 
reaction during the previous infusion, the 
subsequent infusion must be administered 
over 60 (15) minutes. 
 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during and after the infusion 
if clinically indicated. 
4.2.2.2 Paclitaxel 
Paclitaxel will be administered at the 90 mg/m2 dose via 1-hour IV infusion on Days 1, 8, and 15 of every 
28-day cycle. On days of scheduled infusions of atezolizumab and paclitaxel (i.e., Day 1 and Day 15 of 
every cycle), paclitaxel is to be administered after infusion of atezolizumab. Doses of paclitaxel should not 
be administered more frequently than every 7 days. 
In the absence of unacceptable toxicity, paclitaxel will be administered until PD or until the end of the 
study, whichever occurs earlier. Paclitaxel, carboplatin and atezolizumab may be discontinued for toxicity 
independently of each other in the absence of disease progression. 
To reduce the risk of severe hypersensitivity reactions, study patients will be premedicated as described in 
Section 4.3.1.1. Sites should follow their institutional standard of care for determining the paclitaxel dose 
for patients who are obese and for dose adjustments in the event of patient weight changes. The infusion 
site should be closely monitored for possible infiltration during drug administration. 
Guidelines for paclitaxel dosage modification and treatment interruption or discontinuation due to toxicity 
are provided in Section 5.1.5.3.2. 
4.2.2.3 Carboplatin 
In this study, carboplatin will be administered after the completion of paclitaxel administration by short-
term IV infusion over 15 to 60 minutes, to target AUC 2 mg/ml/min on Days 1, 8, and 15 of every 28-day 
cycle. For guidance on carboplatin dose modifications and interruptions due to toxicity, refer to Section 
5.1.6.3.2. 

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There is no known antidote for carboplatin overdose. If necessary, the patient may need supportive 
treatment relating to myelosuppression, renal, hepatic and auditory function impairment. Doses up to 
1600mg/m2 have been associated with patients feeling extremely ill with diarrhea and alopecia developing. 
Use of higher than recommended doses of carboplatin have also been associated with loss of vision 
(Carboplatin SmPC). 
In the absence of unacceptable toxicity, carboplatin will be administered until PD or until the end of the 
study, whichever occurs earlier. Paclitaxel, carboplatin and atezolizumab may be discontinued for toxicity 
independently of each other in the absence of disease progression. 
For further details, refer to the local prescribing information for carboplatin. 
4.2.3 Investigational Medicinal Product accountability 
The IMP Atezolizumab required for completion of this study  will be provided by Roche. The IMPs 
Paclitaxel and Carboplatin are considered standard of care in patients with TNBC and they will be supplied 
by the local Institution. The study site will acknowledge receipt of atezolizumab and confirm the shipment 
condition and content. Any damaged shipments will be replaced and must be reported immediately to the 
study monitor. 
Unused IMPs will either be disposed of at the study site according to the study site’s institutional standard 
operating procedure. The site’s method of destruction of any unused IMP must be agreed to by the 
Sponsor. 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 on the Drug Inventory Log. 
The local site pharmacy department and the investigator are both responsible for study drugs 
accountability, reconciliation, and record maintenance. In accordance with local regulatory requirements, 
the investigator, designated site staff, or head of the medical institution (where applicable) must document 
the amount of investigational product administered to study patients Product accountability records must be 
maintained throughout the course of the study.  
After completion of the study, a final inventory of accountability records and unused study medications 
will be performed by the site personnel and study monitor, according to study procedures. Unused study 
medications will be destroyed and proof of destruction will be forwarded to  the Sponsor. 
4.3 
Concomitant Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 days prior to screening 
to the treatment discontinuation visit. All such medications should be reported to the investigator and 
recorded on the eCRF. 
Between the treatment discontinuation and the End Of Study visit (after 2 years from last patient enrolled), 

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only new anti-cancer treatment will be recorded. 
4.3.1 Permitted Therapy 
4.3.1.1 Premedication 
For the first infusion of atezolizumab, no premedication will be administered. However, should the patient 
experience infusion-related reaction(s) during any infusion, premedication with antihistamines may be 
administered for subsequent infusions at the discretion of the treating physician. 
To reduce the risk of severe hypersensitivity reactions, all patients should be premedicated prior to 
paclitaxel administration. Prior to receiving the first two study infusions of paclitaxel, all patients will 
receive corticosteroids (8-10 mg dexamethasone or equivalent) as part of either the institutional standard of 
care or the following premedication: 
 Dexamethasone 8-10 mg (or equivalent) administered orally approximately 12 and 6 hours prior to 
the paclitaxel infusion 
Patients may be treated with dexamethasone ≤10 mg IV within 1 hour prior to the paclitaxel 
infusion if the patient did not take the oral dexamethasone. 
 Diphenhydramine 50 mg IV (or equivalent) 30-60 minutes prior to the paclitaxel infusion 
 Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30-60 minutes prior to paclitaxel 
infusion. 
Nausea and vomiting, which are generally delayed until 6 to 12 hours after administration of carboplatin, 
may be prevented or controlled with antiemetics. 
Because the effects of corticosteroids on T-cell proliferation have the potential to ablate early 
atezolizumab-mediated anti-tumor immune activity, it is recommended that the dose of dexamethasone (or 
equivalent) is minimized to the extent that is clinically feasible. For example, if paclitaxel is well tolerated 
during the first two weekly infusions without apparent hypersensitivity reaction, a reduction in the dose of 
dexamethasone premedication (or equivalent) should be considered for subsequent cycles if permitted by 
institutional standard of care. This approach has been reported to be successful in the literature (Berger et 
al. 2012). 
4.3.1.2 Treatment of Infusional Adverse Events 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine (or equivalent substitutes, per local practice), and/or 
famotidine or another H2 receptor antagonist, per standard practice. 
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive 

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therapies as clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists) 
4.3.1.3 Other Permitted Therapy 
The following therapies are permitted on study: 
 Prophylactic or therapeutic anticoagulation therapy (such as low-molecular weight heparin or 
warfarin at a stable dose level) 
 Palliative radiotherapy (e.g., treatment of known bone metastases) provided it does not interfere 
with assessment of tumor target lesions. Candidate lesions for radiotherapy must be decided prior to 
study entry. 
Note: It is not required to hold atezolizumab during palliative radiotherapy; paclitaxel and 
carboplatin should be interrupted per institutional standard of care. 
 Inactivated vaccinations (including for influenza) 
 Megestrol administered as an appetite stimulant 
 Inhaled corticosteroids for chronic obstructive pulmonary disease 
 Mineralocorticoids (e.g.,fludrocortisone) 
 Low-dose corticosteroids (≤10 mg prednisone equivalent per day) for patients with orthostatic 
hypotension or adrenocortical insufficiency 
 Bisphosphonates or denosumab for the prevention of skeletal events 
 Anticonvulsants at a stable dose are allowed, e.g., for patients with CNS metastases 
 Narcotic pain medication is permitted as long as the patient is on a stable regimen at study entry. 
In general, investigators should manage a patient’s care with supportive therapies as clinically indicated 
and per local standards. 
Patients who use contraceptives should continue their use during the treatment period and for at least 5 
months after the last dose of study treatment; refer to Section 4.1.1. 
4.3.2 Prohibited and Cautionary Therapy related to atezolizumab 
Cytochrome P450 enzymes, as well as conjugation/glucuronidation reactions, are not involved in the 
metabolism of atezolizumab. No drug interaction studies have been conducted for atezolizumab, and there 
are no known PK interactions with other medicinal products. 
Excessive activation of the immune system is a potential risk associated with atezolizumab and has been 
observed when atezolizumab is used in combination with other immunomodulating agents. Therefore, the 
use of these agents is prohibited (i.e., immune checkpoint modulators) or limited (e.g. interferons or IL-2; 
prohibited within 28 days or five half-lives of the drug prior to enrollment, whichever is longer) prior to 
enrollment, during study treatment, and for 10 weeks after atezolizumab discontinuation. 
Medications that are prohibited while the patient is receiving study treatment, and their respective washout 
periods prior to enrollment are listed in Table 2. 

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Table 2. Prohibited Medications and Treatments 
Prohibited Medication/Class 
Minimum Washout Period 
Prior to initiation of study drug 
Any other systemic anti-cancer therapy  
28 days or five half-lives of the drug (whichever is 
longer) 
Any investigational therapy  
30 days 
Immunomodulatory agents, e.g., interferons or IL 2 [1]  
28 days or five half-lives of the drug (whichever is 
longer) 
Immunosuppressive medications, e.g., cyclophosphamide, 
azathioprine, cyclosporine, methotrexate, thalidomide [2] 
14 days 
Corticosteroids as therapy for CNS disease 
1 day 
Any live, attenuated vaccine (e.g., FluMist) [ 3] 
28 days 
Stereotactic radiation for CNS metastases 
Whole-brain radiation for CNS metastases 
7 days 
14 days 
[1] These agents could potentially increase the risk for autoimmune conditions when received in combination with atezolizumab. 
[2] These agents could potentially alter the activity and the safety of atezolizumab. 
[3] Any live, attenuated vaccine is prohibited within 28 days prior to enrollment, during treatment, and within 5 months 
following the last dose of atezolizumab. 
4.3.3 Additional Restrictions Related to Chemotherapy 
4.3.3.1 Restrictions for Paclitaxel 
The metabolism of paclitaxel is catalysed by cytochrome P450 (CYP) isoenzymes CYP2C8 and CYP3A4. 
The PK of paclitaxel was shown to be altered in vivo as a result of interactions with compounds that are 
substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. Therefore, caution should be exercised 
when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. Caution should also be 
exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and 
rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. 
Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, 
saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been 

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evaluated in clinical trials. 
Granulocyte-colony stimulating factor (G-CSF) as haematopoietic support is permitted for patients 
receiving paclitaxel. The primary prophylaxis should be administered per the ASCO, EORTC, and 
European Society for Medical Oncology (ESMO) guidelines; namely, in patients who have an 
approximately 20% or higher risk for febrile neutropenia based on patient-, disease- and treatment-related 
factors, such as age>65 years, previous chemotherapy or radiation therapy, preexisting neutropenia or bone 
marrow involvement, infection, comorbidities, etc. (Smith et al. 2015; Aapro et al. 2011; Crawford et al. 
2009). 
Consistent with the latest ASCO recommendations (Smith et al. 2015), and results of meta-analyses of 
primary G-CSFs in adults undergoing chemotherapy for a solid tumour or lymphoma (Pinto et al. 2007; 
Cooper et al. 2011; Renner et al. 2012), both conventional (e.g., filgrastim) and long-acting, or pegylated 
(e.g., pegfilgrastim) G-CSFs may be used for the prevention of treatment-related febrile neutropenia. The 
choice of agent will be at the discretion of the investigator, depending on the clinical situation and 
institutional standard of care practice. 
Anti-emetics, anti-allergic measures, and other treatments for concomitant paclitaxel toxicities may be used 
at the discretion of the investigator, taking into account precautions from the local prescribing information 
for paclitaxel. 
Refer to the local prescribing information (label) for paclitaxel for all boxed warnings and 
contraindications. 
4.3.3.2 Restrictions for Carboplatin 
 Concomitant use of yellow fever vaccine is prohibited, and vaccination with other live attenuated 
vaccine should be avoided; 
 Killed or inactivated vaccines may be administered; however, the response to such vaccines may be 
diminished; 
 Concomitant use of phenytoin or fosphenytoin is not recommended due to the risk of exacerbation 
of convulsions, risk of toxicity enhancement or loss of efficacy of the cytotoxic drug; 
 The concomitant use of the following agents should be approached with caution: (i) ciclosporin, 
tacrolimus, and sirolimus (risk of excessive immunosuppression); (ii) nephrotoxic or ototoxic drugs 
such as aminoglycosides, vancomycin, capreomycin and diuretics, including loop diuretics (risk of 
increased, exacerbated, or cumulative toxicity) 
 Concurrent (given together or ≤7 days apart) radiotherapy should be avoided. 
Refer to the local prescribing information (label) for carboplatin for all boxed warnings and 
contraindications. 
4.4 
Study Assessments 
Please see Schedule of Assessments for the schedule of activities to be performed during the study. 

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4.4.1 Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before performing any study-
related procedures or evaluations. Informed Consent Forms for enrolled patients and for patients who are 
screening failures will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility 
criteria before  initiation of study drug. 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. 
4.4.2 Medical History and Demographic Data 
General medical history includes clinically significant diseases, surgeries, reproductive status, smoking 
history, use of alcohol, and drugs of abuse. TNBC history will include prior cancer therapies, procedures, 
and an assessment of tumor mutational status (breast cancer susceptibility gene [BRCA] mutational status, 
where available). In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to 
initiation of study drug (Cycle 1, Day 1) will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.4.3 Physical Examinations 
A complete physical examination should be performed at screening. Any abnormality identified at baseline 
should be recorded on the eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations should 
be performed. Changes from baseline abnormalities should be recorded in patient notes. New or worsened 
clinically significant abnormalities should be recorded as adverse events on the eCRF. 
4.4.4 Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressures 
while the patient is in a seated position, and temperature. 
At all clinic visits where study treatment is administered, vital signs should be determined within 60 
minutes before the first infusion. Vital signs will also be determined during and after the infusions if 
clinically indicated. 
4.4.5 Tumor and Response Evaluations 
Tumor assessments will be performed at screening/baseline, approximately every 12 weeks (± 1 week) (see 
Schedule of Assessments) until disease progression (PD), withdrawal of consent, death, unacceptable 
toxicity or study termination by the Sponsor, whichever occurs first. All sites of measurable and non-
measurable disease must be documented at screening/baseline and re-assessed at each subsequent tumor 
evaluation. 

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4.4.5.1 Screening/Baseline Tumor Evaluations 
Tumor assessments performed as part of standard of care prior to obtaining informed consent and within 28 
days of Cycle 1, Day 1 may be used as baseline assessments rather than repeating the tests. 
Radiologic imaging performed during the screening period should consist of the following: 
1) Initial screening assessments must include computerized tomography (CT) scans (with oral/IV 
contrast 
unless 
contraindicated) 
and/or 
magnetic 
resonance 
imaging 
(MRI) 
of 
the 
chest/abdomen/pelvis. A spiral CT scan of the chest may be obtained but is not a requirement. 
MRIs of the chest, abdomen, and pelvis with a non-contrast CT scan of the chest may be used in 
patients for whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance). If a CT scan for tumor assessment is performed using a positron emission 
tomography (PET)/CT scanner, the CT acquisition must be consistent with the standards for a full 
contrast diagnostic CT scan. 
2) Bone scan or PET scan should be performed to evaluate for bone metastases; 
3) A CT (with contrast) or MRI scan of the head must be performed at screening to evaluate CNS 
metastasis in all patients. An MRI scan of the brain is required to confirm or refute a diagnosis of 
CNS metastasis at screening in the event of an equivocal scan. 
Patients with active or untreated CNS metastasis are not eligible for this study (see Section 4.1.2 for 
CNS-related exclusion criteria); 
4) CT scans of the neck should also be performed if clinically indicated during the screening period; 
5) At the investigator’s discretion, other methods of assessment of measurable disease per RECIST 
v1.1 may be used. 
4.4.5.2 On-treatment Tumor and Response Evaluations 
After enrollment, tumor assessments evaluation of tumor response per RECIST v1.1 (see Appendix 1) will 
be performed according to the schedule of assessments, regardless of treatment delays, interruptions or 
discontinuations. 
For each patient, the same radiographic procedures and technique used to assess disease sites at screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans and/or magnetic 
resonance imaging [MRI]), and results must be reviewed by the investigator before dosing at the next 
cycle. All known sites of disease documented at screening/baseline should be re-assessed at each 
subsequent tumor evaluation. To the extent feasible, assessments should be performed by the same 
evaluator to ensure internal consistency across visits. 
At the investigator’s discretion, CT or other clinically appropriate scans may be repeated at any time if 
progressive disease is suspected. If the initial screening bone scan or PET scan does not show evidence of 
bone metastases, then these procedures do not need to be repeated unless clinically indicated or at the 

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treating physician’s discretion. 
Evaluation of tumor response will be completed by the investigator based on physical examinations, 
computed tomography (CT) scans, and other modalities, per RECIST v1.1 (see Appendix 1).  
If treatment is discontinued prior to disease progression per RECIST v1.1 (e.g., due to study treatment-
related toxicity), tumour response assessment should continue to be performed per the schedule specified in 
the Schedule of Assessments. During the post-treatment follow-up period, only patients with no PD will 
undergo tumor assessments. 
4.4.6 Laboratory, biomarker, and other biological samples 
An overview of the standard safety laboratory, biomarker, and other sampling requirements is provided 
below. For additional details on laboratory assessments and sample handling, refer to the laboratory manual 
4.4.6.1 Local laboratory assessments 
Samples for the following laboratory tests will be analysed by the local laboratory: 
 Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count 
with differential - neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other cells (if 
clinically indicated), and platelet count will be performed at screening, at each treatment visit and at 
the End of Treatment visit. 
 Serum chemistry: blood urea nitrogen (BUN) or urea, creatinine, sodium, potassium, magnesium, 
chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, aspartate transaminase (AST), 
alanine transaminase (ALT), alkaline phosphatase, total protein, and albumin. Bicarbonates should 
only be tested at sites where this test is part of the standard safety laboratory panel will be 
performed at screening, at each treatment visit and at the End of Treatment visit. 
The Cockcroft-Gault formula will be used to calculate creatinine clearance. Patients must have a 
CrCl ≥ 30 mL/min to be eligible for enrolment. Levels of magnesium and phosphorus must be 
tested during screening. During treatment, levels of magnesium and phosphorus should be tested as 
clinically indicated. 
 Coagulation panel: activated partial thromboplastin time (aPTT) and International Normalized 
Ratio (INR); performed at screening/baseline and at the End of Treatment visit. 
 Serum pregnancy test for women of childbearing potential at screening/baseline (within 7 days 
prior to initiation of study drug); after initiation of study drug, urine pregnancy tests will be 
performed at each cycle during treatment and at the End of Treatment visit.. If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test. 
A woman is of childbearing potential if she is postmenarcheal, has not reached a postmenopausal 
state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and 

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has not undergone surgical sterilization (removal of ovaries and/or uterus). 
 Thyroid function testing: thyroid-stimulating hormone (TSH), free T3 (or total T3 for sites where 
free T3 is not performed), free T4; performed at screening, within 96 hours before Day 1 of Cycle 
1, and within 96 hours before every second cycle thereafter, and at the End of Treatment visit. 
 Urinalysis: specific gravity, pH, glucose, protein, ketones, and blood; performed at screening, and 
thereafter only if clinically indicated. 
 In addition, all patients will be tested for HIV antibody, HBsAg, hepatitis B surface antibody 
(HBsAb), total hepatitis B core antibody (HBcAb), and hepatitis C virus antibody (HCVAb) locally 
during screening. HIV-positive patients will be excluded from the clinical trial. In patients with a 
negative HBsAg and positive HBcAb serology, HBV DNA must also be collected prior to initiation 
of study drug. Patients positive for HCVAb require a negative PCR for HCV RNA to confirm 
eligibility. 
 PD-L1 positivity: it’s defined as expression on tumor-infiltrating immune cells ≥1%. The test 
will be performed by each local laboratory on the primary tumor and/or the biopsy of metastatic 
lesion before starting first-line therapy through the SP142 PD-L1 immunohistochemical assay, 
Ventana Medical Systems provided by Roche. 
All laboratory tests results must be available for the Investigator’s review before treatment administration. 
4.4.6.2 Blood-based biomarker assays 
4.4.6.2.1 CLIO Samples 
Blood samples will be analyzed through a multiparametric Cancer agnostic circuLating ImmunOsignature 
(CLIO), based on the combination of immune-related mutations detectable in the circulating tumor DNA 
(ctDNA), buffy 
coat-based RNA 
sequencing 
(bcRNAseq) 
and 
plasma-based 
enzyme-linked 
immunosorbent assay (ELISA). The ctDNA sequencing part will be based on a customized panel that 
includes, but is not limited to, PIK3CA, PTEN, TP53, EMILIN2, MMRN2 and TNFα. PTPRC and 
GAPDH will be used as normalizers for the bcRNAseq analysis. 
CLIO blood samples will be collected at screening, progression and concomitantly to each per-protocol 
imaging based-evaluation (i.e. every 12 weeks). 
4.4.6.2.2 ctDNA Samples 
Tumor-focused ctDNA analyses will be performed through the FoundationOne® Liquid platform 
according to the vendor’s protocols and will be performed at baseline, first evaluation and disease 
progression. 
Since the evaluation is made for research purposes only, FoundationOne® Liquid results will be sent to the 
Center’s investigators only and not to the single enrolled patients. 

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4.4.6.2.3 Blood sample collection and management 
Blood draws timing will follow the schedule reported below: 
 
Timepoint 
Sample Type 
Volume 
Visit 
Day -7 to day 1 (any time before of study 
treatment) 
CLIO 
10 mL 
Screening 
FoundationOne® Liquid  
17 mL  
After 12 week (± 1 week) 
CLIO 
10 mL 
Concomitantly to the first per-
protocol imaging based-evaluation 
FoundationOne® Liquid 
17 mL 
Every 12 week (± 1 week) 
CLIO 
10 mL 
 
Concomitantly to each per-protocol 
imaging based-evaluation 
Possibly within 7 days from the last dose of 
study treatment but always prior to initiating any 
subsequent therapy. 
CLIO 
10 mL 
EOT due to disease progression 
FoundationOne® Liquid  
17 mL 
Table 3. Biological sample collection plan 
Plasma preparation from blood collected in ccfDNA stabilizing tubes for CLIO assesment 
CLIO plasma sample preparation and management protocols are provided in the laboratory manual.  
Buffy-coat preparation from blood collected in ccfDNA stabilizing tubes for CLIO assesment 
CLIO buffy-coat sample preparation and management protocols are provided in the laboratory manual.  
Sample preparation for FoundationOne® Liquid 

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FoundationOne® Liquid sample preparation and management protocols are provided in the vendor’s data 
sheet and are included in the laboratory manual. 
CLIO sample shipment procedures 
CLIO samples will be shipped to the centralized laboratory at the IRCCS CRO Aviano National Cancer 
Institute. Shipment procedures are provided in the laboratory manual. 
 
4.5 
Patient, Treatment, Study, and Site Discontinuation 
4.5.1 Patient Withdrawal 
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance 
Every effort should be made to obtain information on patients who withdraw from the study. The primary 
reason for withdrawal from the study should be documented on the appropriate eCRF. However, patients 
will not be followed for any reason after consent has been withdrawn. Patients who withdraw from the 
study will not be replaced. 
4.5.2 Study Drug Discontinuation 
Patients must discontinue the study drug if they experience any of the following: 
 
Intolerable toxicity related to the study drug 
 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
receiving study drug 
 
Use of another systemic anti-cancer therapy (see Section 4.4.2) 
 
Pregnancy 
 
Radiographic disease progression per RECIST v1.1. 
The primary reason for study drug discontinuation should be documented on the appropriate eCRF. 
Patients who discontinue study treatment prematurely will not be replaced. 

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4.5.3 Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study may 
include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates potential 
health hazard to patients 
 
Patient enrolment is unsatisfactory 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time. Reasons for closing a site may include, but are not 
limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 

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5  
ASSESSMENT OF SAFETY 
5.1 
Safety Plan 
5.1.1 General Plan to Manage Safety Concerns 
The safety plan for patients in this study is based on clinical experience with atezolizumab in completed 
and ongoing studies. The anticipated important safety risks for atezolizumab are outlined in Section 5.1.2 
below. Please refer to the latest atezolizumab Investigator's Brochure for a complete summary of safety 
information. 
Several measures will be taken to ensure the safety of patients participating in this study. 
These include stringent eligibility criteria (see Sections 4.1.1 and 4.1.2), designed to exclude patients at 
higher risk for toxicities, administration of the study drug in a controlled setting, and close safety 
monitoring of patients during the study (see Section 4.5), including assessment of the nature, frequency, 
and severity of adverse events (see Section 5.3.3). Administration of study treatment will be performed in a 
setting with emergency medical facilities and staff who are trained to monitor for and respond to medical 
emergencies. 
General safety assessments will consist of monitoring and recording adverse events, including serious 
adverse events and adverse events of special interest, performing protocol specified physical examinations, 
ECGs and safety laboratory assessments (including serum chemistries and blood counts), measuring 
protocol-specified vital signs, and conducting other protocol-specified tests that are deemed critical to the 
safety evaluation of the study; see Schedule of Assessment for the list and timing of study assessments. 
Laboratory values must be reviewed prior to each infusion. During the study, patients will be closely 
monitored for the development of any adverse events, including signs or symptoms of autoimmune 
conditions and infection. After initiation of study drug, all adverse events (regardless of relationship to 
study drug) will be reported until 30 days after the last dose of atezolizumab or until initiation of new 
systemic anti-cancer therapy, whichever occurs first. Serious adverse events and adverse events of special 
interest will continue to be reported until 90 days after the last dose of atezolizumab or until initiation of 
new systemic anti-cancer therapy, whichever occurs first. After this period, investigators should report 
serious adverse events and adverse events of special interest that are believed to be related to prior 
treatment with study drug; refer to Section 5.3.1 for further details. Adverse events will be defined and 
graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 
5.0 (NCI CTCAE v5.0). All serious adverse events and protocol defined events of special interest will be 
reported in an expedited fashion (see Sections 5.2.2 and 5.2.3, respectively).The potential safety issues 
anticipated in this study, as well as measures intended to avoid or minimize such toxicities, are outlined in 
the following sections. 
5.1.2 Risks Associated with Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase the risk 
of immune-related adverse events, specifically the induction or enhancement of autoimmune conditions. To 

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date, immune-related adverse events associated with atezolizumab include hepatitis, pneumonitis, colitis, 
pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré 
syndrome, hypophysitis, myasthenic syndrome/myasthenia gravis, meningoencephalitis, nephritis and 
myocarditis; refer to Section 5.2.3. Immune-mediated reactions may involve any organ system and may 
lead to hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Additional details 
regarding clinical safety are provided in the latest atezolizumab Investigator’s Brochure. 
Although most immune-related adverse events observed with immunomodulatory agents have been mild 
and self-limiting, such events should be recognized early and treated promptly to avoid potential major 
complications (Di Giacomo et al. 2010). Suggested workup and management of procedures for suspected 
immune-related adverse events are provided in the latest Atezolizumab Investigator’s Brochure. 
5.1.3 Risks Associated with Paclitaxel 
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring 
treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients receiving paclitaxel 
in clinical trials. Fatal reactions have occurred in patients despite premedication. Therefore, study patients 
may be premedicated according to local paclitaxel prescribing information and institutional standard of 
care practice. Such premedication may consist of a corticosteroid (dexamethasone 8 - 10 mg PO 
administered approximately 12 and 6 hours before paclitaxel), diphenhydramine (or its equivalent) 50 mg 
IV 30 to 60 minutes prior to paclitaxel, and a H2 antagonist (cimetidine 300 mg or ranitidine 50 mg IV 30 
to 60 minutes before paclitaxel). Patients who experience severe hypersensitivity reactions to paclitaxel 
despite premedication must not be rechallenged with the drug. 
Warnings related to paclitaxel use include bone marrow suppression (primarily neutropenia), which is 
dose-dependent and is the dose-limiting toxicity during paclitaxel treatment, with neutrophil nadirs 
occurring at a median of 11 days. Infectious episodes occurred in 30% of all patients exposed to paclitaxel 
in clinical trials; these episodes were fatal in 1% of all patients, and included sepsis, pneumonia and 
peritonitis. The use of supportive therapy, including G-CSF, is recommended for patients who have 
experienced severe neutropenia. Thrombocytopenia (platelet count below 100,000 cells/mm3 at least once 
while on treatment) was reported in 20% of the patients, with bleeding episodes in 14% of all patients 
receiving paclitaxel in clinical trials. Anemia (hemoglobin <11 g/dL) was observed in 78% of all patients 
and was severe (hemoglobin <8 g/dL) in 16% of the cases, with no consistent relationship between dose or 
schedule and the frequency of anemia. 
Other warnings for paclitaxel use include severe cardiac conduction abnormalities (documented in <1% of 
patients), which required pacemaker placement in some cases. 
In addition, paclitaxel can cause fetal harm when administered to a pregnant woman. 
Hypotension, bradycardia, and hypertension have been observed during administration of paclitaxel (in 
12%, 3%, and 1% of patients, respectively), but generally do not require treatment. Occasionally paclitaxel 
infusions must be interrupted or discontinued because of initial or recurrent hypertension. Other significant 
cardiovascular events possibly related to single-agent paclitaxel occurred in approximately 1% of all 
patients, and included syncope, rhythm abnormalities, and venous thrombosis. 

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Paclitaxel treatment is frequently associated with peripheral neuropathy; however, the development of 
severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of the 
drug. Other serious neurologic events following paclitaxel administration have been rare (<1%) and have 
included grand mal seizures, syncope, ataxia, and neuroencephalopathy. 
Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of 
erythema, tenderness, skin discoloration, or swelling at the injection site; more severe events such as 
phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have also been reported, with onset 
during or up to 10 days after paclitaxel infusions. 
Caution should be exercised when paclitaxel is concomitantly administered with known substrates, 
inhibitors, and inducers of CYP3A4 or CYP2C8; refer to Section 4.3.3. 
For more details regarding the safety profile of paclitaxel, refer to the local paclitaxel prescribing 
information. 
Patients will be monitored for paclitaxel-related adverse events throughout the study. 
5.1.4 Risks Associated with Carboplatin 
Warnings and precautions related to carboplatin use include: 
 
Myelosuppression (closely related to the renal clearance of the drug), with median day of nadir 
reported as day 21 in patients receiving single agent carboplatin and day 15 in patients receiving 
carboplatin in combination with other chemotherapeutic agents. Peripheral blood counts, renal 
and hepatic function tests should be monitored closely during carboplatin treatment 
 
Allergic reactions: as with other platinum-based drugs, allergic reactions appearing most often 
during administration may occur and necessitate discontinuation of infusion. Patients should be 
observed carefully and an appropriate symptomatic treatment (including antihistamines, 
adrenaline and/or glucocorticoids) must also be initiated in such cases 
 
Renal toxicity (with higher incidence and severity in patients with pre-existing impairment in 
renal function or previous nephrotoxicity as a result of cisplatin therapy) 
 
Hemolytic-uremic syndrome (HUS): Carboplatin should be discontinued at the first signs of any 
evidence of microangiopathic hemolytic anemia (rapidly falling hemoglobin with concomitant 
thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH). 
Renal failure may not be reversible with discontinuation of therapy and dialysis may be required 
 
Neurologic toxicity: may manifest as peripheral neurologic toxicity (generally common, but 
mild), or visual disturbance or loss of vision (generally associated with higher than 
recommended doses or renal impairment, and appears to resolve within weeks of stopping 
carboplatin) 
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior 

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Reversible 
Encephalopathy 
Syndrome 
(PRES): 
a 
rare, 
reversible 
(after 
treatment 
discontinuation), rapidly evolving neurological condition, which can include seizure, 
hypertension, headache, confusion, blindness, and other visual and neurological disturbances 
 
Auditory defects / ototoxicity 
 
Administration of live or live attenuated vaccines in patients immunocompromised by 
chemotherapeutic agents such as carboplatin, may result in serious or fatal infections. 
Vaccination with a live vaccine should be avoided in patients receiving carboplatin. Killed or 
inactivated vaccines may be administered; however, the response to such vaccines may be 
diminished. 
Very common (frequency ≥ 1 per 10 exposed patients) adverse reactions associated with carboplatin 
include the following (listed by preferred term): thrombocytopenia, neutropenia, leucopoenia, anemia, 
vomiting, nausea, abdominal pain, blood urea increased, blood alkaline phosphatase increased, aspartate 
aminotransferase increased, liver function test abnormal, blood sodium decreased, blood potassium 
decreased, blood calcium decreased, blood magnesium decreased. 
For further details on the risks, including adverse reactions associated with carboplatin treatment, refer to 
the current local prescribing information for carboplatin. 
5.1.5 Management of Patients who experience specific Adverse Events 
Toxicities associated or possibly associated with atezolizumab treatment should be managed according to 
standard medical practice. Additional tests, such as autoimmune serology or biopsies, should be used to 
evaluate for a possible immunogenic etiology. 
Although most immune-related adverse events observed with immunomodulatory agents have been mild 
and self-limiting, such events should be recognized early and treated promptly to avoid potential major 
complications. Discontinuation of atezolizumab may not have an immediate therapeutic effect, and in 
severe cases, immune-related toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents. 
Diagnostic criteria for hemophagitic lymphohistio-cystosis (HLH) and macrophage activation syndrome 
(MAS) systemic immune activation are presented in Section 5.1.5.1. For details on the management of 
infusion-related reactions and all other immune related adverse events, including but not limited to, 
gastrointestinal, dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, pancreatic, or eye toxicity 
refer to the current atezolizumab Investigator’s Brochure. 
5.1.5.1 Hemophagocytic lymphohistiocytosis and Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).   

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Patients with suspected HLH should be diagnosed according to published criteria by McClain and Eckstein 
(2014).  A patient should be classified as having HLH if five of the following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100  109/L (100,000/L) 
– 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L (150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations above age-
adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic juvenile 
idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as having MAS if the 
following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
At least two of the following: 
– 
Platelet count  181  109/L (181,000/L) 
– 
AST  48 U/L 
– 
Triglycerides  1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 1. 

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Table 1 
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
 Event 
 Management 
Suspected HLH or 
MAS 
 Permanently discontinue atezolizumab and contact Medical Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
 Consider initiation of IV corticosteroids and/or an immunosuppressive agent. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
5.1.5.2 Pulmonary events/Pneumonitis 
5.1.5.2.1 Atezolizumab 
Management guidelines for pulmonary events are provided in the latest atezolizumab Investigator’s 
Brochure. 
5.1.5.2.2 Paclitaxel 
Pneumonia, interstitial pneumonia, pleural effusion, lung fibrosis, pulmonary embolism,and respiratory 
failure are rare adverse effects, occurring in ≥1/10,000 and <1/1,000 ofpatients, and dyspnoea is a common 
adverse effect, occurring in ≥1/100 and <1/10 of patients treated with paclitaxel. Paclitaxel, particularly in 
combination with radiation of the lung, irrespective of their chronological order, may contribute to the 
development of interstitial or radiation pneumonitis. Fatal cases of pneumonia have also been reported. 
Paclitaxel should be permanently discontinued upon ruling out infectious etiology (using routine 
microbiological and/or immunologic methods) and making a diagnosis of pneumonitis. After infectious 
aetiology is ruled out, IV high-dose corticosteroid therapy should be instituted without delay, with 
appropriate premedication and secondary pathogen coverage. Patients with an added immunological 
component may also require immune modulation with azathioprine or cyclophosphamide. 
Refer to the local paclitaxel prescribing information for further details. 
5.1.5.3 Infusion-Related Reactions 
5.1.5.3.1 Atezolizumab 
No premedication is indicated for the administration of atezolizumab in Cycle 1. However, patients who 
experience an infusion-related reaction with atezolizumab in Cycle 1 may receive premedication with 

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antihistamines or antipyretics/analgesics (e.g., acetaminophen) for subsequent infusions. 
Infusion-related reactions should be managed according to institutional guidelines. 
5.1.5.3.2 Paclitaxel and Carbopaltin 
Paclitaxel and carboplatin infusion should be discontinued immediately in case of severe hypersensitivity 
reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or 
generalized urticaria; these events should be treated with aggressive symptomatic therapy; refer to Section 
5.1.6.2.2. 
5.1.6 Dose Modifications and Interruptions due to Adverse Events 
5.1.6.1 General Considerations 
Reasons for dose modifications or delays, the supportive measures taken, and the outcomes will be 
documented in the patient's chart and recorded on the eCRF. 
When several toxicities with different grades of severity occur at the same time, the dose interruptions or 
modifications should be according to the highest grade observed. 
If, in the opinion of the investigator, a toxicity is considered to be due solely to one component of the study 
treatment (i.e., atezolizumab or paclitaxel or carboplatin) and the dose of that component is delayed or 
modified in accordance with the guidelines below, the other component may be administered if there is no 
contraindication. 
When treatment is temporarily interrupted because of toxicity caused by atezolizumab or paclitaxel or 
carboplatin , the treatment cycles will be restarted such that the atezolizumab, paclitaxel and carboplatin 
infusions remain synchronized. 
If it is anticipated that paclitaxel will be delayed by >2 weeks, then atezolizumab should be given without 
the chemotherapy, as long as there is no contraindication. 
In general, the start of a cycle may be delayed to allow recovery from toxicities, but there should be no 
delays within cycles. Cycle length is fixed at 28 days, and dosing on Days 8 and 15 of a cycle may be 
skipped but should not be delayed outside of the +3 days window. 
The treating physician may use discretion in accelerating the dose modification guidelines described below 
depending on the severity of toxicity and an assessment of the risk versus benefit for the patient. 
5.1.6.2 Events requiring Permanent Treatment Discontinuation 
5.1.6.2.1. 
Atezolizumab 
Patients must permanently discontinue Atezolizumab if they experience any of the following: 

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 Intolerable toxicity related to study treatment, including development of an immune‑mediated adverse 
event determined by the investigator to be unacceptable given the individual patient's potential response 
to therapy and severity of the event 
 Any medical condition that may jeopardize the patient's safety if he or she continues study treatment 
 Investigator or Sponsor determination that treatment discontinuation is in the best interest of the patient 
 Use of another non-protocol anti‑cancer therapy 
 Pregnancy 
 Loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic 
and biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic 
deterioration such as pain secondary to disease) 
For further details, including complete management guidelines for the immune-related events, refer to the 
latest atezolizumab Investigator’s Brochure.  
5.1.6.2.2. 
Paclitaxel 
Paclitaxel infusion should be discontinued immediately in case of severe hypersensitivity reactions, such as 
hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria; 
these events should be treated with aggressive symptomatic therapy. Patients who have developed severe 
hypersensitivity reactions should not be rechallenged with paclitaxel. 
In addition, paclitaxel should be permanently discontinued upon ruling out infectious etiology (using 
routine microbiological and/or immunologic methods) and making a diagnosis of pneumonitis. 
Consideration may be given to performing pulse oximetry and pulmonary function tests to confirm 
respiratory and ventilation compromise in patients with suspected pneumonitis. 
Other events that required discontinuation of paclitaxel in clinical trials include cases of severe 
neurotoxicity, such as peripheral neuropathies (1% of all patients). Occasionally paclitaxel infusions must 
be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, 
particularly during the first hour of paclitaxel infusion, is recommended. 
Refer to the local paclitaxel prescribing information for further details. 
5.1.6.2.3. 
Carboplatin 
Carboplatin infusions should be discontinued immediately in case of severe hypersensitivity reaction, and 
at first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin 
with concomitant thrombocytopoenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, 
or LDH (risk of HUS). 
In addition, carboplatin infusions should be permanently discontinued in case of severe and persistent 

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myelosuppression, or severe impairment in renal or hepatic function. 
Refer to the local carboplatin prescribing information for further details. 
5.1.6.3 Dose Modifications and Interruptions 
5.1.6.3.1 
Atezolizumab 
Dose reduction of atezolizumab is not permitted in this study. 
Atezolizumab infusions may be temporarily suspended in case of an adverse event that requires a dose to 
be held. If atezolizumab is held because of adverse events for >12 weeks beyond the last dose, then the 
patient will be discontinued from atezolizumab treatment and will be followed for safety as specified in 
Section 5.5. If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
resuming atezolizumab after a hold of >12 weeks, study drug may be restarted with the approval of the 
Medical Monitor. 
If a patient must be tapered off steroids used to treat adverse events, atezolizumab may be held for up to 12 
weeks until steroids are discontinued or reduced to prednisone dose (or dose equivalent) of ≤10 mg/day. 
The acceptable length of interruption will depend on agreement between the investigator and the Medical 
Monitor. 
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, may be allowed 
with Medical Monitor approval. The acceptable length of interruption will depend on agreement between 
the investigator and the Medical Monitor. 
5.1.6.3.2 
Paclitaxel and Carboplatin 
Haematologic Toxicities 
Absolute neutrophil count (ANC) must be ≥1500/mL (≥1500 cells/mm3) and platelet count must be 
≥100,000/µL (≥100,000 cells/mm3) for the patient to receive paclitaxel on any treatment day (Day 1, 8, 15 
of any 28-day cycle). 
Dose modifications should be made according to the following table: 
ANC 
 
Platelets 
Paclitaxel dose 
≥1,500/L 
(≥1,500 cells/mm3) 
and 
≥100,000/L 
(≥100,000 cells/mm3) 
90 mg/m2 
1,000-1,499/L 
(1,000-1,499 cells/mm3) 
or 
75,000-99,999/L 
(75,000-99,999 cells/mm3) 
65 mg/m2 
<1,000/L 
(<1,000 cells/mm3) 
or 
<75,000/L 
(<75,000 cells/mm3) 
Hold [1] 
[1] If treatment is held, the CBC should be repeated until ANC ≥1500/L (≥1500 cells/mm3) and platelets 
≥100,000/L (≥100,000 cells/mm3). If paclitaxel/carboplatin therapy must be held for > 3 weeks to allow for 
resolution of haematologic toxicity, the patient will discontinue paclitaxel/carboplatin treatment but may 
continue receiving atezolizumab. 

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For any patient experiencing any of the following hematologic toxicities, the paclitaxel dose should be 
reduced to 65 mg/m² for all subsequent cycles: 
 
Fever (>38.5°C) associated with ANC <1,000/μL (<1,000 cells/mm3) 
 
Absolute granulocyte count <500/ μL (<500 cells/mm3) for > 5 days 
 
Significant bleeding associated with a platelet count <40,000/ μL (<40,000 cells/mm3) 
 
Any platelet count <20,000/ μL (<20,000 cells/mm3). 
If these severe hematologic toxicities recur in subsequent cycles despite dose reduction, paclitaxel should 
be discontinued, however the patient may continue receiving atezolizumab. 
If the start of a cycle is delayed (i.e. both atezolizumab and paclitaxel and carboplatin are held) for low 
counts, Day 1 will be postponed, and dosing resumed when ANC recovers to ≥1500/ μL (≥1500 
cells/mm3) and platelet count returns to ≥100,000/ μL (≥100,000 cells/mm3). 
In certain situations, (see Section 5.1.5.1) a cycle may begin with the administration of atezolizumab alone 
(without paclitaxel and carboplatin on Day 1). If paclitaxel or carboplatin cannot be administered on Day 8 
of the cycle, they may be administered on Day 15 if counts have recovered to permissible levels. If 
paclitaxel and carboplatin cannot be administered on Day 15 of the cycle, the next dose of paclitaxel or 
carboplatin should be administered on Day 1 of the following cycle when ANC and platelets counts have 
recovered to permissible levels. 
Hepatic Toxicities 
In case of hepatic toxicities, dose modifications should be made according to the following table: 
AST 
 
Bilirubin 
Paclitaxel dose 
≤ 5 x ULN 
and 
≤ 1.5 mg/dL (≤ 25.65 μmol/L) 
90 mg/m2 
> 5 but ≤ 10 x ULN 
or 
1.6 - 2.5 mg/dL (27.36 - 42.75 μmol/L) 
65 mg/m2 
> 10 x ULN 
or 
≥ 2.6 mg/dL (≥ 44.46 μmol/L) 
Hold [1] 
AST: aspartate aminotransferase; ULN: upper limit of normal 
[1] Hold therapy until AST < 10 x ULN and bilirubin < 2.5 mg/dL. If paclitaxel must be held for > 3 weeks 
to allow for resolution of hepatic toxicity, the patient will discontinue paclitaxel treatment but may 
continue receiving atezolizumab. 
Patients requiring a delay in paclitaxel therapy due to hepatic toxicity should be evaluated for possible 
progressive hepatic metastases. 
Peripheral Neuropathy  
If grade 3 toxicity develops, paclitaxel/carboplatin treatment should be withheld until the neuropathy 

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recovers to < grade 1 (atezolizumab treatment should continue as scheduled). When treatment is resumed, 
the paclitaxel/carboplatin dose should be reduced permanently to 65 mg/m². If grade 3 neuropathy persists 
for > 3 weeks or recurs after dose reduction, the patient will discontinue paclitaxel/carboplatin treatment 
but may continue receiving atezolizumab. 
Gastrointestinal Toxicity 
Nausea and/or vomiting should be controlled with standard antiemetics and will not result in dose 
modification. 
Anaphylaxis/Hypersensitivity 
 
Mild symptoms (e.g., mild flushing, rash pruritus): No treatment needed. Supervise at bedside 
and complete paclitaxel infusion. 
 
Moderate symptoms (moderate flushing, rash, mild dyspnea, chest discomfort): Stop 
paclitaxel/carboplatin infusion. Administer diphenhydramine 25 mg (or equivalent) and 
dexamethasone 10 mg IV (or equivalent). After recovery of symptoms, resume infusion at half 
the previous rate for 15 minutes. If no further symptoms occur, complete the infusion at the full 
dose rate. If symptoms recur, the reaction should be reported as an adverse event and the patient 
will discontinue paclitaxel/carboplatin treatment but may continue atezolizumab. 
 
Severe life-threatening symptoms (e.g., hypotension requiring pressor therapy, angioedema, 
respiratory distress requiring bronchodilators, generalized urticaria): Stop the infusion and 
administer diphenhydramine 25 mg (or equivalent) and dexamethasone 10 mg IV (or 
equivalent). Add epinephrine or bronchodilators if needed. The reaction should be reported as an 
adverse event and the patient will discontinue paclitaxel/carboplatin treatment but may continue 
atezolizumab. 
Gastrointestinal Toxicity 
If the patient develops any other grade 3 or 4 toxicity considered related to paclitaxel/carboplatin, 
paclitaxel/carboplatin should be held until symptoms resolve to grade 1 or less (atezolizumab treatment 
should continue as scheduled). When treatment is resumed, the paclitaxel/carboplatin dose should be 
reduced permanently to 65 mg/m². If grade 3 toxicity persists for >3 weeks or recurs after dose reduction, 
the patient will discontinue paclitaxel/carboplatin treatment but may continue atezolizumab. 
Refer to the local paclitaxel/carboplatin prescribing information for further details. 
5.2 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording adverse events, including serious adverse 
events and adverse events of special interest, performing protocol-specified safety laboratory assessments, 
measuring protocol-specified vital signs, and conducting other protocol-specified tests that are deemed 
critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 5.4. 

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5.2.1 Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal 
attribution. An adverse event can therefore be any of the following: 
 
Any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, 
or severity of a known condition), except as described in Section 5.3.5.9 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is associated 
with symptoms or leads to a change in study treatment or concomitant treatment or 
discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as biopsies) 
5.2.2 Serious Adverse Events (Immediately Reportable to the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the patient at 
immediate risk of death) 
 
Note: This does not include any adverse event that had it occurred in a more severe form or was 
allowed to continue might have caused death 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the patient or 
may require medical/surgical intervention to prevent one of the outcomes listed above) 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an adverse event 
(e.g., rated as mild, moderate, or severe, or according to NCI CTCAE v5.0; see Section 5.3.3); the event 
itself may be of relatively minor medical significance (such as severe headache without any further 
findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4 for reporting instructions). 

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5.2.3 Adverse Events of Special Interest (Immediately Reportable to the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4 for reporting 
instructions). 
Adverse events of special interest for this study include the following conditions specific for atezolizumab: 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and 
hypophysitis 
 
Hepatitis, including AST or ALT >10 x ULN 
 
Systemic lupus erythematosus 
 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
and meningoencephalitis 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, 
influenza-like illness, systemic inflammatory response syndrome 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myositis 
 
Myopathies, including Rrhabdomyolysis 
 
Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Autoimmune haemolytic anaemia 
 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic epidermal 
necrolysis). 
The following events also require immediate reporting: 
 
Cases of potential drug-induced liver injury that include elevated ALT or AST level in 
combination with either elevated bilirubin levels or clinical jaundice, as defined by Hy’s law (see 
Section 5.3.5.5.1); 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
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. 
5.2.4 Product Complaints 
A product complaint is any deficiency related to identity, quality, safety, strength, purity, reliability, 
durability, effectiveness, or performance of the product. Product complaints are required to be reported by 

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the investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4 for reporting instructions). 
5.3 
Methods and timing for capturing and assessing safety parameters 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for definition) are 
recorded on the eCRF and reported to the Sponsor in accordance with instructions provided in this section 
and in Section 5.4 (immediate reporting), Section 5.5 (follow-up), and Section 5.6 (events occurring after 
the reporting period). 
For each adverse event, the investigator will make an assessment of seriousness (see Section 5.2.2 for 
seriousness criteria), severity (see Section 5.3.3), and causality (see Section 5.3.4) on the eCRF. 
5.3.1 Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact. All adverse events, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s medical record and on 
the eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, discontinuation of 
medications) should be reported (see Section 5.4 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events (regardless of relationship to study drug) will be reported 
until 30 days after the last dose of atezolizumab or until initiation of new systemic anti-cancer therapy, 
whichever occurs first. Serious adverse events and adverse events of special interest will continue to be 
reported until 90 days after the last dose of atezolizumab or until initiation of new systemic anti-cancer 
therapy, whichever occurs first. 
Instructions for reporting adverse events that occur after the adverse event reporting period (defined as 90 
days after the last dose of atezolizumab) are provided in Section 5.6. 
5.3.2 Eliciting Adverse Event information 
A consistent methodology of non-directive questioning should be adopted for eliciting adverse event 
information at all patient evaluation timepoints. Examples of non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
5.3.3 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for assessing adverse 
event severity. Table 3 will be used for assessing severity for adverse events that are not specifically listed 
in the NCI CTCAE. 

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Table 3 -  Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
Grade 1 (mild)  
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
Grade 2 (moderate) 
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of 
daily living, causing discomfort but poses no significant or 
permanent risk of harm to the patient. 
Grade 3 (severe) 
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the patient. 
Grade 4 (life-threatening) 
An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the patient to perform activities of daily 
living (eating, ambulation, toileting, etc). 
Grade 5 (fatal) 
Death (loss of life) as a result of an event. 
It is important to distinguish between serious criteria and severity of an AE. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 5.2.2.  
A Grade 3 AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a nonserious 
event, whereas a Grade 2 seizure resulting in a hospital admission would be considered a SAE. 
5.3.4 Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding the event, and an 
evaluation of any potential alternative causes to determine whether an adverse event is considered related 
to the study drug, and answer "yes" or "no" to the question: “Do you consider that there is a reasonable 
possibility that the event may have been caused by the study drug?” 
Causality will be assessed individually for each protocol-mandated therapy. 
5.3.5 Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse events on the 
eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the eCRF. 
5.3.5.1 Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and are judged to be 
related to study drug infusion should be captured as a diagnosis (e.g., "infusion-related reaction" or 

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"anaphylactic reaction") on the eCRF. If possible, ambiguous terms such as "systemic reaction" should be 
avoided. Associated signs and symptoms should be recorded on the eCRF. If a patient experienced both a 
local and systemic reaction to the same dose of study drug, each reaction should be recorded separately on 
the eCRF, with signs and symptoms also recorded separately on the eCRF. 
5.3.5.2 Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a diagnosis (if known) should 
be recorded on the eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the eCRF. If a diagnosis is subsequently established, 
all previously reported adverse events based on signs and symptoms should be nullified and replaced by 
one adverse event report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 Adverse Events that are secondary to other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, except for severe or serious secondary events. A medically 
significant secondary adverse event that is separated in time from the initiating event should be recorded as 
an independent event on the eCRF. For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, only 
vomiting should be reported on the eCRF 
 
If vomiting results in severe dehydration, both events should be reported separately on the eCRF 
 
If a severe gastrointestinal haemorrhage leads to renal failure, both events should be reported 
separately on the eCRF 
 
If dizziness leads to a fall and consequent fracture, all three events should be reported separately 
on the eCRF 
 
If neutropenia is accompanied by an infection, both events should be reported separately on the 
eCRF 
All adverse events should be recorded separately on the eCRF if it is unclear as to whether the events are 
associated. 
5.3.5.4 Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between patient evaluation 
timepoints. Such events should only be recorded once on the eCRF. The initial severity (intensity or grade) 
of the event will be recorded at the time the event is first reported. If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the eCRF. If the event becomes serious, 
it should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning that the event 
became serious; see Section 5.4 for reporting instructions). The eCRF should be updated by changing the 

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Investigational Drug Substance: atezolizumab 
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event from "non-serious" to "serious," providing the date that the event became serious, and completing all 
data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints and subsequently 
recurs. Each recurrence of an adverse event should be recorded as a separate event on the eCRF. 
5.3.5.5 Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as 
an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms; 
 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation); 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalaemia) or a 
change in concomitant therapy; 
 
Is clinically significant in the investigator’s judgment. 
Note: For oncology trials, certain abnormal values may not qualify as adverse events. 
It is the investigator’s responsibility to review all laboratory findings. Medical and scientific judgment 
should be exercised in deciding whether an isolated laboratory abnormality should be classified as an 
adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 xULN associated with cholestasis), only the diagnosis (i.e., cholestasis) should 
be recorded on eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality 
itself should be recorded on the eCRF, along with a descriptor indicating whether the test result is above or 
below the normal range (e.g., "elevated potassium," as opposed to "abnormal potassium"). If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the clinical term 
should be recorded as the adverse event. For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as "hyperkalaemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit should not be 
repeatedly recorded on the eCRF, unless the aetiology changes. The initial severity of the event should be 
recorded, and the severity or seriousness should be updated any time the event worsens (see Section 5.3.5.4 
for details on recording persistent adverse events). 
5.3.5.5.1 Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (>3 x ULN) in combination with either an elevated total bilirubin 
(>2 x ULN) or clinical jaundice in the absence of cholestasis or other causes of hyperbilirubinemia is 
considered an indicator of severe liver injury (as defined by Hy's law). Therefore, investigators must report 

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as an adverse event the occurrence of either of the following: 
 
Treatment-emergent ALT or AST >3 x ULN in combination with total bilirubin >2 x ULN (of 
which ≥35% is direct bilirubin) 
 
Treatment-emergent ALT or AST >3 x ULN in combination with clinical jaundice. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory values 
should be recorded on the eCRF (see Section 5.3.5.2) and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event), either as a serious adverse event or an adverse event of 
special interest (see Section 5.4). 
5.3.5.6 Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be reported as an 
adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific judgment 
should be exercised in deciding whether an isolated vital sign abnormality should be classified as an 
adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood 
pressure), only the diagnosis (i.e., hypertension) should be recorded on the eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should only be 
recorded once on the eCRF (see Section 5.3.5.4 for details on recording persistent adverse events). 
5.3.5.7 Deaths 
For this protocol, mortality is an efficacy endpoint. All deaths that occur during the protocol-specified 
adverse event reporting period (see Section 5.3.1) that are attributed by the investigator solely to 
progression of mTNBC should be recorded on the eCRF. All other on-study deaths, regardless of 
relationship to study drug, must be recorded on eCRF and immediately reported to the Sponsor (see 
Section 5.4).  
Death should be considered an outcome and not a distinct event. The event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the eCRF. Generally, 
only one such event should be reported. The term "sudden death" should be used only for the occurrence of 
an abrupt and unexpected death due to presumed cardiac causes in a patient with or without preexisting 
heart disease, within 1 hour after the onset of acute symptoms or, in the case of an unwitnessed death, 

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within 24 hours after the patient was last seen alive and stable. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, "unexplained death" 
should be recorded on the eCRF. If the cause of death later becomes available (e.g., after autopsy), 
"unexplained death" should be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of mTNBC should be recorded only on the 
eCRF, while the date of death should be captured on the eCRF. Reporting of deaths that occur after the 
adverse event reporting period is described in Section 5.6. 
5.3.5.8 Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on the eCRF, it is 
important to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., "more frequent headaches"). 
5.3.5.9 Lack of Efficacy or Worsening of Breast Cancer 
Events that are clearly consistent with the expected pattern of progression of the underlying disease should 
not be recorded as adverse events. These data will be captured as efficacy assessment data only. In most 
cases, the expected pattern of progression will be based on RECIST. In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration. However, every effort should be made to 
document progression through use of objective criteria. If there is any uncertainty as to whether an event is 
due to disease progression, it should be reported as an adverse event. 
5.3.5.10 Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.2.2), except as outlined below. 
The following hospitalization scenarios are not considered to be adverse events: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study drug administration or insertion 
of access device for study drug administration) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria are met: 
o 
The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal progression of 
the disease 

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o 
The patient has not experienced an adverse event 
 
Hospitalization due solely to progression of the underlying cancer (including symptoms). 
The following hospitalization scenario is not considered to be a serious adverse event, and should be 
reported as an adverse event instead: 
 
Hospitalization for outpatient care outside of normal outpatient clinic operating hours that is 
required per protocol or per local standard of care. 
5.3.5.11 Special situations 
For this study, the following events are considered “Special Situations”: 
 Accidental overdose: accidental administration of a drug in a quantity that is higher than the assigned 
dose 
 Medication error: accidental deviation in the administration of a drug. In some cases, a medication error 
may be intercepted prior to administration of the drug. 
Any study drug overdose or medical error of study drugs should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4),  noted on the eCRF and reported 
as a protocol deviation. Any overdose or incorrect administration of paclitaxel should be noted on the 
eCRF and reported as a protocol deviation. 
Special situations are not in themselves adverse events, but may result in adverse events.  Each adverse 
event associated with a special situation should be recorded separately on the eCRF. If the associated 
adverse event fulfills seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4). 
5.4 
Immediate reporting requirements  
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to address 
potential new risks in a clinical trial. The investigator must report such events to the Sponsor immediately; 
under no circumstances should reporting take place more than 24 hours after the investigator learns of the 
event. The following is a list of events that the investigator must report to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study drug: 
 Serious adverse events (see Section 5.2.2 for further details) 
 Adverse events of special interest (see Section 5.2.3 for further details) 
 Special situations (see Section 5.3.5.11 for further details)  
 Pregnancies (see Section 5.4.2 for further details) 
 Product complaints (see Section 5.4.3 for further details) 
Contact details of Sponsor Safety Desk for reporting are available in the Safety Desk section of this 
Protocol. 

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All SAEs and adverse events of special interest will be reported, whether or not considered causally related 
to the investigational product, or to the study procedure(s). The reporting period for SAEs is the period 
immediately following the time that written informed consent is obtained through 90 days after the last 
dose of study drug or until the initiation of alternative anticancer therapy. The investigator and/or Sponsor 
are responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE as per 
local requirements.  
The sponsor will indicate, either in the SAE report or the cover page, the causality of events in relation to 
all study medications and if the SAE is related to disease progression, as determined by the principal 
investigator. A SAE report and accompanying cover page will be sent via email to Sponsor by 
Investigator.. 
The investigator must report new significant follow-up information for these events to the Sponsor 
immediately (i.e., no more than 24 hours after becoming aware of the information). New significant 
information includes the following: 
 New signs or symptoms or a change in the diagnosis 
 Significant new diagnostic test results 
 Change in causality based on new information 
 Change in the event’s outcome, including recovery 
 Additional narrative information on the clinical course of the event 
5.4.1 Reporting Requirements for Serious Adverse Events and Adverse Events of Special Interest 
5.4.1.1 Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, discontinuation of 
medications) should be reported. The Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.1.2 Events that Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special interest will be reported 
until 90 after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs 
first. Investigators should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the eCRF. 

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5.4.2 Reporting Requirements for Pregnancies 
5.4.2.1 Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the investigator if they 
become pregnant during the study or within 6 months after the last dose of study drug. The study 
Pregnancy Surveillance Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by scanning 
and emailing the form using the fax number or email address provided to investigators. Pregnancies should 
not be recorded on the eCRF. The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the foetus. Monitoring of the patient 
should continue until the conclusion of the pregnancy. Any serious adverse events associated with the 
pregnancy (e.g., an event in the foetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the eCRF. In addition, the investigator will update 
the Pregnancy Surveillance Form when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.2.2 Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform the investigator 
if their partner becomes pregnant during the study or within 6 months after the last dose of study drugs. A 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by scanning 
and emailing the form using the fax number or email address provided to investigators. 
Attempts should be made to collect and report details of the course and outcome of any pregnancy in the 
partner of a male patient exposed to study drug. Where a report of pregnancy is received, prior to obtaining 
information about the pregnancy, the Investigator must obtain the consent of the patient’s partner. 
Therefore, only in case of pregnancy, the Sponsor should adopt the generic ICF template in line with local 
procedures and submit it to the relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior 
to use. An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the foetus to support an informed 
decision in cooperation with the treating physician and/or obstetrician. 
5.4.2.3 Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers abortions to be 
medically significant), recorded on the eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4). 
5.4.2.4 Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study drug or the female 
partner of a male patient exposed to study drug should be classified as a serious adverse event, recorded on 

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the eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4). 
5.4.3 Reporting requirements for Product complaints 
The investigator must report all product complaints to the Sponsor.  The investigator should document as 
much information as possible on the IMP Deviation Form, including the product batch number, and 
forward the form to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  If 
the complaint is related to an adverse event to the study patient, the event must be reported on the eCRF.  If 
the event is serious, the SAE report has to be completed and forwarded to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event). 
5.5 
Follow-up of patients after adverse events 
5.5.1 Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws 
consent. Every effort should be made to follow all serious adverse events considered to be related to study 
drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented on the eCRF and 
in the patient’s medical record to facilitate source data verification. If, after follow-up, return to baseline 
status or stabilization cannot be established, an explanation should be recorded on the eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome, by following the 
reporting instructions provided in Section 5.4.2. 
5.5.2 Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the Sponsor or a designee 
may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details 
and outcome information (e.g., from hospital discharge summaries, consultant reports, autopsy reports) in 
order to perform an independent medical assessment of the reported case 
5.6 
Adverse Events that occur after the adverse event reporting period 
At the treatment discontinuation visit, the investigator should instruct each patient to report to the 
investigator any subsequent adverse events that the patient’s personal physician believes could be related to 
prior study drug treatment or study procedures. 
The Sponsor should be notified if the investigator becomes aware of any serious adverse event or adverse 
events of special interest that occurs after the end of the adverse event reporting period (defined as 90 days 
after the last dose of the study drug), if the event is believed to be related to prior treatment with study 
drugs. The Sponsor should also be notified if the investigator becomes aware of the development of cancer 
or a congenital anomaly/birth defect in a subsequently conceived offspring of a patient who participated in 

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this study. 
5.7 
Expedited reporting to Health Authorities, Investigators, Institutional Review Boards, and 
Ethics Committees 
The Sponsor will promptly evaluate all serious adverse events and adverse events of special interest against 
cumulative product experience to identify and expeditiously communicate possible new safety findings to 
investigators, IRBs/ECs, and health authority based on Italian legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
 
Atezolizumab Investigator's Brochure 
 
Local prescribing information for paclitaxel and carboplatin 
The Sponsor will compare the severity of each event and the cumulative event frequency reported for the 
study with the severity and frequency reported in the applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality and seriousness, 
with allowance for upgrading by the Sponsor as needed. 

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6  
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
This phase II, single-arm, study is designed to test the hypothesis that the addition of an anti-PDL1 to 1st 
line therapy in metastatic triple-negative breast cancer is associated with a clinically relevant 2-year 
increase in OS over what expected based on historical data (54%; Schmid et al. 2018) 
6.1 
Statisitical Considerations 
The statistical design of this phase II trial is influenced by 2-factors: 
a) The addition of an immunotherapy agent to a polychemotherapy with a considerable activity in 
TNBC is unlikely to produce a substantial improvement in the Response Rate or in Progression 
Free Survival. Therefore, the only study endpoint capable of capturing any effect of this addition 
is Overall Survival. 
b) Although TNBC is possibly the biological variant of breast cancer which is least susceptible to 
medical treatments, short term survival of patients with mTNBC is still quite high, with a median 
OS in excess of 2 years (Tutt et al. 2018; Yardley et al. 2018) 
As a consequence, the standard design of phase II trials, which is focused on short term markers of 
response and incorporates stopping rules for futility based on early interim analyses, cannot be used. 
Instead, this trial is designed as a single stage cohort study in which all patients will be followed til the 
end of the study,  which is set at two years after the enrolement of the last patient, thereby ensuring  a 
minimal potential follow-up of 2 years to all enrolled patients who did not die before 2 years. The 
primary study endpoint will be the proportion of patient alive at two years (2ys OS%), but, OS% at 2.5 
years will represent a important secondary endpoint, since, considering that no less than 1 year will be 
necessary to enroll all patients into the study, at the time of the final analysis (i.e. 2 years after the 
enrolment of the last patient), 50% of the enrolled patients will have a follow-up ≥2.5 years. 
6.2 
Expected results and sample size 
In order to reject with power 80% at the 0.05 (1-sided) significance level the null hypothesis that 2yrsOS in 
mTNBC treated with atezolizumab plus carboplatin and paclitaxel is 54%, under the alternative hypothesis 
that atezolizumab increases this porportion by 12% (i.e. to 66%), it is necessary to enroll into the study 104 
patients. With 104 patients, the minimal observed 2yrsOS% allowing rejection of the null hypothesis at the 
1-sided 5% significance level is 62.5% (=65  survivors at 2yrs /104 enrolled patients)  and the estimated 
2yrsOS will have a precision (= width of the exact 90% CI)  of approximately +/- 8% (e.g., for 65 
successess/104 patients)  0.5401 ≤ p ≤ 0.7044) 
6.3 
Efficacy Analyses 
The primary and secondary efficacy analyses will include all enrolled patients, in accordance with the 
Intention to Treat Principle. 
6.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is % Overall survival at 2 years, defined as the proportion of 
patients alive 2 years after enrollment. Due to the fact that the information of vital status of an individual  

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(alive/dead) is not covered by privacy and is  available  to anyone in Italy from the municipality of 
residence, and that this study will not terminate for at least 2 years after the enrolment of the last patient, no 
censored survival times are expected in the first 2 years of follow-up, making it possible to compute the 
crude proportion of patients  alive at 2 years, which will be used in the primary analysis. However, should 
the information be missing for some patients (e.g. due to adiministrative reasons, or to errors in the 
registration of patient’ data) the proportion of survivors at 2 years estimated by the Kaplan Meier  will be 
used instead. The resulting loss in statistical power  can be considered negligible, as the number of patients 
lost to follow-up and for whom the information on the vital status cannot be retrieved is expected to be 
very small. The proportion of 2-yrs  survivors with its 90% exact CI’s according to Clopper-Pearson will 
be presented 
The comparison between the observed and the expected (54%) proportion of patients surviving at 2 years 
will be based on the exact binomial probability distribution under H0 (Proportion = 54%) 
6.3.2 Secondary Efficacy Endpoints 
 
% Overall survival at 2.5 years  
 
Overall Survival at 2 years in HR <1% and in HR 1-10% 
 
Post-progression survival 
 
Objective response rate 
 
Time to treatment failureIncidence and severity of adverse events and serious adverse events 
6.3.2.1 % Overall survival at 2.5 years 
% Overall survival at 2.5 years is defined as the proportion of patients alive 2.5 years after enrollment. 
6.3.2.2    Overall Survival at 2 years in HR <1% and in HR 1-10% 
% Overall survival at 2 years is defined as the proportion of patients alive 2 years after enrollment in 
patients with Hormonal Receptor (HR) <1% and in patients with HR 1-10% 
6.3.2.3 Post-Progression survival 
Post-Progression Survival (PPS) is defined as the time from tumor progression until death or is censored on 
the date of the last follow-up consultation 
6.3.2.4 Objective Response Rate (see Appendix 1) 
An objective response is defined for patients with measurable disease at baseline as either a partial 
response (PR) or a complete response (CR) using RECIST v1.1. An estimate of ORR (CR plus PR) will be 
calculated  in all patients evaluable for response and its 95% CI will be calculated using the Clopper-
Pearson method. 

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6.3.2.5 Time to treatment failure 
Time to treatment failure (TTF) is defined as the time from enrollment to treatment discontinuation for any 
reason, including disease progression, treatment toxicity, patient preference, or death. 
6.3.2.6  Incidence and severity of adverse events and serious adverse events 
Safety analyses will include all enrolled patients who received at least one dose of study treatment 
(atezolizumab or paclitaxel or carboplatin). 
Safety will be assessed through summaries of adverse events, changes in laboratory test results, changes in 
vital signs, study treatment exposures, and will be presented by treatment arm. 
Treatment-emergent events (defined as events occurring on or after the first dose of study treatment and 
within 30 days prior to the last dose of study treatment) will be summarized by MedDRA term, appropriate 
MedDRA levels (for example, system organ class [SOC] and preferred term [PT]), and NCI CTCAE v5.0 
grade, regardless of relationship to study drug as assessed by the investigator. For each patient, if multiple 
incidences of the same adverse events occur, the maximum severity reported will be used in the summaries. 
The following treatment-emergent adverse events will also be summarized: 
 
Adverse events assessed as related to the study drug 
 
Adverse events leading to permanent discontinuation of study drug (with or without withdrawal 
from the study) 
 
Adverse events leading to dose reduction or interruption 
 
Grade ≥3 adverse events 
 
Grade 5 adverse events 
 
Serious adverse events; and Adverse Events of Special Interest (AESI) 
All deaths and causes of deaths will be summarized. 
Relevant laboratory values will be summarized by time, with NCI CTCAE Grade 3 and Grade 4 values 
identified, where appropriate. Changes in NCI CTCAE grade will be tabulated by treatment arm. 

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7 ETHICAL AND REGULATORY REQUIREMENTS 
7.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmnized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including 
European Directive 2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. 
The protocol and the proposed informed consent form must be reviewed and approved by Independent 
Ethics Committee (IEC) of all participating centers before study start. 
7.2 
Study documentation, record keeping and retention of documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements for the 
protection of confidentiality of subjects. As part of participating in a Oncotech-sponsored study, each site 
will permit authorized representatives of the sponsor(s) and regulatory agencies to examine (and when 
required by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits 
and evaluation of the study safety and progress.  
Source data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ 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, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
Principal Investigator. The study case report form (CRF) is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the CRFs and all other required reports. Data reported on the CRF, that are derived from source 
documents, should be consistent with the source documents or the discrepancies should be explained. All 
data requested on the CRF must be recorded. Any missing data must be explained. For electronic CRFs an 
audit trail will be maintained by the system. The investigator/institution should maintain the trial 
documents as specified in Essential Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and 
as required by applicable regulations and/or guidelines.  
The investigator/institution should take measures to prevent accidental or premature destruction of these 
documents. Essential documents (written and electronic) should be retained for a period of not less than 
twenty-five (25) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time because of 
applicable laws, regulations and/or guidelines. 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
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7.3 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names in any 
documents submitted to the Sponsor. Signed informed consent forms and patient enrollment log must be 
kept strictly confidential to enable patient identification at the site. 
7.4 
Audits and inspections 
Source data/documents must be available to inspections by the Sponsor or designee or Health Authorities. 
7.5 
Financial disclosures 
Financial disclosures should be provided by study personnel who is directly involved in the treatment or 
evaluation of patients at the site - prior to study start. 
7.6 
Patient protection 
The responsible investigator of each site will ensure that this study is conducted in agreement with either 
the Declaration of Helsinki (Tokyo, Venice, Hong Kong and Somerset West amendments) or the laws and 
regulations of the country, whichever provides the greatest protection of the patient. 
7.7 
Subject identification – Personal Data Protection 
All records identifying the subject must be kept confidential and, to the extent permitted by the applicable 
laws and/or regulations, not be made publicly available. The name of the patient will not be asked for nor 
recorded at the Data Center. A sequential identification number will be automatically attributed to each 
patient registered in the study. This number will identify the patient and must be included on all case report 
forms. In order to avoid identification errors, year of birth will also be reported on the case report forms. 
Any and all patient information or documentation pertaining to a clinical trial, to the extent permitting, 
through a “key” kept anywhere, regardless of whether such key is supplied along with the information 
or documentation or not, must be considered as containing sensitive personal data of the patient, and is 
therefore subjected to the provisions of applicable data protection (“privacy”) regulations. Breach of such 
regulations may result in administrative or even criminal sanctions. 
Particularly, an information sheet prepared according to such regulations and a form to evidence the 
consent of patients to the processing of such data must therefore accompany the informed consent 
administered to the patient (see Section 8.8 below). Such information must (i) identify the roles of the 
holder (“titolare”) and processor (“responsible”, appointed by the holder) of the patient personal data 
(also if not directly identifying the patient), as well as the purposes of the personal data collection and 
processing (medical treatment and related/unrelated scientific research), (ii) adequately describe the flows 
of communication involving them, particularly if third parties should become involved, and (iii) seek the 
patient’s prior and specific consent to such processing. 
Patient information or documentation may be considered “anonymous”, and as such not subject to privacy 
regulations, only when no key whatsoever, permitting the identification of the patient, is any longer 

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available. 
Particular attention should therefore be paid (and information/consent materials adapted accordingly) 
whenever patient data are supplied to third parties and may be autonomously processed, or biological 
samples/materials are taken and kept for future research purposes, associated or not with the pathology 
considered in the study. 
7.8 
Informed consent 
All patients will be informed of the aims of the study, the possible adverse events, the procedures and 
possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. They will be 
informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed 
for study purposes by authorized individuals other than their treating physician. 
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further 
participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. 
Documented informed consent must be obtained for all patients included in the study before any study 
procedure starts. This must be done in accordance with the national and local regulatory requirements. 
For European Union member states, the informed consent procedure must conform to the ICH guidelines 
on Good Clinical Practice. This implies that “the written informed consent form should be signed and 
personally dated by the patient or by the patient’s legally acceptable representative”. The process of 
obtaining informed consent should be documented in the patient source documents. The date when a 
subject’s Informed Consent was actually obtained will be captured in their CRFs. 
7.9 
Conflict of Interest 
Any investigator and/or research staff member who has a conflict of interest with this study (such as patent 
ownership, royalties, or financial gain greater than the minimum allowable by their institution) must fully 
disclose the nature of the conflict of interest. 
7.10 
Data ownership 
According to the ICH Guidelines on Good Clinical Practice the sponsor of a study is the owner of the data 
resulting therefrom. All centers and investigators participating in the study should be made aware of such 
circumstance and invited not to disseminate information or data without the Institution’s prior express 
consent.Study insurance 
The sponsor of the Study must ensure that adequate insurance coverage is available to the patients, in 
accordance with Section 5.8 of the ICH Guidelines of Good Clinical Practice. Such coverage must extend 
to all damages deriving from the study, to the exclusion of those attributable to willful misconduct or 
negligence of the institution or investigator. A copy, or excerpt, or insurer’s certificate, attesting the 
existence and amount of such coverage at least for the duration of the study must be supplied as part of the 
study documentation to the review and approval of the IEC. 

Sponsor: Consorzio Oncotech 
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EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
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8  
STUDY MANAGEMENT 
8.1 
Training of study site personnel 
Investigational staff involved in the study will be adequately trained by the local PI and representatives of 
the Contract Research Organization before any activities related to the Study are initiated. 
8.2 
Study timetable and end of study 
Enrollment period: 2 years approximately 
First Patient First Visit (FPFV): Feb  2020 
Last Patient First Visit (LPFV): Feb  2022 
Follow-up: 2 years (from the enrollment of the last patient) 
Total Study Duration: 4 years approximately 

Sponsor: Consorzio Oncotech 
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9  
DATA MANAGEMENT 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable laws and 
regulations. The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant information. 
Access to the system will be controlled by a sequence of individually assigned user identification codes and 
passwords, made available only to authorized personnel who have completed prerequisite training. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Sponsor personnel (or 
designated CRO) will review the protocol and CRFs with the investigators and their staff. During the study, 
the field monitor will visit the site regularly to check the completeness of patient records, the accuracy of 
entries on the CRFs, the adherence to the protocol to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted according to specifications. 
Key study personnel must be available to assist the field monitor during these visits.  
The investigator must maintain source documents for each patient in the study, consisting of case and visit 
notes (hospital or clinic medical records) containing demographic and medical information, laboratory 
data, electrocardiograms and the results of any other tests or assessments.  
All information recorded on CRFs must be traceable to source documents in the patient's file. The 
investigator must also keep the original signed informed consent form (a signed copy is given to the 
patient). The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. The Sponsor monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation of SAEs, 
AESIs, pregnancies and special situations. 
9.3 
Data collection 
This study will use an Electronic Data Capture (EDC) system (eClinical platform provided by Clinical 
Research Technology). The designated investigator staff will enter the data required by the protocol into 
the Electronic Case Report Forms (eCRF). The eCRFs have been built using eClinical platform provided 
by Clinical Research Technology, a fully validated secure web- enabled software that conforms to FDA 
requirements. Investigator site staff will not be given access to the EDC system until they have been 
trained. Automatic validation programs check for data discrepancies in the eCRFs allow modification or 
verification of the entered data by the investigator staff. The Principal Investigator is responsible for 
assuring that the data entered into eCRF is complete, accurate, and that entry and updates are performed in 
a timely manner. 
9.4 
Database management and quality control 
The Sponsor personnel (or designated CRO) will review the data entered by investigational staff for 

Sponsor: Consorzio Oncotech 
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completeness and accuracy. Electronic data queries stating the nature of the problem and requesting 
clarification will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries and to make any 
necessary changes to the data. Concomitant treatments entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. The occurrence of any protocol violations will be 
determined. After the data has been verified to be complete and accurate, the database will be declared 
locked. Authorization is required prior to making any database changes to locked data, by joint written 
agreement between the Biostatistics and Data Management and the Sponsor. 

Sponsor: Consorzio Oncotech 
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10 
PROTOCOL ADHERENCE 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no circumstances 
should the investigator contact the Sponsor, if any, monitoring the study to request approval of a protocol 
deviation, as no authorized deviations are permitted. If the investigator feels a protocol deviation would 
improve the conduct of the study this must be considered a protocol amendment, and unless such an 
amendment is agreed upon by the Sponsor and approved by the IEC it cannot be implemented. 
Any change or addition to the protocol can only be made in a written protocol amendment that must be 
approved by the Sponsor, Health Authorities where required, and the IEC. Only amendments that are 
required for patient safety may be implemented prior to IEC approval. Notwithstanding the need for 
approval of formal protocol amendments, the investigator is expected to take any immediate action 
required for the safety of any patient included in this study, even if this action represents a deviation from 
the protocol. In such cases, the Sponsor should be notified of this action and the IEC at the study site 
should be informed within 10 working days. 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
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11 
PUBLICATION POLICY 
After completion of the study, the Principal Investigator will prepare a draft manuscript containing final 
results of the study on the basis of the statistical analysis. The manuscript will be delivered to the co-
authors for comments and after revision will be sent to a major scientific journal. 
All publications, abstracts, presentations, manuscripts and slides including data from the present study will 
be submitted to and reviewed by all the other Investigators and the Steering Committee for coordination 
and homogeneity purposes: specific advance periods for submission and review may be specified in the 
protocol.  
The timing of publications (in the event several Centers should be participating in the Study) may be 
coordinated, and publication delayed if patentable inventions should be involved (for the time required in 
order to file the relevant patent applications); otherwise, according to the Ministry of Health’s Decree of 
May 12, 2006, investigators cannot be precluded from or limited in publishing the results of their studies 
(IECs must verify that no excessive restriction is contained in the protocols submitted to their review and 
approval). 

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12 
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APPENDIX 1: Response Evaluation Criteria in Solid Tumors: Modified Excerpt from Original 
Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 
(Eisenhauer et al. 2009) are presented below, with slight modifications and the addition of explanatory text 
as needed for clarity. 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows: 
Measurable Tumor Lesions 
Tumor Lesions. Tumor lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of:  
 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (CT/MRI scan 
slice thickness/interval no greater than 5 mm) 
 10-mm caliper measurement by clinical examination (lesions that cannot be accurately measured 
with calipers should be recorded as non-measurable)  
 20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph node must 
be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. See 
also notes below on “Baseline Documentation of Target and Nontarget Lesions” for information on lymph 
node measurement. 
Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by reproducible 
imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions treated with local therapy require particular comment, as outlined 
below. 

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Bone lesions: 
 Bone scan, positron emission tomography (PET) scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to confirm 
the presence or disappearance of bone lesions. 
 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 or MRI can be considered 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 Cystic lesions thought to represent cystic metastases can be considered measurable lesions if they 
meet the definition of measurability described above. However, if noncystic lesions are present in 
the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such lesions 
would be considered measurable. 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 weeks 
before the beginning of the treatment. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during study. Imaging-based evaluation should always be the preferred 
option. 
Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). 
For the case of skin lesions, documentation by color photography, including a ruler to estimate the size of 

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the lesion, is suggested. 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. 
CT, MRI. CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable. 
If prior to enrolment it is known that a patient is unable to undergo CT scans with intravenous (IV) contrast 
due to allergy or renal insufficiency, the decision as to whether a noncontrast CT or MRI (without IV 
contrast) will be used to evaluate the patient at baseline and during the study should be guided by the 
tumour type under investigation and the anatomic location of the disease. For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to whether noncontrast CT 
or MRI (enhanced or nonenhanced) will be performed should also be based on the tumour type and the 
anatomic location of the disease and should be optimized to allow for comparison with the prior studies if 
possible. Each case should be discussed with the radiologist to determine if substitution of these other 
approaches is possible and, if not, the patient should be considered not evaluable from that point forward. 
Care must be taken in measurement of target lesions on a different modality and interpretation of nontarget 
disease or new lesions since the same lesion may appear To have a different size using a new modality. 
Ultrasound. Ultrasound is not useful in the assessment of lesion size and should not be used as a method 
of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The utilization of these techniques for 
objective tumor evaluation cannot generally be advised. 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE DISEASE 
To assess objective response or future progression, it is necessary to estimate the overall tumor burden at 
baseline and to use this as a comparator for subsequent measurements. Measurable disease is defined by 
the presence of at least one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NONTARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a   maximum of five lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline. This means in instances where patients 
have only one or two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded. Other lesions (albeit measurable) in those organs will be recorded as 
non-measurable lesions (even if the size is > 10 mm by CT scan). 

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Target lesions should be selected on the basis of their size (lesions with the longest diameter) and be 
representative of all involved organs, but additionally, should lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be visible by 
imaging even if not involved by tumor. As noted above, pathological nodes that are defined as measurable 
and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only 
the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported 
as two dimensions in the plane in which the image is obtained (for CT scan, this is almost always the axial 
plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is 
the short axis. For example, an abdominal node that is reported as being 20 mm X 30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered nontarget lesions. Nodes that have a short axis < 10 mm are considered nonpathological and 
should not be recorded or followed. A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. If 
lymph nodes are to be included in the sum, then, as noted above, only the short axis is added into the sum. 
The baseline sum of diameters will be used as a reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as nontarget 
lesions and should also be recorded at baseline. Measurements are not required and these lesions should be 
followed as “present,” “absent,” or in rare cases “unequivocal progression.” 
In addition, it is possible to record multiple nontarget lesions involving the same organ as a single item on 
the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response for target 
lesions. 
 Complete response (CR): disappearance of all target lesions Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to < 10 mm. 
 Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters 
 Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (nadir), including baseline In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The 
appearance of one or more new lesions is also considered progression. 

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 Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum on study 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if the 
nodes regress to < 10 mm on study. This means that when lymph nodes are included as target lesions, the 
sum of lesions may not be zero even if CR criteria are met since a normal lymph node is defined as having 
a short axis < 10 mm. 
Target Lesions That Become Too Small to Measure. While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are recorded as target 
lesions at baseline become so faint on the CT scan that the radiologist may not feel comfortable assigning 
an exact measure and may report them as being too small to measure. When this occurs, it is important that 
a value be recorded on the CRF as follows: 
 If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 
 If the lesion is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned and below measurable limit (BML) should be ticked. (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph 
node is believed to be present and is faintly seen but too small to measure, a default value of 5 
mm should be assigned in this circumstance as well and BML should also be ticked.) To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if it 
is below 5 mm, and, in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment.  
When non-nodal lesions fragment, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If the 
lesions have truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the coalesced lesion. 
Evaluation of Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the group of 
nontarget lesions. While some nontarget lesions may actually be measurable, they need not be measured 
and, instead, should be assessed only qualitatively at the timepoints specified in the protocol. 
 CR: disappearance of all nontarget lesions and (if applicable) normalization of tumor marker 
level) All lymph nodes must be non-pathological in size (< 10 mm short axis). 

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Date: November 20th, 2019 
 
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 Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
 PD: unequivocal progression of existing nontarget lesions The appearance of one or more new 
lesions is also considered progression. 
Special Notes on Assessment of Progression of Nontarget Disease 
When the Patient Also Has Measurable Disease. 
In this setting, to achieve unequivocal progression on the basis of the nontarget disease, there must be an 
overall level of substantial worsening in nontarget disease in a magnitude that, even in the presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy. A modest increase in the size of one or more nontarget lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of change in 
nontarget disease in the face of SD or PR of target disease will therefore be extremely rare. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not attributable to 
differences in scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor (for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions). This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic 
lesion, which it is not. A lesion identified during the study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression. If a new lesion is equivocal, for 
example because of its small size, continued therapy and follow-up evaluation will clarify if it represents 
truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan. 
EVALUATION OF RESPONSE 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. 
Table A provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore nontarget) disease only, Table B is to be used. 
Table A Timepoint Response: Patients with Target Lesions (with or without Nontarget Lesions) 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
Non-CR/non-PD 
No 
No 
CR 
PR 

Sponsor: Consorzio Oncotech 
Investigational Drug Substance: atezolizumab 
EudraCT number: 2019-001388-55 
GIM25-CAPT Clinical Study Protocol - Version Number 1.0 
Date: November 20th, 2019 
 
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CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
Not evaluated 
Non-PD or Not all 
evaluated 
Non-PD or Not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
 
No 
 
No 
Yes or no 
Yes or no 
Yes 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
CR =complete response; NE=not evaluable; PD=progressive disease; PR=partial response; SD=stable 
disease 
 
Table B Timepoint Response: Patients with Nontarget Lesions Only 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
Non-CR/non-PD 
Not evaluated 
Unequivocal PD 
Any 
No 
No 
No 
Yes or no 
Yes or no 
CR 
Non-CR/non-PD 
NE 
PD 
PD 
 
 
Missing Assessments and Not-Evaluable Designation 
 
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable at that 
timepoint. If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered not evaluable at that timepoint, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned timepoint response. This would be most 
likely to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and, during the study, only two lesions were assessed, but those gave a sum of 80 mm, 
the patient will have achieved PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or the scan could not 
be assessed because of poor image quality or obstructed view, the response for target lesions should be 
“unable to assess” since the patient is not evaluable. Similarly, if one or more nontarget lesions are not 
assessed, the response for nontarget lesions should be “unable to assess” except where there is clear 
progression. Overall response would be “unable to assess” if either the target response or the nontarget 
response is “unable to assess,” except where this is clear evidence of progression as this equates with the 
case being not evaluable at that timepoint.