Clinical trial NCT04793399
Conditions: Chronic Phase-Chronic Myeloid Leukemia
Sponsor: Fundacion Espanola para la Curacion de la Leucemia Mieloide Cronica
Start date: 2021-02-24; Completion date: 2021-09-24
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The combination of bosutinib plus atezolizumab in first line treatment in newly diagnosis chronic-phase Chronic Myeloid Leukemia (CML) patients could potentially increase molecular responses and therefore treatment discontinuation probabilities in these patients. We propose an Open-Label Phase Ib/II Study of Bosutinib in Combination with Atezolizumab for the Treatment of New Diagnosis Chronic Phase-Chronic Myeloid Leukemia Patients.

Detailed description:
The combination of bosutinib and atezolizumab in first line treatment in newly diagnosis chronic-phase Chronic Myeloid Leukemia (CML) patients could potentially increase molecular responses and consequently treatment discontinuation probabilities in these patients. We would like to propose an Open-Label Phase Ib/II Study of Bosutinib in Combination with Atezolizumab for the Treatment of New Diagnosis Chronic Phase-Chronic Myeloid Leukemia Patients.

Arms: arm 1: Drugs to be administered:

Bosutinib 400 milligram (mg)/day Oral Tablet \[Bosulif 100mg oral tablets\] for 1 year Atezolizumab 1680 mg/28 days \[Tecentriq 840 MG in 14 ML Injection\] for 1 year
Interventions: intervention 1: Bosutinib 400 MG Monotherapy intervention 2: Bosutinib 400 MG + Atezolizumab 840 MG in 14 ML Injection
Intervention descriptions: intervention 1: One cycle (28 days) only with bosutinib 400 mg/day therapy at the beginning of the trial + 12 cycles with bosutinib 400 mg/day therapy after combined therapy intervention 2: 12 cycles with bosutinib 400 mg/day plus atezolizumab 1680 mg q4w therapy between the monotherapy bosutinib cycles

Protocol documents:
Prot_000.pdf: 
Confidential 
 
Page 1 of 100 
 
 
 
 
Multicenter, open-label, Phase Ib/II trial to evaluate safety and efficacy for the 
combination of bosutinib plus atezolizumab in newly diagnosed chronic myeloid 
leukemia patients 
 
 
Protocol Number: ZEROLMC-01 
Study Phase: 
Ib/II 
Products Name: 
Bosutinib (Bosulib®, Pfizer) and  
Atezolizumab (Tecentriq®, Roche Registration GMBH) 
EudraCT Number: 
2020-000166-41 
Sponsor: 
 Fundación ZeroLMC (Fundación Española para la curación de la Leucemia 
Mieloide Crónica) 
 
Plaza San Francisco, S/N, portal 13, planta 1, puerta 5 
 
50006 Zaragoza 
Protocol Issue Date: May 05th, 2021 
Version Number: 
2.0 
 
 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 2 of 100 
PROTOCOL REVISION HISTORY 
Protocol Version 
AMENDMENT RATIONALE 
Changes To The Protocol 
Version 1.1 (13/11/2020) 
Responses to clarifications requested 
by the Ethics Committee 
Section 11.6.2.12 Systemic Immune 
activation. Management of grade 4 adverse 
reactions have been changed to:  
Permanently discontinue atezolizumab and 
contact the Sponsor. 
Consider referring to an immunologist for 
evaluation 
Consider treatment with 
methylprednisolone, or equivalent, or the 
best way of treatment according to the 
physician's judgement 
 
Version 1.2 (02/12/2020) 
Responses to clarifications requested 
by AEMPS 
 Section 9.3.1 Group 1: The first 10 patients 
and Study Design (Protocol Synopsis). “At 
the investigator discretion is deleted from 
the definition to eliminate subjective 
criteria to DLT. definition. It is specified 
that DLTs will be graded according to the 
NCI CTCAE. 
 High-efficacy birth control methods of 
inclusion criteria 7.c. are adjusted 
according to CTFG Recommendations. 
 Test pregnancy each month during the 
study is added into the section 12.7, 
section 13.14, and tables 14, 15, 16 and 17. 
 Section 15.5 Sample Size Calculation and 
Statistical Analysis within the protocol 
synopsis are updated to make clear that it 
is expected that 15% of the 36 patients 
that will be included will not enter in 
bosutinib and atezolizumab combination 
treatment and, therefore, approximately 
30 subjects will be evaluated for the 
combination. References to previous 
studies have been added. 
 The sentence “Women of childbearing 
potential must have a negative pregnancy 
test documented prior enrollment.” Has 
been added to the inclusion criteria 
number 7 within the protocol summary. 
 Definition of women of childbearing 
potential has been rewritten in section 
10.2 Inclusion criteria, to match CTFG 
recommendations. Reference has been 
added. 
Version 2.0 (05/May/2021) 
Recently the AEMPS have granted the 
authorization of commercialization of 
the 400 mg tablets in Spain, and could 
be used for the purposes of this trial 
 Section 11.1 study treatments: Bosutinib 
(Bosulif® 400 mg film-coated tablets, Pfizer 
S.L.U.) is added to the study drugs. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 3 of 100 
Protocol Version 
AMENDMENT RATIONALE 
Changes To The Protocol 
reducing the number of tablets that 
the patients will have to take each 
day.  
Correction of minor typographic 
mistakes 
 Section 11.2.1 Bosutinib Treatment: The 
possibility that only 1 tablet of 400 mg 
could be prescribed to the patients is 
included. 
 Section 11.3.1 Bosutinib treatment: Tablets 
containing 400 mg of Bosutinib as active 
ingredient are included in this section 
 Table 14,  
o 
Header. 860 mg of Atezolizumab is 
corrected to the right concentration, 
840 mg. 
o 
Visit 2, 4 and 6: eliminate the 
pregnancy test from these visits. 
 Tables 15 and 17: assessments for 4th 
Phase is corrected to assessments for 3rd 
Therapy 
 Section 12.17 Pregnancy Test: Include the 
possibility to conduct the pregnancy test 
during visit 1, before drug administration. 
 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 4 of 100 
TABLE OF CONTENTS 
List of tables .............................................................................................................................. 9 
List of Figures ............................................................................................................................ 9 
1 
SIGNATURE PAGES ...................................................................................................... 10 
1.1 
Sponsor Signature Page .................................................................................................. 10 
1.2 
Investigator Signature .................................................................................................... 11 
2 
CONTACT INFORMATION ............................................................................................ 12 
3 
ABBREVIATIONS ......................................................................................................... 13 
4 
DEFINITION OF TERMS ................................................................................................ 17 
5 
PROTOCOL SYNOPSIS .................................................................................................. 19 
6 
BACKGROUND ............................................................................................................ 25 
6.1 
Chronic Myeloid Leukemia: Pathogenesis and Treatment ................................................ 25 
6.2 
Overview of Bosutinib .................................................................................................... 25 
6.3 
Overview of Atezolizumab .............................................................................................. 27 
7 
STUDY RATIONALE AND PURPOSE............................................................................... 28 
8 
STUDY OBJECTIVE ....................................................................................................... 30 
8.1 
Primary Objective ........................................................................................................... 30 
8.2 
Secondary Objectives ..................................................................................................... 30 
9 
STUDY DESIGN ............................................................................................................ 30 
9.1 
Patient Screening ........................................................................................................... 34 
9.2 
First therapy................................................................................................................... 34 
9.3 
Second Therapy .............................................................................................................. 34 
9.3.1 
Group 1: The first 10 patients .......................................................................................... 34 
9.3.2 
Group 2: The next 26 patients ......................................................................................... 35 
9.4 
Third Therapy ................................................................................................................. 35 
9.5 
Withdrawal criteria ........................................................................................................ 35 
10 POPULATION .............................................................................................................. 36 
10.1 Patient Population ......................................................................................................... 36 
10.2 Inclusion Criteria ............................................................................................................ 36 
10.3 Exclusion Criteria ............................................................................................................ 37 
11 TREATMENT ............................................................................................................... 39 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 5 of 100 
11.1 Study Treatment ............................................................................................................ 39 
11.2 Treatment Administration .............................................................................................. 39 
11.2.1 Bosutinib Treatment ........................................................................................................ 39 
11.2.2 Atezolizumab Treatment.................................................................................................. 40 
11.3 Formulation, Packaging, and Labeling ............................................................................. 40 
11.3.1 Bosutinib Treatment ........................................................................................................ 40 
11.3.2 Atezolizumab Treatment.................................................................................................. 40 
11.4 Treatment Storage, Dispensing, and Accountability ......................................................... 41 
11.4.1 Bosutinib Treatment ........................................................................................................ 41 
11.4.2 Atezolizumab Treatment.................................................................................................. 41 
11.5 Treatment Duration ....................................................................................................... 42 
11.6 .Dose Modification and Dose Delay ................................................................................ 42 
11.6.1 Dose reduction steps for bosutinib .................................................................................. 43 
11.6.2 Dose reduction steps for atezolizumab ........................................................................... 45 
11.7 Disposition of Used Supplies ........................................................................................... 57 
11.8 Inventory of Unused Supplies ......................................................................................... 57 
12 VISIT SCHEDULE AND ASSESSMENTS ........................................................................... 58 
12.1 Schedule of Events ......................................................................................................... 58 
12.2 Screening Period Procedures .......................................................................................... 65 
12.3 Eligibility Screening ........................................................................................................ 65 
12.4 Information to Be Collected on Screening Failures ........................................................... 65 
12.5 Medical/Surgical History and Demographics ................................................................... 65 
12.6 Recent Medication Prior to First IMP Dose ...................................................................... 66 
12.7 Leukemia Diagnosis and Prior Cancer Therapy................................................................. 66 
12.8 Sokal Risk Score ............................................................................................................. 66 
12.9 Vital Signs ...................................................................................................................... 66 
12.10 Height and Weight ......................................................................................................... 67 
12.11 Electrocardiogram .......................................................................................................... 67 
12.12 Physical Examination and Extra-medullary Leukemia Involvement .................................. 68 
12.13 Eastern Cooperative Oncology Group (ECOG) Performance Status ................................... 68 
12.14 Blood Samples for BCR-ABL Molecular Response Assessment .......................................... 69 
12.15 Laboratory Evaluations ................................................................................................... 70 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 6 of 100 
12.15.1 Complete Blood Count (CBC) With Differential ............................................................... 70 
12.15.2 Chemistry ......................................................................................................................... 70 
12.15.3 Serology ............................................................................................................................ 71 
12.16 Bone Marrow Analysis and Cytogenetics ......................................................................... 71 
12.17 Pregnancy Test ............................................................................................................... 71 
12.18 Inmunological Studies .................................................................................................... 72 
12.19 Adverse Events and Concomitant Medications ................................................................ 72 
12.20 End of Treatment or Early Termination Procedures ......................................................... 73 
12.21 End of Study. Follow-up Safety Procedures ..................................................................... 73 
12.22 Biological Samples Treatment after the End of the Study ................................................. 73 
13 ADVERSE EFFECTS REPORTING .................................................................................... 74 
13.1 AE Definition .................................................................................................................. 74 
13.2 Abnormal Test Findings .................................................................................................. 75 
13.3 Performing AE Assessment ............................................................................................. 75 
13.4 Reporting Period ............................................................................................................ 75 
13.5 AE Severity ..................................................................................................................... 76 
13.6 Causality ........................................................................................................................ 76 
13.7 Expectedness ................................................................................................................. 77 
13.8 SAEs ............................................................................................................................... 77 
13.9 Adverse Event of Special Interest (AESI) Definition .......................................................... 78 
13.9.1 Adverse Event of Special Interest .................................................................................... 78 
13.10 Information to Be Provided by the Investigator for a SAE or AESI ..................................... 79 
13.11 Follow-up Information on a SAE or AESI .......................................................................... 80 
13.12 Required Follow-up for SAEs or AESIs.............................................................................. 80 
13.13 Expedited Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)........ 80 
13.14 Contraception and Pregnancy ......................................................................................... 81 
13.15 Overdose, medication error, abuse, misuse ..................................................................... 81 
14 CO-TREATMENT AND TREATMENT SUPPLY .................................................................. 82 
14.1 Prior and Concomitant Treatment................................................................................... 82 
14.2 Permitted Treatment ...................................................................................................... 82 
14.3 Prohibited Treatments/Therapy ..................................................................................... 82 
15 PLANNED STATISTICAL ANALYSIS ................................................................................ 83 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 7 of 100 
15.1 Analysis Sets .................................................................................................................. 83 
15.1.1 Full Analysis Set ................................................................................................................ 83 
15.1.2 Safety Set ......................................................................................................................... 83 
15.1.3 Per-Protocol Set ............................................................................................................... 83 
15.2 Patient Demographics/other Baseline Characteristics...................................................... 83 
15.3 Primary Objective ........................................................................................................... 83 
15.3.1 Analysis Set and Grouping for the Analyses..................................................................... 84 
15.3.2 Adverse Events ................................................................................................................. 84 
15.3.3 Laboratory Abnormalities ................................................................................................ 84 
15.3.4 Other Safety Data ............................................................................................................. 85 
15.3.5 Immunological Analysis .................................................................................................... 85 
15.4 Secondary objectives ...................................................................................................... 85 
15.4.1 Secondary efficacy variables: ........................................................................................... 85 
15.4.2 Analyses Methods for Secondary Objectives ................................................................... 86 
15.5 Sample Size Calculation .................................................................................................. 86 
16 QUALITY CONTROL AND QUALITY ASSURANCE ............................................................ 87 
16.1 Investigators and Study Administrative Structure ............................................................ 87 
16.2 Study Monitoring ........................................................................................................... 87 
17 ETHICAL CONDUCT OF THE STUDY ............................................................................... 88 
17.1 Institutional Review Board or Ethics Committee Approval ............................................... 88 
17.2 Patient Information and Consent .................................................................................... 88 
17.3 Patient Confidentiality.................................................................................................... 89 
17.4 Publication of the Study Protocol and Results ................................................................. 89 
17.5 Study Documentation ..................................................................................................... 89 
17.6 Confidentiality of Study Documents ................................................................................ 90 
17.7 Audits and Inspections ................................................................................................... 90 
17.8 Financial Disclosures ...................................................................................................... 90 
17.9 Protocol Adherence ........................................................................................................ 90 
17.10 Amendments to the Protocol .......................................................................................... 90 
18 DATA HANDLING AND RECORD KEEPING ..................................................................... 91 
18.1 Case Report Forms and Study Records ............................................................................ 91 
18.2 Access to Source Documentation: Data Confidentiality .................................................... 91 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 8 of 100 
18.3 Site Monitoring .............................................................................................................. 92 
18.4 Data Collection ............................................................................................................... 92 
18.5 Database Management and Quality Control .................................................................... 92 
18.6 Retention of Data ........................................................................................................... 93 
18.7 Termination of Study ...................................................................................................... 93 
19 REFERENCES ............................................................................................................... 94 
APPENDIX A: Drug-induced QT prolongation and Torsades de Pointes ............................... 98 
APPENDIX B: National Cancer Institute Common Terminology Criteria for Adverse Events100 
 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 9 of 100 
List of tables 
Table 1. Non-Hematologic Treatment-Related Toxicities ................................................................... 43 
Table 2. Hematologic Treatment-Related Toxicity .............................................................................. 44 
Table 3. Management Guidelines for Pulmonary Events, including pneumonitis .............................. 46 
Table 4. Management Guidelines for Hepatic Events ......................................................................... 46 
Table 5. Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) ........................... 47 
Table 6. Management Guidelines for Endocrine Events ..................................................................... 48 
Table 7. Management Guidelines for Ocular Events ........................................................................... 50 
Table 8. Management Guidelines for Immune-Related Myocarditis .................................................. 51 
Table 9. Management Guidelines for Pancreatic Events, Including Pancreatitis ................................ 52 
Table 10. Management Guidelines for Dermatologic Events .............................................................. 53 
Table 11. Management Guidelines for Neurologic Disorders, Including Meningoencephalitis.......... 53 
Table 12. Management Guidelines for Immune-Related Nephritis .................................................... 55 
Table 13. Systemic Immune Activation ................................................................................................ 55 
Table 14. Schedule of Assessments 1st and 2nd Therapies for the First 10 Patients ............................ 59 
Table 15. Schedule of Assessments 4th Phase for the first 10 patients .............................................. 61 
Table 16: Schedule of Assessments 3rd Phase for Other 26 Patients .................................................. 62 
Table 17. Schedule of assessments 4th Phase for Other 26 patients ................................................. 64 
Table 18: Sokal Formulation ................................................................................................................ 66 
Table 19. ECOG Performance Status Scale .......................................................................................... 68 
 
List of Figures 
Figure 1. Chronogram of the study ...................................................................................................... 32 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 10 of 100 
1 SIGNATURE PAGES 
1.1 
Sponsor Signature Page 
Fundación Zero LMC has approved this protocol and assures that this study will be conducted 
according to all stipulations of the protocol, including all statements regarding confidentiality. 
 
 
 
 
 
 
 
Name 
   
 
        Signature  
     Date (dd-mmm-yyyy) 
 
 
 
 
 
 
 
 
Name 
   
 
     Signature 
 
      Date (dd-mmm-yyyy) 
 
 
 
 
 
 
 
 
Name 
   
 
        Signature  
       Date (dd-mmm-yyyy) 
 
 
 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 11 of 100 
1.2 
Investigator Signature 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will follow this protocol as outlined therein, including all statements regarding 
confidentiality. I will make a reasonable effort to complete the study within the designated time. I will 
provide copies of the protocol and access to all information furnished by the sponsor to study personnel 
under my supervision. I will discuss this material with them to ensure they are fully informed about the 
study drug and the study. I understand that the study may be terminated or enrollment suspended at 
any time by the sponsor, with or without cause, or by me if it becomes necessary to protect the best 
interests of the study subjects. 
I agree to conduct this trial in compliance with the protocol, GCP and the applicable regulatory 
requirement(s). 
 
 
 
 
 
 
 
 
 
 
Investigator’s Name 
 Investigator’s Signature              Date (dd-mmm-yyyy) 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 12 of 100 
2 CONTACT INFORMATION 
Sponsor 
Fundación Española para la Curación de la Leucemia
Mieloide Crónica (Fundación Zero LMC) 
Plaza San Francisco, S/N, portal 13, planta 1, puerta 5 
50006 Zaragoza 
Spain 
Telephone: +34 976 306 420 
Sponsor Medical Monitor: 
Ignacio Galicia, Clinical Pharmacologist, MD 
Head of the Clinical Investigation Department 
Fundación Teófilo Hernando 
Telephone: +34 - 636 849 505 
E-mail: ignacio.galicia@ifth.es 
Sponsor Monitor: 
Aurelio Morales Guerrero CRA  
Fundación Teófilo Hernando 
Telephone: +34 – 911 923 700  
E-mail: aurelio.morales@ifth.es 
Coordinating Investigator: 
Dr J Valentín García Gutiérrez 
Scientific Expert 
Servicio Hematología y Hemoterapia 
Hospital Ramón y Cajal 
E-mail: jvalentingg@gmail.com  
Sponsor Pharmacovigilance and 
Risk Management 
Clinical Investigation Department 
Fundación Teófilo Hernando 
Telephone : +34 – 911 923 700 
E-mail: farmacovigilancia@ifth.es  
 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 13 of 100 
3 ABBREVIATIONS 
Abbreviation 
Definition 
2GTKIs 
2nd Generation Tyrosine Kinase Inhibitors 
ABL 
Abelson leukemia oncogene 
AC 
Accelerated Phase 
ACTH 
Adrenocorticotropic Hormone 
AE  
Adverse Event 
AEMPS 
Agencia Española de Medicamentos y Productos Sanitarios 
AESI 
Adverse Event of Special Interest 
ALT  
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT 
ANC  
Absolute Neutrophil Count 
AP  
Accelerated Phase 
AST  
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT 
AUC  
Area Under the Curve 
BAL 
Bronchoalveolar lavage 
BC  
Blast Crisis 
BCR  
Break point Cluster Region 
BCR-ABL  
BCR-ABL oncoprotein product of BCR-ABL fusion gene 
BM 
Bone Marrow 
BP 
Blast Phase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
CCAA 
Comunidades Autónomas (Autonomous Communities)  
CCyR  
Complete Cytogenetic Response 
CEIm 
Ethics committees for investigation with medicinal products. 
CHF 
Congestive Heart Failure 
CHR  
Complete Hematologic Response 
CIB  
Clinical Investigator’s Brochure 
CML  
Chronic Myeloid Leukemia 
CMR  
Complete Molecular Response 
CP  
Chronic Phase 
CP-CLM 
Chronic phase Chronic Myeloid Leukemia 
CRA  
Clinical Research Associate 
CRF  
Case Report/Record Form; the term CRF can be applied to either EDC or paper 
CRO 
Clinical Research Organisation 
CRP 
C-Reactive Protein  
CSP  
Clinical Study Protocol 
CSR  
Clinical Study Report 
CT 
Computed Tomography 
CTA 
Clinical Trial Assistant 
CTCAE  
NCI Common Terminology Criteria for Adverse Events 
CV  
Coefficient of Variation 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 14 of 100 
Abbreviation 
Definition 
CYP3A4  
Cytochrome 3A4 
CyR 
Cytogenetic Response 
DLT 
Dose-Limiting Toxicity 
EC  
European Commission 
eCFR 
Electronic Case Report Form 
ECG  
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
Electronic Case Report/record Form 
EDC  
Electronic Data Capture 
ELN  
European Leukemia Net 
EMA  
European Medicines Agency 
EOS  
End of Study 
EOT  
End of Treatment 
ESR  
Expedited Safety Report 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration (USA) 
FISH  
Fluorescent In-Situ Hybridization 
FPFV 
First Patient First Visit 
FTH 
Fundación Teófilo Hernando 
GCP  
Good Clinical Practice 
GELMC 
Grupo Español de Leucemia Mieloide Crónica 
GGT 
Gamma-glutamil transpeptidase 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonization 
IEC  
Independent Ethics Committee 
IFN  
Interferon 
IL-2 
Interleukin-2 
IM 
Imatinib 
IMP 
Investigational Medicinal Product 
IRB  
Institutional Review Board 
IRR 
Infusion-Related Reaction 
IS  
International Scale 
IUD 
IntraUterine Device 
IUS 
IntraUterine System 
IV 
Intravenous 
IVIG 
Intravenous Immunoglobulin 
Kg 
Kilogram 
LFT 
Liver Function Test 
LN 
Lymph Node 
LPLV 
Last Patient Last Visit 
LVEF 
Left Ventricular Ejection Fraction 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 15 of 100 
Abbreviation 
Definition 
MCyR  
Major Cytogenetic Response 
MCyR 
Minor Cytogenetic Response 
MDSC 
Myeloid Derived Suppressor Cells 
MedDRA  
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MMR  
Major Molecular Response 
MR  
Molecular Response 
MR4  
Molecular Response 4.0 log reduction from baseline 
MR4.5  
Molecular Response 4.5 log reduction from baseline 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
N/A 
Not Applicable 
NCCN  
National Comprehensive Cancer Network 
n-TEAE 
No Treatment Emerged Adverse Event 
NYHA 
New York Heart Association 
OD 
Once Daily 
OS  
Overall Survival 
PCR  
Polymerase Chain Reaction 
PCyR  
Partial Cytogenetic Response 
PD-L1 
Programmed Death-ligand 1 
PFS  
Progression Free Survival 
Ph+  
Philadelphia chromosome 
PHI  
Protected Health Information 
PPS  
Per-Protocol Set 
Pts 
Patients 
Q2WK 
Every 2 weeks 
QD  
Once a Day 
QT 
QT interval; a measure of the time between the start of the Q wave and the 
end of the T wave in the heart's electrical cycle 
QTcF 
QT interval corrected (Fridericia)  
REB  
Research Ethics Board 
REec 
Registro Español de Estudios Clínicos 
RP3D 
Recommended Phase III Dose 
RR 
Relative Risk 
RT-qPCR 
Real Time-Quantitative Reverse Transcription PCR 
SAE  
Serious Adverse Event 
SD  
Standard Deviation 
SOP 
Standard Operating Procedure 
SS  
Safety Set 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TBil 
Total Bilirubin 
TEAE 
Treatment Emerged Adverse Event  


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 16 of 100 
Abbreviation 
Definition 
TFR  
Treatment-Free Remission 
TFS  
Treatment-Free Survival 
TKI  
Tyrosine Kinase Inhibitor 
Treg 
Regulatory T cells 
TSH 
Thyroid Stimulating Hormone 
ULN  
Upper Limit of Normal 
VAD 
Ventricular Assist Device 
VOE 
Vascular Occlusive Event 
WBC  
White Blood Cell 
WHO 
World Health Organization 
 
 
 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 17 of 100 
4 DEFINITION OF TERMS 
Assessment 
A procedure used to generate data required by the study. 
Accelerated Phase (AP) 
 ≥ 15% blasts in the peripheral blood or bone marrow aspirate, but < 
30% blasts in both the peripheral blood and bone marrow aspirate; 
 ≥ 30% blasts plus promyelocytes in peripheral blood or bone 
marrow aspirate; 
 ≥ 20% basophils in the peripheral blood; 
 Thrombocytopenia (<100 x 109/L) that is unrelated to therapy. 
Blast Crisis (BC) 
≥ 30% blasts in peripheral blood or bone marrow aspirate 
Appearance 
of 
extra 
medullary 
involvement 
other 
than 
hepatosplenomegaly proven by biopsy (i.e., chloroma). 
Complete Hematologic Response (CHR) 
• Complete normalization of peripheral blood counts with leukocyte 
count <10 x 109/L 
• Platelet count <450 x 109/L 
• No immature cells, such as myelocytes, promyelocytes, or blasts in 
peripheral blood 
• No signs and symptoms of disease with disappearance of palpable 
splenomegaly 
Complete Molecular Response (CMR) 
Undetectable BCR-ABL levels with high sample sensitivity (10-5 or greater) 
for a minimum of 2 years. 
Cytogenetic Response (CyR) 
 
Complete (CCyR): 0% Ph+ metaphases. 
 
Partial (PCyR): > 0 to 35% Ph+ metaphases. 
 
Minor (mCyR): >35 to 65% Ph+ metaphases. 
 
Minimal: >65 to 95% Ph+ metaphases. 
 
None: > 95 to 100% Ph+ metaphases. 
Cycle of treatment 
28 days of treatment 
Disease Progression 
The following events are considered disease progression: 
 
AP. 
 
BC. 
 
CML-related death. 
Enrollment 
It is the time until all patients are included in the study, i.e. all patients 
received at least one dose of study medication. Previously they must have 
signed an informed consent (i.e., prior to starting any of the procedures 
described in the protocol). 
Full Analysis Set (FAS) 
The full analysis set (FAS) comprises all patients who complete the 
treatment with bosutinib in combination with atezolizumab for 12 cycles 
successfully. 
Medicinal product for Human Use or 
Investigational Drug 
Any substance or combination of substances presented as having 
properties for treating or preventing disease in human beings or which 
may be used in or administered to human beings either with a view to 
restoring, correcting or modifying physiological functions by exerting a 
pharmacological, immunological or metabolic action, or to making a 
medical diagnosis (Royal Decree 1090/2015, of 4 December). 
Loss of Complete Hematologic Response 
Loss of CHR is defined as the appearance of any of the following, 
confirmed by a second determination ≥ 4 weeks later (unless 
associated with progression to AP/BC or CML-related death): 
 WBC count that rises to > 20.0 x 109/L; 
 Platelet count that rises to ≥ 600 x 109/L; 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 18 of 100 
 Progressing hepatosplenomegaly to a size ≥ 5 cm below the left 
intercostal margin; 
 Appearance of ≥ 5% myelocytes + metamyelocytes in the 
peripheral blood; 
 Appearance of blasts or promyelocytes in the peripheral blood. 
Molecular Response (MR) 
 
MMR – BCR-ABL ≤ 0.1% (IS). 
 
MR4 – BCR-ABL ≤ 0.01% (IS). 
 
MR4.5 ≤ 0.0032% (IS). 
 
UNDETECTABLE. 
Overall Survival (OS) 
OS is calculated from the first day of therapy to the date of death. 
Surviving patients will be censored at the time of the last follow-up. 
Subject Number 
A unique identifying number assigned to each patient who enrolls (i.e. 
signs the IC) in the study. 
Per-Protocol Set (PPS) 
A subset of the full analysis set (FAS) who is compliant with the clinical 
study protocol (i.e. Composed by subjects that have not incurred in major 
protocol deviations that could jeopardize the validity of the data and the 
study outcomes). 
Premature Patient Withdrawal 
When a subject exits from the study prior to the planned completion of 
all study treatment administration and/or assessments or procedures. 
From this time, all study treatment administration is discontinued and no 
further assessments or procedures will be done, other than the 
monitoring for progression and/or survival. 
Progression Free Survival (PFS) 
Progression free survival (PFS) is defined as the time from the date of first 
treatment administration until the time of disease progression. Subjects 
who die without a reported progression will be considered to have 
progressed on the date of their death. Subjects who do not progress nor 
die will be censored on the date of their last hematological assessment. 
Safety Set (SS) 
Composed by all subjects who received at least one dose of study 
medication. 
Study Treatment 
Includes any drug or combination of drugs in any study arm 
administered to the subject as part of the required study procedures. 
Trial Subject 
An individual who participates in a clinical trial, either as recipient of an 
investigational medicinal product or as a control. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points. 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 19 of 100 
5 PROTOCOL SYNOPSIS 
Sponsor 
Fundación Española para la Curación de la Leucemia Mieloide Crónica (Fundación Zero 
LMC) 
Plaza San Francisco, S/N, portal 13, planta 1, puerta 5 
50006 Zaragoza 
Spain 
Telephone: +34 976 306 420 
Study Treatment 
Bosutinib and Atezolizumab 
Study Title 
Multicenter, Open-Label, Phase Ib/II Clinical Trial to Evaluate Safety and Efficacy for the 
Combination of Bosutinib plus Atezolizumab in newly diagnosed Chronic Myeloid 
Leukemia Patients 
Phase 
Phase Ib/II 
Eligible Population 
Naïve patients with chronic-phase Chronic Myeloid Leukemia (CP-CML) 
Summary 
and 
Study 
Rationale  
Since the introduction of imatinib and subsequent second-generation tyrosine kinase 
inhibitors (2GTKIs), the prognosis of chronic-phase Chronic Myeloid Leukemia (CP-CML) 
has improved greatly. Initially considered a lethal disease with a median estimated overall 
survival (OS) of 3.2 years, CP-CML is now regarded as a chronic disease with a life 
expectancy similar to that of the healthy population. However, Chronic Myeloid Leukemia 
(CML) patients, despite their treatment response, cannot be considered cured and must 
take the treatment indefinitely. 
Recently, data from different clinical trials have shown how a minority of patients who 
achieve and maintain a deep molecular response with imatinib, could discontinue the 
treatment safely. Therefore, treatment free remission (TFR) has been established as a new 
goal for CML patients. However, at this moment, TFR is only available for a small group of 
patients, since deep molecular response is achieved in 5 years only in approximately 20% 
of patients treated with imatinib, and, unfortunately, 50% of patients will eventually 
relapse. In addition, recent data have shown how a time exposure to imatinib longer than 
7 years can be a prognostic factor for TFR. Starting treatment with 2GTKIs  (dasatinib, 
nilotinib and bosutinib) has demonstrated higher probabilities of deep molecular 
responses. 
Suppression of the immune system in CML patients at diagnosis is mediated in part by 
hematopoietic stem cells, which acquire a proliferative/survival advantage and lose the 
ability to undergo apoptosis. Release of tumor-derived cytokines/chemokines drives the 
expansion of immune suppressor MDSC and Treg, facilitating downregulation of antitumor 
effector immunity. PD-L1 is upregulated on CML cells, where it interacts with the co-
inhibitory receptor PD-1, and contributes to protection of the malignant cells from 
immune destruction. MDSC originate from the malignant BCR-ABL1 clone and mediate 
their suppressive activity via a number of mechanisms, including increased production of 
reactive oxygen and nitrogen species (NO, ROS), arginase-1, and TGF-β1. MDSC can induce 
Treg expansion, and Treg also express PD-1 to promote enhanced suppressor function. We 
know how PD-1 is expressed on T cells at diagnosis in CML patients, and that its expression 
decreases considerablyafter achieving deep molecular response. The combination of TKI 
plus interferon has resulted into higher probabilities of deep molecular responses 
compare to TKI monotherapy in several clinical trials. 
It is also known how the immune system plays a crucial role in treatment free remission 
strategies. The lack of overt relapse in patients who have previously achieved a deep 
molecular response, despite the presence of very low levels of residual disease has been 
attributed to immunological control of CML. IFN/imatinib induction treatment followed 
by a temporary IFN maintenance may enable a higher rate of treatment discontinuation 
in CML patients in at least MMR when stopping. The TIGER study (NCT01657604) is 
currently investigating de-escalating maintenance therapy using low dose IFN as an 
inducer of immune surveillance following nilotinib discontinuation. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 20 of 100 
Upregulation of the immune checkpoint receptor PD-L1 and its receptors, PD-1 and B7.1, 
has been demonstrated in peripheral blood mononuclear cells from patients with CML. 
During the past 5 years, immune checkpoint inhibitors have revolutionized the 
management and treatment of cancer, because they have been associated with striking 
improvements in clinical outcomes in patients with some tumor types. 
Programmed death ligand 1 (PD-L1) is an immune-checkpoint protein expressed on tumor 
cells and tumor-infiltrating immune cells that downregulates antitumoral T-cell function 
through binding to programmed death 1 (PD-1) and B7.1 (also known as CD80) receptors. 
The engineered, humanized IgG1 monoclonal anti-PD-L1 antibody atezolizumab blocks 
PD-L1–PD-1 and PD-L1–B7.1 interactions, resulting in restoration of antitumor T-cell 
activity and enhanced T-cell priming. Blocking PD-L1–B7.1 binding on T cells and antigen-
presenting cells might additionally inhibit downregulation of immune responses, thus 
preventing inhibition of T-cell activation and cytokine production. Direct targeting of PD-
L1 leaves the PD-L2–PD-1 interaction intact, potentially avoiding effects on immune 
homoeostasis. Atezolizumab is engineered to eliminate binding to Fc receptors and 
prevent Fc-effector function. This modification eliminates antibody-dependent cell 
mediated cytotoxicity and thus avoids potential loss of PD-L1-expressing T-effector cells 
and reduced anticancer immunity. 
The combination of bosutinib plus atezolizumab in first line treatment in newly diagnosis 
chronic-phase CML patients would increase molecular responses and therefore TFR 
probabilities in these patients. 
We propose an Open-Label Phase Ib/II Study of Bosutinib in Combination with 
Atezolizumab for the Treatment of New Diagnosis Chronic Phase-Chronic Myeloid 
Leukemia Patients. 
Study Objectives 
Primary endpoint:  
Safety profile of bosutinib 400 mg daily in combination with atezolizumab in participants 
with chronic myeloid leukemia as first line treatments 
Secondary endpoints:  
• 
To evaluate the Major Molecular Response (MMR) and Molecular Response (MR) 
rates at 3, 6, 12 months and at the End of Treatment (EoT) visit.  
• 
Percentage of Participants Alive at Month 6, 12 and the EoT visit. 
• 
Number of confirmed MR4 and MR4.5 at end of treatment. 
• 
The rate of confirmed MR4 and MR4.5 at the end of treatment. 
• 
Number of Complete Cytogenetic Responses (CCyR) [Time Frame: At 1 year] 
• 
The rate of Complete Cytogenetic Response (CCyR) at 1 year. 
• 
Number of days to response (CCyR, MMR, MR4, MR4.5) [Time Frame: at the EoT 
visit] 
• 
The median time to response and the overall estimated probability of response 
(CCyR, MMR, MR4, MR4.5). 
• 
Number of overall surviving patients [Time Frame: at the EoT visit] 
• 
Number of progression-free survival patients [Time Frame: at the EoT visit] 
• 
Number of failure-free survival patients [Time Frame at the EoT visit] 
• 
Number of event-free survival patients [Time Frame: at the EoT visit] 
• 
Immunological Studies 
Study Design 
This is a phase Ib/II, simple arm, open-label and dose-escalation study designed to 
determine the safety profile and the recommended phase III dose (RP3D) of bosutinib 
when administered in combination with atezolizumab in naïve patients with chronic 
myeloid leukemia in chronic phase. 
 
The patients will be divided in two groups, with different start points, and will have three 
different therapy combinations during the study, which are described below. The first 10 
patients included in the study will begin first. If at least 9 of these patients do not suffer 
DLTs during the first 2 cycles of the combined treatment (bosutinib 400 mg/day plus 
atezolizumab 840 mg every two weeks), the following 26 patients will be included, 
otherwise, the study will be terminated. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 21 of 100 
 
First therapy 
All patients included, both the first 10 patients and the next 26 patients, will receive 
bosutinib 400 mg/day in monotherapy for one cycle. All patients who tolerate this cycle 
of bosutinib treatment will continue to the second therapy (bosutinib plus atezolizumab). 
 
 
Second Therapy 
*Group 1: The first 10 patients included 
Only for the first ten patients included in the study, atezolizumab will be introduced at a 
dose of 840 mg every two weeks combined with 400 mg/day of bosutinib for 2 cycles (8 
weeks). These patients will be closely monitored for safety issues.  
If dose-limiting toxicities (DLTs) appear in 2 or more patients the study will end. If no 
relevant safety issues regarding the combination of drugs is detected the study will 
continue. 
These initial 10 patients will cross-over from bosutinib 400 mg/day plus atezolizumab 840 
mg every 2 weeks to bosutinib 400 mg/day plus atezolizumab 1680 mg every 4 weeks for 
10 cycles (40 weeks). 
 
*Group 2: The next 26 patients included 
After receiving bosutinib 400 mg/day in monotherapy for one cycle (1st therapy), the last 
26 patients included will receive bosutinib 400 mg/day plus atezolizumab 1680 mg every 
4 weeks for 12 cycles.  
 
Patients will be closely monitoring. If DLTs appear in 2 or more patients at a dose of 1680 
mg of Atezolizumab every 4 weeks, the dose of atezolizumab will be reduced for all 
patients to an 840 mg Atezolizumab every 2 weeks dose. 
 
All patients completing 12 treatment cycles (48 weeks) will begin the last therapy of study.  
 
- 
Third Therapy 
All patients completing cycle 12 with the combined bosutinib plus atezolizumab therapy 
will continue with bosutinib 400 mg/day in monotherapy for 12 more cycles.  
 
A DLT would include either of the following adverse events occurring during of the 
bosutinib/atezolizumab therapy and that is considered at least possibly related to 
bosutinib and/or atezolizumab: 
• Grade 4 neutropenia (<500/l) persisting for >7 day duration or Grade 4 white cell 
count decrease for >7 day duration (<1000/l). 
• Febrile neutropenia (ANC<1000/l and fever ≥38.5°C). 
• Grade 4 thrombocytopenia >48 hour duration or with bleeding requiring platelet 
transfusion. 
• Any Grade 3 or 4 clinically evident non-hematological toxicity 
• Any ≥Grade 3 toxicity that requires >14 days to resolve (to ≤Grade 1 despite optimal 
medical therapy). 
DTLs will be graded according to the NCI CTCAE, v5.0. 
Diagnosis and Main 
Inclusion Criteria 
Patients must fulfill the following criteria to be eligible for the study: 
1. Male or female patient ≥ 18 years of age. 
2. Evidence of a personally signed and dated informed consent document indicating 
that the patient (or a legal representative) has been informed of all pertinent 
aspects of the study. 
3. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 22 of 100 
4. Newly Patient with Philadelphia chromosome positive chronic phase CML and 
BCR-ABL1 transcript detected at diagnosis. 
5. ECOG Performance Status of 0, 1, or 2. 
6. Adequate hepatic, renal and pancreatic function defined as: 
a. Total bilirubin within normal range or Direct bilirubin ≤ 1.5 x ULN, 
b. Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤2.5 
x upper limit of normal (ULN) or ≤5 x ULN if attributable to liver 
involvement of leukemia, 
7. Women of childbearing potential must have a negative pregnancy test 
documented prior enrollment. Women of childbearing potential and men must 
be using an adequate method of contraception. 
Exclusion Criteria 
Patients eligible for inclusion in the study must not fulfill the following exclusion criteria: 
1. 
Pregnant or lactating women, 
2. 
Participation in another clinical trial with any investigational drug within 30 days 
prior to study enrollment, 
3. 
Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), 
with the exception of hydroxyurea, 
4. 
Period of time since CML diagnosis longer than 6 months, 
5. 
Hypersensitivity to the active substances or to any of the excipients of the 
bosutinib and/or atezolizumab formulations, 
6. 
Major surgery or radiotherapy within 14 days of enrollment, 
7. 
Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease, 
8. 
Concomitant use of or need for medications known to prolong the QTc interval, 
9. 
Concomitant use with strong CYP3A inhibitors (ketoconazole, itraconazole, 
clarithromycin), moderate CYP3A inhibitors (erythromycin, fluconazole, 
diltiazem), or strong CYP3A inducers (rifampin, carbamazepine, phenytoin), 
10. History of clinically significant or uncontrolled cardiac disease, including:  
a. Stage II to IV congestive heart failure (CHF) as determined by the New 
York Heart Association (NYHA) classification system for heart failure.  
b. Myocardial infarction within the previous 6 months, 
c. 
Symptomatic cardiac arrhythmia requiring treatment, 
d. Diagnosed or suspected congenital or acquired prolonged QT history or 
prolonged QTc. (QTcF should not exceed 500 msec), 
11. Grade III or IV fluid retention, 
12. Uncontrolled hypomagnesemia or uncorrected symptomatic hypokalemia, due 
to potential effects on the QTc interval, 
13. Uncontrolled or symptomatic hypercalcemia, 
14. Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. Crohn's 
Disease, Ulcerative Colitis or prior total or partial gastrectomy, 
15. Autoimmune or infectious active disease that require treatment, 
16. CML patient not in chronic phase at diagnosis, 
17. Patients with known atypical transcript. An atypical transcript is defined by the 
presence of any transcript in the absence of the major transcripts b3a2 (e14a2) 
and b2a2 (e13a2) or p210 protein, 
18. Patients with known resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V). It 
is not necessary to perform mutation tests on the patient to be included in the 
study if they were not previously performed, 
19. Individuals with an active malignancy, 
20. Known seropositivity to human immunodeficiency virus (HIV), current acute or 
chronic hepatitis B (hepatitis B surface-antigen positive) and/or hepatitis C. 
21. Any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that contraindicates the use of an investigational drug.  
22. Patients with severe renal impairment 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 23 of 100 
Number of Patients 
36 patients of both genders 
Approximate Duration 
of Patient Participation 
Approximately two years with treatment (25 cycles of 28 days). 
Approximate Duration 
of Study 
The estimated duration of the clinical trial is approximately 36 months, including 12 
months for enrollment and 26 cycles of treatment/follow-up. 
Approximate Number of 
Study Centers 
Up to 10 centers; national (Spain). 
Dosage Administration 
Group 1: The first 10 patients: 
1. One cycle only with bosutinib 400 mg/day therapy. 
2. 2 cycles with bosutinb 400 mg/day plus atezolizumab 840 mg q2w therapy. 
3. 10 cycles with bosutinb 400 mg/day plus atezolizumab 1680 mg q4w therapy. 
4. 12 cycles with bosutinib 400 mg/day therapy. 
Group 2: The next 26 patients: 
1. One cycle only with bosutinib 400 mg/day therapy. 
2. 12 cycles with bosutinb 400 mg/day plus atezolizumab 1680 mg q4w therapy. 
3. 12 cycles with bosutinib 400 mg/day therapy. 
Efficacy Evaluation 
Hematologic response rate, cytogenetic response rate, molecular response rate, and 
disease progression will be assessed according to standard criteria, as follows: 
 
Bone marrow aspirates for assessment of cytogenetic response every 3 months 
after initiating bosutinib treatment. After complete cytogenetic response (CCyR) has 
been achieved, only if there is suspicion of disease progression,  
 
BCR-ABL assessment to determine molecular response every 3 months after 
initiating bosutinib treatment, 
 
Complete blood count (CBC) for assessment of hematologic response every 3 
months, 
 
Survival follow-up. 
Safety Evaluation 
Safety assessments will include physical and laboratory examinations. AEs will be graded 
according to the NCI CTCAE, v5.0. 
 
All patients receiving at least 1 dose of bosutinib will be considered evaluable for safety. 
The AE and VOE incidence rates, as well as the frequency of occurrence of overall toxicity 
-categorized by toxicity grades (severity). Listings of laboratory test results will also be 
generated, and descriptive statistics summarizing the changes clinically significant in 
laboratory tests over time will be presented. 
Statistical Analysis 
Statistical analysis and number of patients planned: There will be no formal calculation of 
the sample size for the study. The sample size is selected to allow sufficient data collection 
for the DLT and safety assessment. The minimum number of patients for the DLT 
evaluation will be 10 if no DLT is observed. After MTD is calculated, 26 more patients will 
be recruited for the dose escalation phase. 36 patients (both, a first group of 10 patients 
and a second of 26 patients) will receive bosutinib 400 mg/day in monotherapy during one 
cycle of treatment. According to previous experience (Tim H Brümmendorf et al, 2015; 
Jorge E cortes. el al, 2018), we assume that, at most, 15% of the patients included will not 
enter the dose escalation phase after the first month of treatment with bosutinib, due to 
side effects. Consequently, a total of 30-31 patients will receive the combination of 
bosutinib plus atezolizumab. Data will be analyzed using descriptive statistics. Continuous 
variables will be summarized using the number of observations, mean, standard deviation 
(SD), coefficient of variation, median and range as appropriate. The categorical values will 
be summarized using the number of observations and percentage as appropriate. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 24 of 100 
This plan is extensively detailed in “PLANNED STATISTICAL ANALYSIS” of the project. 
Study timelines 
The first patient first visit (FPFV) is planned for September 2020 and the recruitment 
period is planned to last 1 year. The data cutoff date will be the date of the last patient 
last visit (LPLV).  
Rationale for Number of 
Patients 
This is a single-arm exploratory study. 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 25 of 100 
6 BACKGROUND 
6.1 
Chronic Myeloid Leukemia: Pathogenesis and Treatment 
Chronic Myeloid Leukemia (CML) is a hematological stem cell disorder associated with a specific 
chromosomal translocation known as the Philadelphia (Ph) chromosome; it is found in 95% of 
patients (Nowell and Hungerford 1960; Rowley 1973). The translocation consists in the fusion 
of the ABL proto-oncogene with the BCR gene, resulting in the production of an activated form 
of the ABL protein-tyrosine kinase (Bartram et al, 1983; Heisterkamp et al, 1983). Expression 
of the BCR-ABL protein causes leukemia in mice, suggesting this protein is linked to disease 
pathogenesis (Daley et al, 1990; Kelliher et al, 1990). 
Clinically, CML progresses through three distinct phases of increasing refractoriness to therapy: 
chronic phase (CP) (median duration 3-4 years; median survival up to 10 years with allogenic 
bone marrow transplant and 5-6 years with interferon (IFN), accelerated phase (AP) (median 
duration 3-9 months; median survival 8-18 months), and blast crisis (BC) (median survival 3-6 
months) (Enright & McGlave 2000). Most patients suffer the CP form, which is characterized by 
splenomegaly and leukocytosis with generally few symptoms. 
National Comprehensive Cancer Network (NCCN) guideline on CML (NCCN guideline v1.2019) 
(Radich, 2018) and European Leukemia Net (ELN) (Steegmann et al, 2016) recommend 
continuing tyrosine kinase inhibitor (TKI) treatment (i.e., imatinib, nilotinib, dasatinib, 
ponatinib, bosutinib) indefinitely in all responding patients. Treatment discontinuation may be 
considered in individual patients, also outside studies, if proper, high-quality, and certified 
monitoring can be ensured at monthly intervals. 
Imatinib (IM) rapidly became the gold standard therapy in CML that dramatically changed the 
prognosis of the disease (Druker et al., 2006). More potent second-generation tyrosine-kinase 
inhibitors (TKI) have been consecutively developed to counteract resistance to IM in a 
substantial proportion of patients such as dasatinib, nilotinib, bosutinib and ponatinib. Efficacy 
of second and third generation TKIs was first shown in second-line therapy for patients 
intolerant or resistant to IM. Superiority of dasatinib and nilotinib over IM was thereafter 
demonstrated in first-line therapy (DASISION and ENESTnd phase III trials), in terms of 
achievement of complete cytogenetic response (CCyR) at 12 months and an increased rates of 
major molecular responses (MMR) and deep molecular responses (Fujisawa S et al., 2014; 
Larson RA et al., 2012). 
6.2 
Overview of Bosutinib 
Bosutinib is an oral, once-daily, second-generation tyrosine kinase inhibitor, with a 
manageable and distinct safety profile. Bosutinib exhibits dose-proportional increases in 
exposure between 200 and 600 mg, and its absorption increases with food. It has extensive 
tissue distribution, is highly bound to plasma proteins, and is primarily metabolized in the liver 
by cytochrome P450 (CYP) 3A4. Hepatic and renal impairment increases the exposure to 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 26 of 100 
bosutinib. Metabolic drug–drug interactions of bosutinib are limited in scope to CYP3A 
inhibitors and inducers but are significant in their extent. Coadministration of bosutinib with 
strong or moderate CYP3A inhibitors or inducers should be avoided (Abbas, 2016). 
Bosutinib is used for the treatment of chronic phase (CP), accelerated phase (AP), and blast 
phase (BP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML) 
previously treated with one or more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, 
nilotinib and dasatinib are not considered appropriate treatment options (EMA, 2019). 
This indication for bosutinib is based principally on the results of an open-label, single-arm, 
multicenter, phase 1/phase 2 study in adults with chronic, accelerated, or blast phase CML 
following therapy with either imatinib alone or imatinib followed by dasatinib and/or nilotinib; 
patients were intolerant of or had a disease that was resistant to imatinib. In this study, 546 
patients received bosutinib 500 mg once daily (increased to 600 mg daily if complete 
hematologic or cytogenetic response was not achieved by week 8 or 12, respectively). The 
median duration of therapy with bosutinib was 22 months in patients with chronic phase CML 
previously treated with only imatinib; patients previously treated with imatinib followed by 
dasatinib and/or nilotinib received therapy with bosutinib for a median duration of 8 months 
(EMA, 2019; FDA, 2019). 
At the time of data analysis, patients with chronic phase CML previously treated with imatinib 
alone or imatinib followed by dasatinib and/or nilotinib had been followed for at least 23 or 13 
months, respectively. The primary efficacy end point of this study was major cytogenetic 
response (defined as elimination or substantial reduction [by at least 65%] of Ph+ 
hematopoietic cells) at 24 weeks. In this study, resistance to imatinib was defined as failure to 
achieve or maintain any hematologic improvement within 4 weeks of therapy; or failure to 
achieve a complete hematologic response by 3 months, a cytogenetic response by 6 months, 
or a major cytogenetic response by 12 months; or disease progression after a previous 
cytogenetic or hematologic response; or evidence of the genetic mutation in the Bcr-Abl gene 
associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate 
imatinib because of toxicity, or disease progression with imatinib and inability to receive a 
higher dosage because of toxicity. Definitions of resistance and intolerance to both dasatinib 
and nilotinib were similar to those for imatinib. Major cytogenetic response was achieved at 
24 weeks in 34% of patients in chronic phase CML who were previously treated with imatinib 
alone and in 27% of those previously treated with imatinib followed by dasatinib or nilotinib. 
At the time of data analysis, median durations of response had not been reached. Disease 
progression (i.e., transformation from chronic phase to accelerated or blast phase CML) 
occurred in 4.3% of patients with chronic phase CML. In an exploratory analysis, treatment 
with bosutinib resulted in confirmed complete hematologic responses at 48 weeks in 30 or 
15% of patients in accelerated or blast phase CML, respectively; the median duration of 
therapy with bosutinib for these patients previously treated with at least imatinib who were in 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 27 of 100 
the accelerated or blast phase of the disease was 10 or 3 months, respectively (EMA, 2019; 
FDA, 2019). 
More recently, bosutinib was also authorized in adult patients with newly‑diagnosed chronic 
phase (CP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML) 
(EMA, 2019) based on the results obtained in the BFORE study (Cortes, 2018a). In this study 
bosutinib was compared with imatinib in 536 newly diagnosed CML patients in the ‘chronic 
phase’. The main measure of effectiveness was the number of patients who had a ‘major 
molecular response’. After one year of treatment, 47% (116 out of 246) of patients treated 
with bosutinib had a major molecular response, compared with 37% (89 out of 241) of patients 
treated with imatinib. 
Diarrhea is the most frequent side effect related to bosutinib in clinical trials (80% any grade, 
<10% 
of 
grade 
3–4). 
This 
side-effect 
is 
usually 
well-managed 
with 
dose 
reductions/interruptions, since <1% of the patients treated with bosutinib in the BEFORE study 
discontinued treatment due to diarrhea (Cortes, 2012; Cortes, 2018b). In general, pleural 
effusion is a rare complication in bosutinib treated patients. However, patients who had 
pleural effusion while on dasatinib and later received bosutinib treatment had a high risk of 
recurrence of this complication (Gambacorti, 2018). Cardiac and vascular toxicity have been 
evaluated in bosutinib treated patients enrolled in clinic al trials showing a good safety profile. 
Similar incidences were observed with bosutinib (first or later lines) or comparing to imatinib 
treated patients (Cortes, 2016). A decrease in the glomerular filtration rate has been observed 
with long-term exposure to bosutinib. Renal AEs were reported in 73/570 patients (13%) 
receiving bosutinib as a second-line or later treatment, and in 22/248 (9%) receiving bosutinib 
as first-line treatment (Cortes, 2017). 
6.3 
Overview of Atezolizumab 
Atezolizumab is a monoclonal antibody targeting programmed death ligand 1 (PD-L1 or CD274 
antigen). PD-L1 is thought to play an important role in suppressing the immune system 
triggered by disease, by reducing the proliferation of antigenspecific CD8+ T-cells and 
controlling the accumulation of foreign antigen-specific T-cells. Up-regulation of PD-L1 has 
been suggested as a mechanism used by cancer cells to evade the host immune system 
(Markham, 2016). Atezolizumab has been approved in Europe (EMA, 2019) as monotherapy is 
for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma 
(UC): 
 after prior platinum containing chemotherapy, or 
 who are considered cisplatin ineligible, and whose tumours have a PD-L1 expression ≥ 
5%. 
Also, in combination with bevacizumab, paclitaxel and carboplatin, atezolizumab is indicated 
for the first-line treatment of adult patients with metastatic non-squamous non small cell lung 
cancer (NSCLC). In patients with EGFR mutant or ALK-positive NSCLC, atezolizumab, in 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 28 of 100 
combination with bevacizumab, paclitaxel and carboplatin, is indicated only after failure of 
appropriate targeted therapies. 
Atezolizumab as monotherapy is indicated for the treatment of adult patients with locally 
advanced or metastatic NSCLC after prior chemotherapy. Patients with EGFR mutant or ALK 
positive NSLCLC should also have received targeted therapy before receiving atezolizumab. 
Atezolizumab at a dose of 1–20 mg/kg produced a dose-proportional increase in exposure to 
the drug. Typical clearance was 0.20 L/day, volume of distribution at steady state was 6.9 L, 
and the terminal half-life was 27 days, according to a population analysis of patients in the 
dose range (n = 472). This population analysis also suggested steady state occurs after 6–9 
weeks treatment (2–3 dosage cycles). Systemic accumulation in terms of area under the 
plasma concentration time curve (AUC), maximum concentration (Cmax) and trough 
concentration (Cmin) was 1.91, 1.46 and 2.75-fold, respectively. The systemic exposure to 
atezolizumab was not significantly affected when analysed according to patient age, body-
weight, gender, positive anti-therapeutic antibody status, albumin levels, tumour burden, 
region or race, mild or moderate renal impairment, mild hepatic impairment, level of PD-L1 
expression, or Eastern Cooperative Oncology Group (ECOG) performance status. The potential 
for atezolizumab to interact with other drugs is unknown (Markham, 2016; EMA, 2019). 
Major common AEs involved fatigue, decreased appetite, nausea, diarrhea, pyrexia, pruritus, 
cough, edema peripheral, and rash. The most common severe AEs were fatigue, anemia, and 
dyspnea. 
The 
overall 
atezolizumab-related 
death 
rate 
was 
much 
lower 
than 
chemotherapeutics-related death rate. Atezolizumab has better overall survival and lower risk 
of AEs compared with chemotherapy (Tie, 2019).  
7 STUDY RATIONALE AND PURPOSE 
Since the introduction of imatinib and subsequent second generation tyrosine kinase inhibitors 
(2GTKIs), the prognosis of chronic-phase Chronic Myeloid Leukemia (CP-CML) has improved 
greatly. Initially considered to be a lethal disease with a median estimated overall survival (OS) 
of 3.2 years, CP-CML is now regarded as a chronic disease with a life expectancy similar to that 
of the healthy population. However, CML patients, despite their treatment response, cannot 
be considered cured and should take the treatment indefinitely.  
Recently, data from different clinical trials have shown how a minority of patients who achieve 
a deep molecular response with imatinib and maintain the response, could stop treatment 
safety. Therefore, treatment free remission (TFR) has been established as a new goal for CML 
patients. However, currently, TFR is only available for a small group of patients since deep 
molecular response is achieved by 5 years only in approximately 20% of patients treated with 
imatinib, and unfortunately, 50% of patients will eventually relapse. In addition, recent data 
have shown a time exposure to imatinib longer than 7 years as a prognostic factor for TFR. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 29 of 100 
Starting treatment with 2GTKIS (dasatinib, nilotinib and bosutinib) have demonstrated higher 
probabilities of deep molecular responses. 
Suppression of the immune system in CML patients at diagnosis is mediated in part by 
hematopoietic stem cells, which acquire a proliferative/survival advantage and lose the ability 
to undergo apoptosis. Release of tumor-derived cytokines/chemokines drives the expansion of 
immune suppressor MDSC and Treg, facilitating downregulation of antitumor effector 
immunity. PD-L1 is upregulated on CML cells, where it interacts with the co-inhibitory receptor 
PD-1, and contributes to protection of the malignant cells from immune destruction. MDSC 
originate from the malignant BCR-ABL1 clone and mediate their suppressive activity via a 
number of mechanisms, including increased production of reactive oxygen and nitrogen 
species (NO, ROS), arginase-1, and TGF-β1. MDSC can induce Treg expansion, and Treg also 
express PD-1 to promote enhanced suppressor function. We know how PD-1 is expressed at 
diagnosis in CML patients on T cells, and that its expression considerable decreases after 
achieving deep molecular response. The combination of TKI plus interferon has translated into 
higher probabilities of deep molecular responses compared to TKI monotherapy in several 
clinical trials. 
It is also known how the immune system plays a crucial role in treatment free remission 
strategies. The lack of overt relapse in patients who have previously achieved a deep molecular 
response, despite the presence of very low levels of residual disease has been attributed to 
immunological control of CML. IFN/imatinib induction treatment followed by a temporary IFN 
maintenance may enable a higher rate of treatment discontinuation in CML patients in at least 
MMR when stopping. The TIGER study (NCT01657604) is currently investigating de-escalating 
maintenance therapy using low dose IFN as an inducer of immune surveillance following 
nilotinib discontinuation. 
Upregulation of the immune checkpoint receptor PD-L1 and its receptors, PD-1 and B7.1, has 
been demonstrated in peripheral blood mononuclear cells from patients with CML. 
During the past 5 years, immune checkpoint inhibitors have revolutionized the management 
and treatment of cancer, because they have been associated with striking improvements in 
clinical outcomes in patients with some tumor types. 
Programmed Death Ligand 1 (PD-L1) is an immune-checkpoint protein expressed on tumor cells 
and tumor-infiltrating immune cells that downregulates antitumoral T-cell function through 
binding to programmed death 1 (PD-1) and B7.1 (also known as CD80) receptors. The 
engineered, humanized IgG1 monoclonal anti-PD-L1 antibody atezolizumab blocks PD-L1–PD-
1 and PD-L1–B7.1 interactions, resulting in restoration of antitumor T-cell activity and 
enhanced T-cell priming. Blocking PD-L1–B7.1 binding on T cells and antigen-presenting cells 
might additionally inhibit downregulation of immune responses, thus preventing inhibition of 
T-cell activation and cytokine production. Direct targeting of PD-L1 leaves the PD-L2–PD-1 
interaction intact, potentially avoiding effects on immune homoeostasis. Atezolizumab is 
engineered to eliminate binding to Fc receptors and to prevent Fc-effector function. This 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 30 of 100 
modification eliminates antibody-dependent cell mediated cytotoxicity and thus avoids 
potential loss of PD-L1-expressing T-effector cells and reduced anticancer immunity. 
The combination of bosutinib plus atezolizumab in first line CML chronic phase patients would 
increase molecular responses and therefore TFR probabilities in newly diagnosed CML patients. 
8 STUDY OBJECTIVE 
8.1 
Primary Objective 
The primary objective is to evaluate the safety profile of bosutinib 400mg/day in combination 
with atezolizumab as a first line treatment in participants with chronic phase-chronic myeloid 
leukemia. 
8.2 
Secondary Objectives 
 To evaluate the Major Molecular Response (MMR) and Molecular Response (MR) rates at 3, 
6, 12 months and at the End of Treatment (EoT) visit. Based on: 
o MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of ≤ 0.1% on the 
International Scale (IS) 
o Molecular Response (MR): As defined in section 4. Definition of Terms 
 Percentage of participants alive at months 6 and 12 and at the EoT visit. 
 Number of confirmed MR4 and MR4.5 at end of treatment. 
 The rate of confirmed MR4 and MR4.5 at the end of treatment. 
 Number of Complete Cytogenetic Responses (CCyR) at 1 year] 
 The rate of Complete Cytogenetic Response (CCyR) at 1 year. 
 Number of days to response (CCyR, MMR, MR4, MR4.5). [Time Frame: at the EoT visit] 
 The median time to response and the overall estimated probability of response (CCyR, MMR, 
MR4, MR4.5). 
 Number of overall surviving patients [Time Frame: at the EoT visit] 
 Number of progression-free survival patients.[Time Frame: at the EoT visit] 
 Number of failure-free survival patients. [Time Frame at the EoT visit] 
 Number of event-free survival patients. [Time Frame: at the EoT visit] 
 Immunological Studies 
9 STUDY DESIGN 
This is a phase Ib/II, two arms, open-label and dose-escalation study designed to determine the 
safety profile and the recommended phase III dose (RP3D) of bosutinib when administered in 
combination with atezolizumab in naïve patients with chronic myeloid leukemia in chronic 
phase. This study has two groups of patients (Figure 1). 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 31 of 100 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 32 of 100 
Figure 1. Chronogram of the study 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 33 of 100 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 34 of 100 
9.1 
Patient Screening 
This study will be conducted on those naïve patients with chronic-phase Chronic Myeloid 
Leukemia (CP-CML) who meet the established selection criteria (see below). The patients that 
sign the IC and meet the selection criteria will be selected to enter the study. 
Results of all screening evaluations must be reviewed by the Principal Investigator or his/her 
designee prior to the enrollment of a patient into the study to assure that all inclusion and none 
exclusion criteria have been satisfied. 
All study patients must be thoroughly informed about all aspects of the study, including the 
study visit schedule and required assessments for informed consent. The written informed 
consent must be obtained prior to any screening evaluations. If a patient is unable to read, an 
impartial witness should be present during the entire informed consent discussion. 
This is an open label clinical trial, and no randomization or blinding procedures are required. 
The patients will be divided in two groups, with different start points, and will have three 
different therapy combinations during the study, which are described below. The first 10 
patients included in the study will begin first. If at least 9 of these patients do not suffer DLTs 
during the first 2 cycles of the combined treatment (bosutinib 400 mg/day plus atezolizumab 
840 mg every two weeks), the following 26 patients will be included, otherwise, the study will 
be terminated. 
9.2 
First therapy 
All patients included, both the first 10 patients and the next 26 patients, will receive bosutinib 
400 mg/day in monotherapy during one cycle of treatment. All patients who tolerate this cycle 
of bosutinib treatment will continue to the second therapy (bosutinib plus atezolizumab). 
9.3 
Second Therapy 
9.3.1 Group 1: The first 10 patients 
Only for the first ten patients included in the study, atezolizumab will be introduced at a dose 
of 840 mg every two weeks combined with 400 mg/day of bosutinib for 2 cycles (8 weeks). 
These patients will be closely monitored for safety issues.  
If dose-limiting toxicities (DLTs) appear in 2 or more patients the study will end.  
A DLT would include either of the following adverse events that occurred during bosutinib 
therapy in combination with atezolizumab, if it is considered at least possibly related to 
bosutinib and/or atezolizumab: 
• 
Grade 4 neutropenia (<500/l) persisting for > 7 day duration or Grade 4 white cell 
count decrease for >7 day duration (<1000/l). 
• 
Febrile neutropenia (ANC<1000/l and fever ≥38.5°C). 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 35 of 100 
• 
Grade 4 thrombocytopenia > 48 hour duration or with bleeding requiring platelet 
transfusion. 
• 
Any Grade 3 or 4 clinically evident non-hematological toxicity. 
• 
Any ≥Grade 3 toxicity that requires >14 days to resolve (to ≤Grade 1 despite optimal 
medical therapy). 
DTLs will be graded according to the NCI CTCAE, v5.0. 
If no relevant safety issue, regarding the combination is detected the study will continue. 
These initial 10 patients will cross-over from bosutinib 400 mg/day plus atezolizumab 840 mg 
every 2 weeks to bosutinib 400 mg/day plus atezolizumab 1680 mg every 4 weeks for 10 cycles 
(40 weeks). 
9.3.2 Group 2: The next 26 patients 
After receiving bosutinib 400 mg/day in monotherapy for one cycle (1st therapy), the last 26 
patients included will receive bosutinib 400 mg/day plus atezolizumab 1680 mg every 4 weeks 
for 12 cycles. 
Patients will continue to be closely monitoring. If DLTs appear in 2 or more patients at a dose 
of 1680 mg of Atezolizumab every 4 weeks, the dose of atezolizumab will be reduced for all 
patients to an 840 mg Atezolizumab every 2 weeks dose. 
All patients completing 12 treatment cycles (48 weeks) will begin the last therapy of study. 
9.4 
Third Therapy 
All patients completing cycle 12 with bosutinib plus atezolizumab therapy will continue with 
bosutinib 400 mg/day in monotherapy for 12 more cycles. 
9.5 
Withdrawal criteria 
Patients may suspend their participation in the study whenever they wish, based on his/her 
own judgement and opinion, without giving any explanation, although the investigator may 
investigate the reasons of a voluntary dropout.  
The investigator may also decide to withdraw a patient from the trial if he/she does not comply 
with the protocol, due to AEs or treatment inefficacy or toxicity. 
Patients who do not comply with at least 70% of the scheduled doses of bosutinib or that, in 4 
or more times, the administration of atezolizumab is cancelled, will be withdrawn from the 
study. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 36 of 100 
10 POPULATION 
10.1 Patient Population 
The target population of this study includes naïve adult patients of both genders with chronic myeloid 
leukemia in chronic phase. 
10.2 Inclusion Criteria 
Patients eligible for inclusion in this study have fulfill the following criteria: 
1. 
Male or female patient ≥ 18 years of age. 
2. 
Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legal representative) has been informed of all pertinent aspects of the study. 
3. 
Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures 
4. 
Newly Patient with Philadelphia chromosome positive chronic phase CML and BCR-ABL1 
transcript detected at diagnosis. 
5. 
ECOG Performance Status of 0, 1, or 2. 
6. 
Adequate hepatic, renal and pancreatic function defined as: 
a. Total bilirubin within normal range or Direct bilirubin ≤ 1.5 x ULN, 
b. Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤2.5 x upper limit 
of normal (ULN) or ≤5 x ULN if attributable to liver involvement of leukemia, 
7. 
Have a negative pregnancy test documented prior to enrollment (for females of childbearing 
potential). A woman is considered of childbearing potential, i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy (CTFG, 
21/09/2020). These women, must have a negative serum or urine pregnancy test before 
initiation of study treatment and must also use highly effective methods of contraception 
while enrolled in the study. The use of highly effective contraception should continue for at 
least 14 days after the last dose of study treatment. Acceptable forms of highly effective 
contraception methods include (CTFG, 21/09/2020): 
a. Total abstinence [when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception]  
b. Male/female sterilization. These defined as: 
 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed and documented by follow-up hormone level assessment. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 37 of 100 
 
Male sterilization (at least 6 months prior to screening). For female patients on 
the study, study participation assumes the vasectomized male partner is the sole 
partner for that patient. 
c. Contraceptive methods: 
i. 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal or transdermal. 
ii. 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable or implantable. 
iii. 
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy with or without hysterectomy or tubal ligation at least six 
weeks prior to enrolling. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment is she considered not of child bearing potential.  
If a study patient gets pregnant or is suspected of being pregnant during the study or 
within 30 days as part of safety evaluations after the final dose of bosutinib, the study 
Doctor needs to be informed immediately and any ongoing study treatment with 
bosutinib has to be stopped immediately. 
10.3 Exclusion Criteria 
Patients eligible for this study must not fulfill the following criteria: 
1. Pregnant or lactating women, 
2. Participation in another clinical trial with any investigational drug within 30 days prior to study 
enrollment, 
3. Any prior medical treatment for CML including tyrosine kinase inhibitors (TKIs) with the 
exception of hydroxyurea, 
4. Period of time since CML diagnosis longer than 6 months, 
5. Hypersensitivity to the active substances or to any of the excipients of the bosutinib and/or 
atezolizumab formulations, 
6. Major surgery or radiotherapy within 14 days of enrollment, 
7. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, 
cirrhosis, and inherited liver disease, 
8. Concomitant use of or need for medications known to prolong the QT interval, 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 38 of 100 
9. Concomitant use with strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin), 
moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem), or strong CYP3A inducers 
(rifampin, carbamazepine, phenytoin), 
10. History of clinically significant or uncontrolled cardiac disease, including:  
a. Stage II to IV congestive heart failure (CHF) as determined by the New York Heart 
Association (NYHA) classification system for heart failure,  
b. Myocardial infarction within the previous 6 months, 
c. Symptomatic cardiac arrhythmia requiring treatment, 
d. Diagnosed or suspected congenital or acquired prolonged QT history or prolonged 
QTc. (QTcF should not exceed 500 msec.), 
11. Grade III or IV fluid retention, 
12. Uncontrolled hypomagnesemia or uncorrected symptomatic hypokalemia, due to potential 
effects on the QT interval, 
13. Uncontrolled or symptomatic hypercalcemia, 
14. Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. Crohn's Disease, 
Ulcerative Colitis or prior total or partial gastrectomy, 
15. Autoimmune or infectious active disease that require treatment, 
16. CML patient not in chronic phase at diagnosis, 
17. Patients with known atypical transcript. An atypical transcript is defined by the presence of 
any transcript in the absence of the major transcripts b3a2 (e14a2) and b2a2 (e13a2) or p210 
protein, 
18. Patients with known resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V). It is not 
necessary to perform mutation tests on the patient to be included in the study if they were 
not previously performed, 
19. Individuals with an active malignancy, 
20. Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic 
hepatitis B (hepatitis B surface-antigen positive) and/or hepatitis C, 
21. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding that contraindicates the use of an investigational drug, 
22. Patients with severe renal impairment. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 39 of 100 
11 TREATMENT 
11.1 Study Treatment 
Study treatments:  
Bosutinib (400 mg/day orally) 
 
 
Atezolizumab (840 mg q2wk or 1680 mg q4wk) 
Study drugs:  
Bosutinib (Bosulif® 100 mg film-coated tablets, Pfizer S.L.U.) 
 
 
Yellow oval (width: 5.6 mm; length: 10.7 mm) biconvex, film-coated 
tablet debossed with “Pfizer” on one side and “100” on the other 
side. Each tablet contains 100 mg bosutinib (as monohydrate). 
 
Bosutinib (Bosulif® 400 mg film-coated tablets, Pfizer S.L.U.) 
 
 
Orange oval (width: 8.8 mm; length: 16.9 mm) biconvex, film-coated 
tablet debossed with “Pfizer” on one side and “400” on the other 
side. Each tablet contains 400 mg bosutinib (as monohydrate). 
 
Atezolizumab (Tecentriq 840 mg concentrate for solution for infusion, Roche 
Registration GmbH) 
Bosutinib study drug will be provided by Pfizer Europe MA EEIG and Atezolizumab will be 
provided by Roche Registration GmbH. 
Patients will receive bosutinib at 400 mg/day orally. Bosutinib will be self-administered by the 
patient on a daily schedule.  
Atezolizumab should be given intravenously in the site. If the first infusion is tolerated 
(intravenously administration over 60 minutes), all subsequent infusions may be delivered over 
30 minutes. Patients will receive atezolizumab 840 mg q2w or 1680 mg q4w. Each 28-days (4 
weeks) is referred to as 1 cycle. 
Study treatments will be provided only to eligible patients at qualified centers. 
11.2 Treatment Administration 
11.2.1 Bosutinib Treatment 
Patients will take the prescribed 4 tablets of 100 mg or 1 tablet of 400 mg of bosutinib with 
water and food, at approximately the same time each day (preferably in the morning).  
Patients who forget to take their dose more than 12 hours after it is due, should not make up 
the missed dose. Any missing doses should be recorded, and subsequent training of patients 
should be documented in the appropriate source record (e.g. clinic chart). 
The day that atezolizumab is administered; the patients will take the corresponding dose of 
bosutinib after the administration of atezolizumab. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 40 of 100 
A diary card or equivalent where the date and time of administration will be recorded will be 
provided to the patients. 
11.2.2 Atezolizumab Treatment 
For the administration of atezolizumab the patient will go to the hospital, in scheduled visit, 
and will receive 840 mg or 1680 mg, the two therapeutic options available in this study. If the 
dose is 840 mg, the patient will receive atezolizumab 840 mg every 2 weeks in each cycle, at 
the beginning of the first day of the cycle, while if the dose is 1680 mg the patient will receive 
atezolizumab 1680 mg on the first day of cycle (every 4 weeks). The initial dose of atezolizumab 
must be administered over 60 minutes; if the first infusion is well tolerated, all subsequent 
infusions may be administered over 30 minutes. 
11.3 Formulation, Packaging, and Labeling 
11.3.1 Bosutinib Treatment 
Bosutinib investigational drug product is supplied as tablets. Each tablet contains either 100 mg 
or 400 mg of bosutinib as active ingredient. Other ingredients are typical pharmaceutical 
excipients: in tablet core [Microcrystalline cellulose (E460), Croscarmellose sodium (E468), 
Poloxamer 188, Povidone (E1201), Magnesium stearate (E470b)] and in film coating [Polyvinyl 
alcohol; Titanium dioxide (E171); Macrogol 3350; Talc (E553b); Iron oxide yellow (E172), Iron 
oxide red (E172) (only in the 400 mg tablets]. Tablets will be supplied as follows: 
 
White opaque 3-ply PVC/Polychlorotrifluoroethene/PVC blister sealed with push-through foil backing 
containing either 14 or 15 tablets per blister (2 blisters in each package). 
Carton labels will bear the appropriate label text as required by governing regulatory agencies. 
Such text will include, at least, product name, product strength, number of tablets, lot number 
and expiration date. 
Bosutinib will not be dosed by weight or body surface area.  
11.3.2 Atezolizumab Treatment 
Atezolizumab investigational drug product is supplied as a concentrate solution for infusion. Each 
vial of concentrate contains 840 mg of atezolizumab (Atezolizumab is an Fc-engineered, 
humanized IgG1 anti-programmed death-ligand 1 [PD-L1] monoclonal antibody produced in 
Chinese hamster ovary cells by recombinant DNA technology). Other ingredients are typical 
pharmaceutical excipients: L-histidine, Glacial acetic acid, Sucrose, Polysorbate 20, and Water for 
injections. Vials will be supplied as follows: 
 Vial of 840 mg: Type I glass vial with a butyl rubber stopper and an aluminum seal with a 
plastic, grey flip-off cap containing 14 mL of concentrate for solution for infusion. 
Carton and vial labels will bear the appropriate label text as required by governing regulatory 
agencies. At a minimum, such text will include product name, product strength, number of 
tablets, lot number and expiration date. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 41 of 100 
Atezolizumab will not be dosed by weight or body surface area. 
11.4 Treatment Storage, Dispensing, and Accountability 
All investigational treatment is to be stored in a secure locked area while under the 
responsibility of the principal investigator. An authorized person at the investigator’s site must 
record receipt and dispensing of investigational treatments. 
The study pharmacist or designee at the investigative site will be responsible for handling and 
dispensing study drug and completing associated documentary paperwork. 
The Investigator will confirm receipt of the investigational product in writing (date and storage 
conditions).  
Supplies will be shipped to the investigative site at appropriate intervals, depending on patient 
accrual. The site must use either an appropriate dispensing log/accountability form provided 
by the sponsor or an acceptable substitute. Each time study medication(s) is dispensed for a 
patient, the following information is recommended to be recorded: the patient’s study number, 
tablet and vial strength, the number of tablets (with the corresponding lot number) and vials 
dispensed, and the initials of the person dispensing the drug. These logs are to be maintained 
by the study investigator and will be periodically verified by a representative of the sponsor. 
The principal investigator is responsible for ensuring that the patient diary card(s) and study 
drug provided to the patient and returned from the patient are accounted for and noted in 
source documentation. 
The responsible CRA will check the drug supply for inventory purposes and to ensure proper 
storage at regular intervals throughout the study. 
11.4.1 Bosutinib Treatment 
The recommended storage condition for bosutinib is ≤ 30°C. 
Patients will receive bosutinib at 400 mg/day orally. Bosutinib will be self-administered by the 
patient on a daily schedule.  
The investigator will dispense the bosutinib to the patients every 3 cycles, starting at the time 
when the patient is included in the clinical trial. Patients will have sufficient medication to 
continue treatment until the next dispensed medication-visit is scheduled, even if it takes place 
out of visit the window of plus 14 days. Unused medication and empty blister cards should be 
returned to the site at dispensed medication-visits and will not be dispensed again.  
11.4.2 Atezolizumab Treatment 
Atezolizumab must be stored in a refrigerator (2 °C – 8 °C).  
Patients will receive an intravenous dose of 840 mg of atezolizumab every 2 weeks or 1680 mg 
every 4 weeks administrated by the investigator in the site.  


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 42 of 100 
The first infusion of Atezolizumab should be given intravenously over 60 minutes. If this 
infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.  
11.5 Treatment Duration 
The patients included will remain in the study for at least 100 weeks, 4 weeks (1 cycle) in the 
first treatment phase, 48 weeks (12 cycles) in the second treatment phase, and 48 weeks (12 
cycles) in the third treatment phase), unless discontinue early.  
The First 10 Patients: 
 First cycle, they will receive bosutinib 400 mg/day in monotherapy. 
 Second and third cycles, they will receive bosutinib 400 mg/day in combination with 
atezolizumab 840 mg every two weeks.  
 If no safety issues are detected, these patients will cross-over from bosutinib 400 
mg/day plus atezolizumab 840 mg every 2 weeks to bosutinib 400 mg/day plus 
atezolizumab 1680 mg every 4 weeks for 10 more cycles.  
 After 12 cycles of treatment with bosutinib plus atezolizumab combination, the patients 
will continue with bosutinib 400 mg/day in monotherapy for 12 more cycles. 
Other 26 Patients: 
 First cycle, they will receive bosutinib 400 mg/day in monotherapy. 
 Second cycle, they will receive bosutinib 400 mg/day plus atezolizumab 1680 mg every 
4 weeks for 12 cycles.  
 After 12 cycles of treatment with bosutinib plus atezolizumab combination, the patients 
will continue with bosutinib 400 mg/day in monotherapy for 12 more cycles. 
If, at any point during the treatment with bosutinib 400 mg/day plus atezolizumab 1680 mg 
every 4 weeks, 2 or more patients experience DLTs, atezolizumab dosage will change to 840 
mg every 2 weeks. 
11.6 Dose Modification and Dose Delay 
The following section summarizes dosing modifications of bosutinib or atezolizumab to manage 
possible toxicity. Administration of bosutinib or atezolizumab could be stopped for an 
individual subject in the event of a treatment-related toxicity that, in the Investigator’s 
assessment, warrants discontinuation. Exceptions to these guidelines will require approval 
from the Medical Monitor.  
A maximum discontinuation of 1 month is allowed for the treatment with bosutinib if required 
due to the onset of adverse events, investigator decision, of other major circumstances. If a 
subject discontinued treatment for more than one month he/she will be withdrawn from the 
study and the appropriate follow-up procedures will be conducted. Also, to be included in the 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 43 of 100 
efficacy analysis (Per protocol set population), a subject must comply with at least 70% of 
treatment with bosutinib. Regarding atezolizumab treatment, fail to administrate up to 3 out 
of the 11 administrations scheduled, will be allowed to continue in the study. If, for any reason, 
atezolizumab could not be administered 4 or more times during the course of the study, the 
subject will be withdrawn from the study and the appropriate follow-up procedures will be 
conducted. All deviations from the scheduled treatments regime shall be recorded in the 
patients’ clinical history and the eCRF and explained if required. 
11.6.1 Dose reduction steps for bosutinib 
In case of a toxicity event possibly related to bosutinib, a dose reduction from 400 mg to 300 
mg, unless the toxicity resolves (Grade ≤1) is permitted. If a patient requires a second dose 
reduction from 300 mg to 200 mg, the Investigator should contact the Sponsor to determine if 
the patient may continue on treatment at a lower dose. The second dose reduction must be 
approved by the sponsor and will only be considered if the patient in question displays 
optimum response to bosutinib treatment at the time-point at which the dose reduction is 
being considered. Patients should remain on the 200 mg dose for a maximum of 4 weeks or 
until the toxicity resolves, whichever is sooner. In line with the dose reduction and dose 
escalation guidelines detailed, the dose can then be re-escalated following the escalation 
guidelines. Any patient on the 200 mg dose with ongoing toxicity after the 4-week point will be 
discontinued from treatment and will continue with Follow-up evaluations. Dose reductions of 
bosutinib below 200 mg will not be permitted. 
If the Investigator and the Sponsor decide that it is not in the best interest of the patient to 
remain on treatment at a dose lower than 300 mg/day, the patient will be discontinued from 
treatment and will continue with Follow-up evaluations. 
Once the dose has been reduced for a patient, the patient should remain on that dose unless 
the toxicity resolves (Grade ≤1). In that case, the dose can be escalated to the previous starting 
dose. 
11.6.1.1 Management of Non-Hematologic Treatment-Related Toxicities 
The management of non-hematologic treatment-related toxicities is summarized in Table 1. 
Table 1. Non-Hematologic Treatment-Related Toxicities 
Adverse Event 
Action 
Elevated liver 
transaminases 
If elevations in liver transaminases (ALT, AST) > 5 × institutional upper limit of normal (ULN) 
occur, bosutinib should be interrupted until recovery to ≤ 2.5×ULN and may be resumed at 
400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of 
bosutinib should be considered. If transaminase elevations ≥3×ULN occur concurrently with 
bilirubin elevations  
>2×ULN and alkaline phosphatase <2×ULN, bosutinib should be discontinued. 
Diarrhea 
For Grade 3/4 diarrhea, bosutinib should be interrupted and may be resumed at 400 mg once
daily upon recovery to Grade ≤ 1. 
Grade 1 
Current dose level 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 44 of 100 
Grade 2 
For persistent clinically relevant toxicityb not responding to optimal management: 
Temporarily interrupt treatment, and reintroduce at the same dose or reduce dose by 1 level 
upon recovery to Grade ≤1 within 4 weeks of stopping test article. 
Grade 3 a  
For persistent clinically relevant toxicityb not responding to optimal management: Withhold 
treatment, then dose reduce by 1 level upon recovery to Grade ≤1within 4 weeks of stopping 
test article. If recovery takes longer than 4 weeks, the Investigator should contact the 
Sponsor to determine if the patient may continue on treatment. 
Grade 4 a 
Withhold treatment. Investigator and Sponsor to review to determine if patient may 
continue on treatment with appropriate dose reduction. 
a. 
For patients requiring dose reduction due to toxicity, who have been free of the toxicity (Grade ≤ 1) for at least 1 
month and are otherwise tolerating study drug, the Investigator may choose to re-escalate dose by 1 dose level 
back to starting dose. 
b. 
Persistent Clinically Relevant Toxicity is defined as -  symptoms of toxicity which, despite optimal medical 
management, persist for ≥ 14 days (“persistent”) and cause sufficient symptoms or signs of illness in the subject 
to warrant further intervention, i.e. dose adjustment (“clinically relevant”). 
 
Subjects with Grade 3 non-hematological toxicity that does not respond to optimal 
management, will be managed by withholding treatment, followed by dose reduction by 1 level 
upon recovery to Grade ≤ 1. If, on re-challenge at reduced dose, the subject remains free of 
toxicity (Grade ≤ 1) for at least 1 month, the Investigator may choose to re-escalate the dose 
by 1 level back to the starting dose. 
11.6.1.2 Hematologic Treatment-Related Toxicity 
Dose 
reductions 
are 
recommended 
for severe or persistent 
neutropenia 
and 
thrombocytopenia. The management of hematologic treatment-related toxicities is 
summarized in Table 2. 
Table 2. Hematologic Treatment-Related Toxicity 
Adverse Event Action 
Grade 1 
Current dose level 
Grade 2 
Current dose level 
Grade 3 a 
Withhold treatment: 
If recovered to Grade ≤2 within 2 weeks of treatment hold: re-introduce study drug at same 
dose. If recovered within 4 weeks of treatment hold: reduce study drug by 1 dose level. 
At subsequent occurrences of Grade 3 toxicity, dose must be reduced upon recovery to 
Grade ≤2. 
If recovery takes longer than 4 weeks, the Investigator should contact the Sponsor to determine 
if the patient may continue on treatment. 
Grade 4 a 
Withhold treatment. Investigator and Sponsor to review to determine if patient may 
continue on treatment with appropriate dose reduction. 
a. 
For patients requiring dose reduction due to toxicity, who have been free of the toxicity (Grade ≤ 1) for at least 1 
month and are otherwise tolerating study drug, the Investigator may choose to re-escalate dose by 1 dose level 
back to starting dose 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 45 of 100 
 
Subjects fulfilling criteria for dose escalation due to suboptimal response, but also exhibiting 
Grade 2 hematologic treatment related toxicity will be eligible for dose escalation; however, if 
hematologic toxicity increases to Grade 3 or 4 after dose escalation, the subject will be 
managed as per the instructions for Grade 3 or 4 hematological toxicities in Table 2. 
11.6.2 Dose reduction steps for atezolizumab 
Although most immune-mediated 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-mediated toxicities may require 
acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. 
The investigator should consider the benefit-risk balance a given subject may be experiencing 
prior to further administration of atezolizumab. Atezolizumab should be permanently 
discontinued in subjects with life-threatening, immune-mediated adverse events. Specific 
guidelines for immune-mediated events are provided in Tables 3 to 13. 
For all other non-immune mediated adverse events, including infections, atezolizumab should 
be withheld for Grade 3 or higher toxicity with the following exceptions: 
 Grade 3 nausea that responds to antiemetic treatment within 7 days 
 Grade 3 vomiting that responds to antiemetic treatment within 7 days 
 Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
 Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of atezolizumab 
 Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of atezolizumab 
Administration of atezolizumab may be restarted upon recovery from toxicity to Grade 1 or 
baseline. 
11.6.2.1 Pulmonary Events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  
All pulmonary events should be thoroughly evaluated, as follows, for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, 
heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension. For specific 
management guidelines, please see table 3. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 46 of 100 
Table 3. Management Guidelines for Pulmonary Events, including pneumonitis 
Adverse Event 
Management 
Pulmonary 
event, Grade 1 
 
Continue atezolizumab and monitor closely. 
 
Re-evaluate on serial imaging. 
 
Consider subject referral to pulmonary specialist. 
Pulmonary 
event, Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer subject to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL. 
 
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor. c 
Pulmonary 
event, Grade 3 
or Grade 4 
 
Permanently discontinue atezolizumab and contact the Sponsor. c 
 
Bronchoscopy or BAL is recommended. 
 
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent. 
 
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. 
BAL=bronchoscopic alveolar lavage; IVIG=intravenous immunoglobulin 
a.  Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for corticosteroids 
(if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Sponsor. 
b.  If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c.  Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Sponsor 
 
11.6.2.2 Hepatic Events 
Immune-mediated hepatitis has been associated with the administration of atezolizumab. 
Eligible subjects must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminases, and liver function will be monitored throughout study 
treatment. 
While in this study, subjects who present with right upper-quadrant abdominal pain or 
unexplained nausea or vomiting should have liver function tests (LFTs) performed immediately 
and reviewed before administration of the next dose of study drug. 
If LFTs worsened, concurrent medications, viral hepatitis, and toxic or neoplastic etiologies 
should be considered and addressed, as appropriate. 
For specific management guidelines please see Table 4. 
Table 4. Management Guidelines for Hepatic Events 
Adverse Event 
Management 
Hepatic event, Grade 1 
 
Continue atezolizumab. 
 
Monitor LFTs until values resolve to within normal limits. 
Hepatic event, Grade 2 
All events: 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 47 of 100 
Adverse Event 
Management 
 
Monitor LFTs more frequently until return to baseline values. 
Events of >5 days’ duration: 
 
Withhold atezolizumab for up to 12 weeks after event onset.a 
 
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent. 
 
If event resolves to Grade 1 or better, resume atezolizumab.b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact 
Hepatic event, Grade 3 or 
4 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
 
Consider subject referral to gastrointestinal specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury. 
 
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent. 
 
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. 
LFT =liver function tests. 
a. Atezolizumab may be withheld for a longer period (ie, > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period must 
be agreed upon by the investigator and the Sponsor. 
b. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Sponsor 
11.6.2.3 Gastrointestinal Events 
Immune-mediated colitis has been associated with the administration of atezolizumab. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. If the event is of significant duration or magnitude or is associated with signs of 
systemic inflammation or acute phase reactants (e.g., increased C-reactive protein [CRP], 
platelet count, or bandemia), the following are recommended: 
 Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with 3 to 5 
specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates for confirmation of the diagnosis of colitis. 
For specific management guidelines please see Table 5. 
Table 5. Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Adverse Event 
Management 
Diarrhea or colitis, 
Grade 1 
 
Continue atezolizumab. 
 
Initiate symptomatic treatment. 
 
Endoscopy is recommended if symptoms persist for >7 days. 
 
Monitor closely. 
Diarrhea or colitis, 
Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset.a 
 
Initiate symptomatic treatment. 
 
Subject referral to GI specialist is recommended. 
 
For recurrent events or events that persist >5 days, initiate treatment with 1-2 
mg/kg/day oral prednisone or equivalent. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 48 of 100 
Adverse Event 
Management 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor. c 
Diarrhea or colitis, 
Grade 3 
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer subject to gastrointestinal specialist for evaluation and confirmatory biopsy.
 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor c 
Diarrhea or colitis, 
Grade 4 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
 
Refer subject to gastrointestinal specialist for evaluation and confirmation biopsy.
 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
a.  Atezolizumab may be withheld for a longer period (ie, >12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period must 
be agreed upon by the investigator and the Sponsor. 
b.  If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c.  Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Sponsor 
11.6.2.4 Endocrine Events 
Thyroid disorders, type 1 diabetes mellitus, adrenal insufficiency, and pituitary disorders have 
been associated with the administration of atezolizumab. 
Subjects with unexplained symptoms such as fatigue, myalgias, impotence, constipation, or 
mental status changes, should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies. An endocrinologist should be consulted if an endocrinopathy is suspected. 
Thyroid stimulating hormone (TSH), triiodothyronine 3 (T3), and free thyroxine (T4) levels 
should be obtained to determine whether thyroid abnormalities are present. Pituitary 
hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle-
stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels and 
ACTH stimulation test) and MRI of the brain (with detailed pituitary sections) may help to 
differentiate primary adrenal insufficiency from primary pituitary insufficiency. 
For specific management guidelines, please see Table 6. 
Table 6. Management Guidelines for Endocrine Events 
Adverse Event 
Management 
Asymptomatic 
hypothyroidism 
 
Continue atezolizumab. 
 
Initiate treatment with thyroid replacement hormone. 
 
Monitor TSH weekly. 
Symptomatic 
 
Withhold atezolizumab. 
 
Initiate treatment with thyroid replacement hormone. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 49 of 100 
Adverse Event 
Management 
hypothyroidism 
 
Monitor TSH weekly. 
 
Consider subject referral to endocrinologist. 
 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥0.1 mU/L and <0.5 mU/L: 
 
Continue atezolizumab. 
 
Monitor TSH every 4 weeks. 
TSH <0.1 mU/L: 
 
Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
 
Withhold atezolizumab. 
 
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole as 
needed. 
 
Consider subject referral to endocrinologist. 
 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
 
Permanently discontinue atezolizumab and contact the Sponsor for life-threatening
immune-related hyperthyroidism.a 
Symptomatic 
adrenal 
insufficiency,  
Grade 2-4 
 
Withhold atezolizumab for up to 12 weeks after event onset. b 
 
Refer subject to endocrinologist. 
 
Perform appropriate imaging. 
 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
 
If event resolves to Grade 1 or better, resume atezolizumab. c 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.a 
Hyperglycemia,  
Grade 1 or 2 
 
Continue atezolizumab. 
 
Initiate treatment with insulin if needed. 
 
Monitor for glucose control. 
Hyperglycemia,  
Grade 3 or 4 
 
Withhold atezolizumab. 
 
Initiate treatment with insulin. 
 
Monitor for glucose control. 
 
Resume atezolizumab when symptoms resolve and glucose levels are stable. 
Hypophysitis pan-
hypopituitarism),  
Grade 2-3 
 
Withhold atezolizumab for up to 12 weeks after event onset. b 
 
Refer subject to endocrinologist. 
 
Perform brain MRI (pituitary protocol). 
 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
 
If event resolves to Grade 1 or better, resume atezolizumab. c 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.a 
 
For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis pan-
hypopituitarism),  
Grade 4 
 
Permanently discontinue atezolizumab and contact the Sponsor.a 
 
Refer subject to endocrinologist. 
 
Perform brain MRI (pituitary protocol). 
 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.b 
 
Initiate hormone replacement therapy if clinically indicated. 
TSH=thyroid-stimulating hormone 
a.  Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 50 of 100 
Adverse Event 
Management 
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Sponsor. 
b.  Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for corticosteroids 
(if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period 
of time must be agreed upon by the investigator and the Sponsor. 
c.  If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed 
11.6.2.5 Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events) referred by 
the study subjects. 
For specific management guidelines, please see Table 7. 
Table 7. Management Guidelines for Ocular Events 
Adverse Event 
Management 
Ocular event, Grade 1 
 
Continue atezolizumab. 
 
Subject referral to ophthalmologist is strongly recommended. 
 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 
If symptoms persist, treat as a Grade 2 event. 
Ocular event, Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset.b 
 
Subject referral to ophthalmologist is strongly recommended. 
 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 
If event resolves to Grade 1 or better, resume atezolizumab.a 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.c 
Ocular event, Grade 3 or 
4 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
 
Refer subject to ophthalmologist. 
 
Initiate treatment with 1-2 mg/kg/day oral prednisone or equivalent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
a.  If corticosteroids have been initiated, they must be tapered over ≥1 month to≤10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
b.  Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for corticosteroids 
(if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period 
of time must be agreed upon by the investigator and the Sponsor. 
c.  Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Sponsor 
11.6.2.6 Immune-Related Myocarditis 
Immune-related myocarditis has been associated with the administration of atezolizumab. 
Immune-related myocarditis should be suspected in any subject presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope. Immune-related myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g., in a 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 51 of 100 
subject who reports a recent history of gastrointestinal illness), ischemic events, underlying 
arrhythmias, exacerbation of pre-existing cardiac conditions, or progression of malignancy. 
All subjects with possible myocarditis should be evaluated urgently by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if 
clinically indicated. Subjects with signs and symptoms of myocarditis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 8. 
Table 8. Management Guidelines for Immune-Related Myocarditis 
Adverse Event 
Management 
Immune-related 
myocarditis, Grade 1 
 
Refer subject to cardiologist 
 
Initiate treatment as per institutional guidelines. 
Immune-related 
myocarditis, Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset and contact Sponsor. 
 
Refer subject to cardiologist. 
 
Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as appropriate. 
 
Consider treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.a 
 
If event resolves to Grade 1 or better, resume atezolizumab.b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.c 
Immune-related 
myocarditis, Grade 3 
or 4 
 
Permanently discontinue atezolizumab and contact Sponsor.c 
 
Refer subject to cardiologist 
 
Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as appropriate. 
 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.a,b 
 
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 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device 
a. Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for corticosteroids (if
initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of
time must be agreed upon by the investigator and the Sponsor. 
b. If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent
before atezolizumab can be resumed. 
c. Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by both
the investigator (or an appropriate delegate) and the Sponsor 
 
11.6.2.7 Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis. Appropriate work-up should 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 52 of 100 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests. For 
specific management guidelines please see Table 9. 
Table 9. Management Guidelines for Pancreatic Events, Including Pancreatitis 
Adverse Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
 
Continue atezolizumab. 
 
Monitor amylase and lipase weekly. 
 
For prolonged elevation (e.g., >3 weeks), consider treatment with 10 mg/day 
oral prednisone or equivalent. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 
Withhold atezolizumab for up to 12 weeks after event onset.a 
 
Refer subject to gastrointestinal specialist. 
 
Monitor amylase and lipase every other day. 
 
If no improvement, consider treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
 
If event resolves to Grade 1 or better, resume atezolizumab.b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.c 
 
For recurrent events, permanently discontinue atezolizumab and contact the 
Sponsor.c 
Immune-related 
pancreatitis, Grade 2 or 
3 
 
Withhold atezolizumab for up to 12 weeks after event onset.a 
 
Refer subject to gastrointestinal specialist. 
 
Initiate treatment with 1-2 mg/kg/day intravenous methylprednisolone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 
If event resolves to Grade 1 or better, resume atezolizumab.b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor.c 
 
For recurrent events, permanently discontinue atezolizumab and contact the 
Sponsor.c 
Immune-related 
pancreatitis, Grade 4 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
 
Refer subject to gastrointestinal specialist. 
 
Initiate treatment with 1-2 mg/kg/day intravenous methylprednisolone or 
equivalent and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 
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. 
a.  Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for corticosteroids (if
initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of
time must be agreed upon by the investigator and the Sponsor. 
b.  If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent
before atezolizumab can be resumed. 
c.  Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by both
the investigator (or an appropriate delegate) and the Sponsor 
11.6.2.8 Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus. A dermatologist should evaluate 
persistent or severe rash or pruritus. A biopsy should be considered unless contraindicated. For 
specific management guidelines please see Table 10. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 53 of 100 
Table 10. Management Guidelines for Dermatologic Events 
Adverse Event 
Management 
Dermatologic event, 
Grade 1 
 
Continue atezolizumab. 
 
Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines). 
Dermatologic event, 
Grade 2 
 
Continue atezolizumab. 
 
Consider subject referral to dermatologist. 
 
Initiate treatment with topical corticosteroids. 
 
Consider treatment with higher-potency topical corticosteroids if event does not 
improve 
Dermatologic event, 
Grade 3 
 
Withhold atezolizumab for up to 12 weeks after event onset. 
 
Refer subject to dermatologist. 
 
Initiate treatment with 10 mg/day oral prednisone or equivalent, increasing 
dose to 1-2 mg/kg/day if event does not improve within 48-72 hours. 
 
If event resolves to Grade 1 or better, resume atezolizumab.b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Sponsor. 
Dermatologic event, 
Grade 4 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
a.  Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow for corticosteroids
(if initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of
time must be agreed upon by the investigator and the Sponsor. 
b.  If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent
before atezolizumab can be resumed. 
c.  Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by both
the investigator (or an appropriate delegate) and the Sponsor 
11.6.2.9 Neurologic Disorders 
Myasthenia gravis, Guillain-Barré syndrome, and meningoencephalitis have been observed 
with single agent atezolizumab. Subjects may present with signs and symptoms of sensory or 
motor neuropathy. Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternate etiologies. For specific management guidelines please see 
Table 11. 
Table 11. Management Guidelines for Neurologic Disorders, Including Meningoencephalitis 
Adverse Event 
Management 
Immune-related 
neuropathy,  
Grade 1 
 
Continue atezolizumab. 
 
Investigate etiology. 
Immune-related 
neuropathy,  
Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset.a 
 
Investigate etiology. 
 
Initiate treatment as per institutional guidelines. 
 
If event resolves to Grade 1 or better, resume atezolizumab.b 
 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the sponsor 
Immune-related 
neuropathy,  
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
 
Initiate treatment as per institutional guidelines. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 54 of 100 
Adverse Event 
Management 
Myasthenia 
gravis 
and 
Guillain-Barré 
syndrome 
(any 
grade) 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
 
Refer subject to neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
Consider initiation of 1-2 mg/kg/day oral or IV prednisone or equivalent. 
Immune-related 
meningoencephalitis, 
all grades 
 
Permanently discontinue atezolizumab and contact the Sponsor.c 
 
Refer subject to neurologist. 
 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
 
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. 
IV=intravenous 
a.  Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for corticosteroids (if
initiated) to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of
time must be agreed upon by the investigator and the Sponsor. 
b.  If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent
before atezolizumab can be resumed. 
c.  Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the
immune-related event. Subjects can be rechallenged with atezolizumab only after approval has been documented by both
the investigator (or an appropriate delegate) and the Sponsor 
11.6.2.10 
 Immune-Related Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any subject 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered 
or depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection 
(bacterial, viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic 
process. All subjects being considered for meningoencephalitis should be evaluated urgently 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. 
If deemed safe by the treating physician, a lumbar puncture should be performed and a 
neurologist should be consulted. For specific management guidelines. 
11.6.2.11 
 Immune-related Nephritis 
Immune-related nephritis is an identified risk associated with the administration of 
atezolizumab. Immune-related nephritis is a relatively rare complication of checkpoint inhibitor 
therapy with the most common reported underlying pathology being acute tubulo-interstitial 
nephritis (ATIN). The most common presentation is asymptomatic increase in creatinine levels. 
In the absence of alternative etiologies (e.g., prerenal and postrenal causes, and concomitant 
medications), immune-related nephritis is defined as renal dysfunction requiring steroids 
treatment and/or confirmed by biopsy. For specific management guidelines, please see Table 
12. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 55 of 100 
Table 12. Management Guidelines for Immune-Related Nephritis 
Adverse Event 
Management 
Immune-related 
nephritis, Grade 2 
 
Withhold atezolizumab and contact Sponsor. 
 
Refer subject to renal specialist 
 
Initiate treatment as per institutional guidelines and consider renal biopsy and 
supportive measures. 
 
Corticosteroids and/or additional immunosuppressive agents should be 
administered as clinically indicated. 
Immune-related 
nephritis, Grade 3-4 
 
Permanently discontinue atezolizumab and contact Sponsor. 
 
Refer subject to renal specialist 
 
Initiate treatment as per institutional guidelines and consider renal biopsy and 
supportive measures. 
 
Corticosteroids and/or additional immunosuppressive agents should be 
administered as clinically indicated. 
11.6.2.12 
 Systemic Immune Activation 
Systemic immune activation is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk when given in combination with other immunomodulating agents. 
Systemic immune activation should be included in the differential diagnosis for subjects who, 
in the absence of an alternate etiology, develop a sepsis-like syndrome after administration of 
atezolizumab, and the initial evaluation should include the following: 
 Complete blood count (CBC) with peripheral smear 
 Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer 
 Ferritin 
 Triglycerides 
 AST, ALT, total bilirubin 
 Lactate dehydrogenase (LDH) 
 Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 Serum sample for cytokine analysis 
If systemic immune activation is still suspected after the initial evaluation, atezolizumab should 
be withheld with the provision of appropriate supportive medical care, including corticosteroid 
therapy. The Sponsor should be contacted for additional recommendations. Please see Table 
13. 
Table 13. Systemic Immune Activation 
Systemic Immune Activation 
Major Criteria 
Minor Criteria 
 
Fever ≥ 38.5ºC (on more than one occasion)  
 
Splenomegaly 
 
Ferritin > 3000 ng/mL 
 
Hemophagocytosis 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 56 of 100 
Systemic Immune Activation 
Major Criteria 
Minor Criteria 
 
Cytopenias 
BM, spleen or LN 
Grade 2 in two or more lineages 
 
Elevated GGT or LFTs (AST/ALT/tBili) 
 
≥2 age-adjusted SD elevation soluble IL-2 receptor 
 
Elevated triglycerides 
 
Severe multi-organ dysfunction 
 
Elevated LDH 
 
Decreased fibrinogen 
 
Decreased natural killer-cell activity 
 
Number of Criteria 
Management 
Consistent with systemic 
immune activation 
4 criteria 
Permanently discontinue atezolizumab and contact 
the Sponsor. 
Consider referring to an immunologist for 
evaluation 
Consider treatment with methylprednisolone, or 
equivalent, or the best way of treatment according 
to the physician's judgement. 
Probable systemic immune 
Activation 
3 major criteria 
OR 
2 major criteria 
AND 
3 minor criteria 
Depending on clinical severity, subject can be 
treated as per “Consistent with systemic immune 
activation” 
or 
“Possible 
systemic 
immune 
activation” case definition. 
Contact 
the 
Sponsor 
for 
additional 
recommendations 
Possible systemic immune 
Activation 
1 major criteria 
 
Consider methylprednisolone (1g IV QD) 
Contact 
the 
Sponsor 
for 
additional 
recommendations. 
As per “Consistent with systemic immune 
activation” recommendations if no improvement or 
clinically worsening 
BM = bone marrow; GGT = gamma-glutamyl transpeptidase; IL-2 = interleukin-2; IV = intravenous; LFT = liver function test; 
LN= lymph node; QD = once daily; tBili = total bilirubin. 
Notes: Criteria adapted from a Delphi Survey of 26 experts regarding helpful criteria in the positive diagnosis of 
Hemophagocytic Syndrome in adult subjects (Hejblum G. et al PLoS One, April 2014; Volume 9, Issue 4). Standard-of-care 
for systemic immune activation has not been established. Case reports and recommendations have been published for 
cytokine release syndrome (Lee 2014, Maude 2014, Teachey 2013), and based on etiologic similarities, these practices have 
been incorporated into the above treatment recommendations. 
These recommendations do not replace clinical judgment and are intended as suggested guidance. 
11.6.2.13 
Infusion-related Reactions 
No premedication is indicated for the administration of atezolizumab in Cycle 2. Subjects who 
experience an infusion-related reaction (IRR) with Cycle 2 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions. Metamizole (dipyrone) is prohibited in treating atezolizumab associated 
IRRs, due to its potential for causing agranulocytosis. Table 14 provides management guidelines 
for atezolizumab IRRs in Cycle 2. 
Severity 
Management 
Grade 1 
 
Reduce infusion rate to half the rate being given at the time of event onset. 
 
After the event has resolved, the investigator should wait for 30 minutes while delivering 
the infusion at the reduced rate. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 57 of 100 
Severity 
Management 
 
If tolerated, the infusion rate may then be increased to the original rate 
Grade 2 
 
Interrupt atezolizumab infusion. 
 
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, anti- 
pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen). 
 
Restart only after the symptoms have adequately resolved to baseline grade. 
 
The infusion rate at restart should be half of the infusion rate that was in progress at the 
time of the onset of the IRR. 
 
At next cycle, administer oral premedication with antihistamine and anti-pyretic and 
monitor closely for IRR. 
Grade 3-4 
 
Stop infusion. 
 
Proper medical management which may include oral or IV antihistamine, anti-pyretic, 
glucocorticoids, epinephrine, bronchodilators, and oxygen 
 
Discontinue atezolizumab. 
 
Contact the Sponsor if atezolizumab is discontinued. 
IRR = infusion-related reaction; IV = intravenous. 
 
For subsequent cycles, infusion-related reactions should be managed according to institutional 
guidelines. 
11.7 Disposition of Used Supplies 
The blisters, cartons or bottles either used by the subjects or unused, must not be destroyed 
until the monitor has verified the accountability of the IMP. 
During the trial, at the pre-defined visits, and at termination, patients must return all used and 
unused study drug supplies, and the return of these unused study drug supplies must be 
recorded. Returned supplies must not be re-dispensed. 
All unused vials or capsules of study drug must be destroyed in an appropriate manner 
according to the standard practice at each study center. Destruction of such supplies will be 
documented, and a representative of the sponsor will verify disposition records. 
No other utilization of the bosutinib and atezolizumab intended for use in this study is 
authorized by the Sponsor. The principal investigator or his/her designee will be responsible 
for the appropriate handling and disposition of residual study drugs. Each site is responsible 
for proper and careful destruction of study drug returned by patients. 
11.8 Inventory of Unused Supplies 
Periodically throughout the study and at its conclusion, a representative of the sponsor will 
conduct an inventory of unused study drugs. At the completion of the trial, a final study drug 
accountability review will be conducted. Any discrepancies must be investigated. All unused 
study drug must be destroyed on site following the standard operating procedures of the 
investigative site. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 58 of 100 
12 VISIT SCHEDULE AND ASSESSMENTS 
12.1 Schedule of Events 
Details on scheduling and sample collection are described in Tables 14-17. The tables 14 and 
15 for 1st group of patients (first 10 patients included), and the tables 16 and 17 for 2nd group 
of patients (the last 26 patients included).  
All data obtained from these assessments must be recorded in the source documentation. The 
CRF will not be used as a source document for any study data.  
Please maintain a special awareness of the assessments of the primary and secondary 
endpoints. 
All visits should be completed on the designated day or as close as possible. However, the 
windows allowed by protocol will be: 
 For visits that take place every two weeks, the window will be ±3 days. 
 For visits that take place every 4 weeks, the window will be ±3 days. 
 For visits that take place every 3 cycles (every 12 weeks), and the End of Treatment visit, 
the window allowed will be ±14 days. 
For this purpose, a cycle equal to 28 days (4 weeks) will be defined and one month will be 
considered to be equivalent to one cycle. 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 59 of 100 
Table 14. Schedule of Assessments 1st and 2nd Therapies for the First 10 Patients 
The following visit schedule will apply if the atezolizumab dose does not need to be adjusted during 2nd therapy due to DLTs. If the dose of atezolizumab has to be 
modified to the 840 mg every two weeks, additional visits will be scheduled for the administration of atezolizumab. The only procedure to be conducted during these 
additional visits is the administration of atezolizumab 
1st Group of Patients (The 10 First Patients) 
1st Therapy 
2nd Therapy 
VISIT 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Visit 
11 
Visit 12 Visit 
13 
Visit 14 Visit 15 Visit 
16 
Cycle 
Screening 
/ Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 Cycle 5 Cycle 
6 
Cycle 7 Cycle 
8 
Cycle 9 Cycle 
10 
Cycle 
11 
Cycle 
12 
Cycle 
13 
Day within Cycle (Visit Window ± 3 Days) 
-28/-1 
1 
15 
1 
15 
1 
15 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Consecutive Days in the Study (D) 
-28/-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D113 
D141 
D169 
D197 
D225 
D253 
D281 
D309 D337 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria (Checklist) 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History and 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recent Medication Prior to First Dose 
of IMP 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukemia Diagnosis and Prior Cancer 
Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sokal Risk Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
Weight 
X 
X(1) 
 
X(1) 
 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
X(1) 
As clinically indicated 
Physical Examination and Extra-
medullary Leukemia Involvement 
X 
X(1) 
X(1) 
X(1) 
 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
ECOG 
X 
X(1) 
 
X(1) 
 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
Blood Sample for BCR-ABL1 
Assessment 
X 
 
 
X(1) 
 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 60 of 100 
1st Group of Patients (The 10 First Patients) 
1st Therapy 
2nd Therapy 
VISIT 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Visit 
11 
Visit 12 Visit 
13 
Visit 14 Visit 15 Visit 
16 
Cycle 
Screening 
/ Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 Cycle 5 Cycle 
6 
Cycle 7 Cycle 
8 
Cycle 9 Cycle 
10 
Cycle 
11 
Cycle 
12 
Cycle 
13 
Day within Cycle (Visit Window ± 3 Days) 
-28/-1 
1 
15 
1 
15 
1 
15 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Consecutive Days in the Study (D) 
-28/-1 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
D113 
D141 
D169 
D197 
D225 
D253 
D281 
D309 D337 
Complete Blood Count with 
Differential 
X 
X(1) 
X(1) 
X(1) 
 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
Chemistry 
X(2) 
X(1) 
 
X(1)(2) 
 
 
 
X(1)(2) 
 
 
X(1)(2) 
 
 
X(1)(2) 
 
 
X(1)(2
) 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate and 
Cytogenetic, if no-CCyR 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pregnancy Test 
 
X 
 
X  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunological Studies 
X 
 
 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
X(1) 
Adverse Events 
Medical 
History 
Continuous 
Concomitant Medications 
Medical 
History 
Continuous 
Dispensing or Return of Bosutinib 
 
X(4) 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Atezolizumab Administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 (1): The tests will be performed before IMP dose administration.  
(2): Determination of lipase and amylase levels included. 
(3): If the patient achieves CCYR, the cytogenetic assessment is not necessary. 
(4) Dispense only bousutinib treatment.  


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 61 of 100 
Table 15. Schedule of Assessments 3rd Therapy for the first 10 patients 
1st Group of Patients 
3rd Therapy 
VISIT 
Visit 17 
Visit 18 
Visit 19 
Visit 20 
Visit 21 (EOT) 
Visit 22 (EOS) 
Cycle 
Cycle 14 
Cycle 17 
Cycle 20 
Cycle 23 
Cycle 25 
Follow-up 
Day within Cycle (Visit Window 
± 14 Days) 
1 
1 
1 
1 
29 
28 days after 
the last dose 
Consecutive Days in the Study 
(D) 
D365 
D449 
D533 
D617 
D700 
D728 
Vital Signs 
X(1) 
X 
X 
X 
X 
X 
Weight 
X(1) 
X 
X 
X 
X 
X 
12-Lead Electrocardiogram 
As clinically indicated 
X 
Physical Examination and Extra-
Medullary Leukemia 
Involvement 
X(1) 
X 
X 
X 
X 
X 
ECOG 
X(1) 
X 
X 
X 
X 
X 
Blood Sample for BCR-ABL1 
Assessment 
 
X 
X 
X 
X 
 
Complete Blood Count with 
Differential 
X(1) 
X 
X 
X 
X 
X 
Chemistry 
X(1) 
 
X 
 
X 
X 
Bone Marrow Aspirate and 
Cytogenetic, if No CCYR 
X 
X 
X 
X 
X 
X 
(2)Pregnancy Test 
X 
X 
X 
X 
X 
X 
Immunological Studies 
X(1) 
 
 
 
X 
X 
Adverse Events 
Continuous 
Concomitant Medications 
Continuous 
Dispensing or Return of 
Bosutinib 
X 
X 
X 
X 
X (Return) 
 
(1): The tests will be performed before bosutinib administration 
(2): Between visits to the center, the patient will perform a pregnancy test each month at her house. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 62 of 100 
 
Table 16: Schedule of Assessments 3rd Phase for Other 26 Patients 
2nd Group of patients (The Next 26 Patients) 
1st Therapy 
2nd Therapy 
VISIT 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 
10 
Visit 11 
Visit 12 
Visit 
13 
Visit 14 
Cycle 
Screening / 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 
7 
Cycle 
8 
Cycle 9 
Cycle 
10 
Cycle 11 
Cycle 
12 
Cycle 13 
Day within Cycle (Visit Window ± 3 Days) 
-28/-1 
1 
15 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Consecutive Days in the Study (D) 
-28/-1 
D1 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
D197 
D225 
D253 
D281 
D309 
D337 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria (Checklist) 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History and 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recent Medication Prior to First Dose of 
IMP 
X 
X(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukemia Diagnosis and Prior Cancer 
Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sokal Risk Score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
X(1) 
Weight 
X 
X(1) 
 
X(1) 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
Height 
X 
As clinically indicated 
12-Lead Electrocardiogram 
X 
 
 
X(1) 
As clinically indicated 
Physical Examination and Extra-medullary 
Leukemia Involvement 
X 
X(1) 
X(1) 
X(1) 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
ECOG 
X 
X(1) 
 
X(1) 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
Blood Sample for BCR-ABL1 Assessment 
X 
 
 
X(1) 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
Complete Blood Count with Differential 
X 
X(1) 
X 
X(1) 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
 
 
X(1) 
Chemistry 
X(2) 
X(1) 
 
X(1)(2) 
 
X(1)(2) 
 
 
X(1)(2) 
 
 
X(1)(2) 
 
 
X(1)(2) 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 63 of 100 
2nd Group of patients (The Next 26 Patients) 
1st Therapy 
2nd Therapy 
VISIT 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 
10 
Visit 11 
Visit 12 
Visit 
13 
Visit 14 
Cycle 
Screening / 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 
7 
Cycle 
8 
Cycle 9 
Cycle 
10 
Cycle 11 
Cycle 
12 
Cycle 13 
Day within Cycle (Visit Window ± 3 Days) 
-28/-1 
1 
15 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Consecutive Days in the Study (D) 
-28/-1 
D1 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
D197 
D225 
D253 
D281 
D309 
D337 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate and Cytogenetic, if 
no-CCyR 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pregnancy Test 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunological Studies 
X 
 
 
X(1) 
 
 
 
 
 
 
 
 
 
 
X(1) 
Adverse Events 
Medical 
History 
Continuous 
Concomitant Medications 
Medical 
History 
Continuous 
Dispensing or Return of Bosutinib 
 
X(4) 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Atezolizumab Administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(1): The tests will be performed before IMP dose administration.  
(2): Determination of lipase and amylase levels included. 
(3): If the patient achieves CCYR, the cytogenetic assessment is not necessary. 
(4) Dispense only bousutinib treatment. 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 64 of 100 
 
Table 17. Schedule of assessments 3rd Therapy for Other 26 patients 
2nd Group of Patients 
3rd Therapy 
VISIT 
Visit 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 (EOT) 
Visit 20 (EOS) 
Cycle 
Cycle 14 
Cycle 17 
Cycle 20 
Cycle 23 
Cycle 25 
Follow-up 
Day within Cycle (Visit Window 
± 14 Days) 
1 
1 
1 
1 
29 
28 days after 
the last dose 
Consecutive Days in the Study 
(D) 
D365 
D449 
D533 
D617 
D700 
D728 
Vital Signs 
X(1) 
X 
X 
X 
X 
X 
Weight 
X(1) 
X 
X 
X 
X 
X 
12-Lead Electrocardiogram 
As clinically indicated 
X 
Physical Examination and Extra-
Medullary Leukemia 
Involvement 
X(1) 
X 
X 
X 
X 
X 
ECOG 
X(1) 
X 
X 
X 
X 
X 
Blood Sample for BCR-ABL1 
Assessment 
 
X 
X 
X 
X 
 
Complete Blood Count with 
Differential 
X(1) 
X 
X 
X 
X 
X 
Chemistry 
X(1) 
 
X 
 
X 
X 
Bone Marrow Aspirate and 
Cytogenetic, if No CCYR 
X 
X 
X 
X 
X 
X 
(2)Pregnancy Test 
X 
X 
X 
X 
X 
X 
Immunological Studies 
X(1) 
 
 
 
X 
X 
Adverse Events 
Continuous 
Concomitant Medications 
Continuous 
Dispensing or Return of 
Bosutinib 
X 
X 
X 
X 
X (Return) 
 
(1): The tests will be performed before bosutinib administration. 
(2):  Between visits to center, the patient will perform a pregnancy test at her house.


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 65 of 100 
The following describes the procedures/tests required for this study: 
12.2 Screening Period Procedures 
Written informed consent must be obtained before performing any study specific medical 
procedures. The screening visit will take place at study days -28 to zero. All patients must take 
part in the informed consent process. During the consent process, the person obtaining consent 
must inform the patient of all elements of informed consent. Adequate time must be allowed 
for the patient to make questions and to make a voluntary decision. No protocol-specific 
procedures are to be performed until the patient has signed and dated an informed consent 
form (IC) approved by an Ethics Committee for investigation with medicinal products (CEIm). 
Each patient's participation in the trial begins with the signing and dating of the informed 
consent form. 
During the screening visit, inclusion and exclusion criteria will be assessed.  
For details of assessments required during screening, please refer to Tables 14 and 16. 
The screening RT-qPCR blood sample will be analyzed by a Sponsor designated central 
laboratory. In case the BCR-ABL1 status cannot be determined on this sample (e.g., due to 
technical or logistical issues) another blood sample for RT-qPCR is to be collected immediately 
and submitted to the central laboratory for determination of the BCR-ABL1 status.  
Laboratory baseline assessments (including hematology and chemistry), physical examination 
including performance status, height, weight, ECG and vital signs must be performed within 28 
days prior to Cycle 1/study Day 1, before the first IMP dose. As long as a patient that has signed 
the IC fulfill all inclusion criteria and none of the exclusion criteria, he/she could be included in 
this study. 
12.3 Eligibility Screening 
The investigator will send the eligibility check form to the Sponsor by email 
(farmacovigilancia@ifth.es). The investigator will be allowed to assign treatment to the patient 
if he/she fulfills all inclusion criteria and none exclusion criteria. 
12.4 Information to Be Collected on Screening Failures 
Patients who sign the study informed consent but fail to start the treatment for any reason will 
be considered a screen failure. The reason(s) for not starting the treatment will be recorded on 
the source document and the CRF. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screening Failure patients, if it is possible. 
No other data will be entered into the CRF for those subjects who are screen failures. 
12.5 Medical/Surgical History and Demographics 
Medical and surgical history and demographic information will be recorded. Medical and 
surgical history includes diagnoses, therapies, and medical and surgical treatments. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 66 of 100 
Demographic information consists of the patient’s age, gender, and race. 
12.6 Recent Medication Prior to First IMP Dose 
The relevant medication at the time of the IC signature will be obtained from each patient at 
the time of screening and before the first IMP dose. It will be recorded in the CRF. 
  
12.7 Leukemia Diagnosis and Prior Cancer Therapy 
Both the initial leukemia diagnosis and the current screening diagnosis must be recorded. Note: 
Only patients currently in CP-CLM and those with no prior history of CML-AP, or CML-BC, or 
stem cell transplant are eligible.  
12.8 Sokal Risk Score  
Sokal risk score will be collected at screening. Risk category based on Sokal score is calculated 
using the following formula based on parameters from time of diagnosis: 
Table 18: Sokal Formulation 
Sokal Variables (from Sokal et al, 1984) 
Age (years) 
0.0116 (age - 43.4) 
* Spleen (cm) 
0.0345 (spleen - 7.51)  
Platelets (x 109/L) 
0.188 [(platelets/700)2 – 0.563] 
^ Blasts (%) 
0.0887 (blasts - 2.10) 
Relative Risk (RR) 
Exponential of the total 
* Maximum distance from costal region 
^ Percent in peripheral blood 
 
In the Sokal formulation, all four variables are continuous. 
 Low risk patients have a Relative Risk (RR) < 0.8 
 Intermediate risk patients have a RR ≥ 0.8 and ≤ 1.2 
 High risk patients have a RR > 1.2 
12.9 Vital Signs 
Vital signs are temperature, pulse, respiratory rate, and blood pressure (when the patient is 
seated). The vital signs must be performed before treatment at the following visits: 
 Screening 
 During first therapy:  
o Day 1 of cycle 1 (before treatment). 
o Day 15 of cycle 1 
 During second therapy (before treatment): 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 67 of 100 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab combination 
for first time. 
o The vital signs test should also be performed on days 15 of cycles 2 and 3, only for the 
first group of patients. 
o Day 1 of cycles 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13. 
 During third therapy: 
o Day 1 of cycle 14. Before the patient takes bosutinib 400 mg/day in monotherapy, for 
the first time again for the treatment of CML. 
o Day 1 of cycles 17, 20 and 23.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 
o At the End of Study, (visit EOS or follow up): 28 days after the last dose. 
12.10 Height and Weight 
Height in centimeters (cm) and body weight in Kg (reported to the first decimal) (in indoor 
clothing, but without shoes) will be measured.  
Height measurement is required at screening only.  
Weight will be measured at: 
 Screening 
 During first therapy (before treatment): 
o Day 1 of cycle 1. 
 During second therapy (before treatment): 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab combination 
for first time. 
o Day 1 of cycles 4, 7, 10, and 13. 
 During third therapy: 
o Day 1 of cycle 14. Before the patient takes bosutinib 400 mg/day in monotherapy, for 
the first time again for the treatment of CML. 
o Day 1 of cycles 17, 20 and 23.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 
o At the End of Study, (visit EOS or follow up): 28 days after the last dose. 
12.11 Electrocardiogram 
The screening ECG must be performed within the 28-day screening, also during the first visit of 
the 2nd cycle, before starting the treatment with Atezolizumab, and during the EoS visit in all 
participants. If medications known to prolong the QTcF interval are used while a patient is on 
study, then additional ECG monitoring should be performed as clinically indicated. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 68 of 100 
12.12 Physical Examination and Extra-medullary Leukemia Involvement 
A complete physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. Presence of extra-medullary leukemic involvement will 
be checked along with each physical examination as outlined above. Findings on physical 
examination consistent with extra-medullary leukemic involvement will be recorded (e.g., 
lymph nodes, liver and spleen size). With regards to lymph nodes, only those palpable lymph 
nodes should be considered to be CML related if leukemic blast infiltration has been confirmed 
via biopsy/histology or by technically adequate (not contaminated with peripheral blood) 
aspiration cytology. When extra-medullary involvement other than the spleen or liver is the 
only evidence of blast crisis, this finding must be confirmed by technically adequate (not 
contaminated with peripheral blood) aspiration cytology and /or biopsy (especially for isolated 
lymph nodes) and data entered into the extra-medullary involvement eCRF. 
Information about the physical examination must be present in the source documentation at 
the study center and will be collected during the following visits:  
 Screening 
 During first therapy: 
o Day 1 of cycle 1 (before treatment). 
o Day 15 of cycle 1. 
 During second therapy (before treatment): 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab combination 
for first time. 
o Day 1 of cycles 4, 7, 10, and 13. 
 During third therapy: 
o Day 1 of cycle 14. Before the patient takes bosutinib 400 mg/day in monotherapy, for 
the first time again for the treatment of CML. 
o Day 1 of cycles 17, 20 and 23.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 
o At the End of Study, (visit EOS or follow up): 28 days after the last dose. 
12.13 Eastern Cooperative Oncology Group (ECOG) Performance Status 
ECOG performance status should be evaluated during each physical examination.    
Table 19. ECOG Performance Status Scale 
Description 
Grade 
Fully active, able to carry on all pre-disease activities without restriction. 
0 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature e.g., light housework, office work. 
1 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 69 of 100 
Description 
Grade 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of waking
hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4 
Dead. 
5 
 
Information about ECOG must be recorded in the source documentation at the study center 
and will be collected on the following visits:  
 Screening 
 During first therapy (before treatment): 
o Day 1 of cycle 1 (visit 1/D1). 
 During second therapy (before treatment): 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab combination 
for first time. 
o Day 1 of cycles 4, 7, 10, and 13. 
 During third therapy: 
o Day 1 of cycle 14. Before the patient takes bosutinib 400 mg/day in monotherapy, for 
the first time again for the treatment of CML. 
o Day 1 of cycles 17, 20 and 23.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 
o At the End of Study, (visit EOS or follow up): 28 days after the last dose. 
12.14 Blood Samples for BCR-ABL Molecular Response Assessment 
MR will be assessed in all patients. Levels of BCR-ABL transcripts will be determined by real-
time quantitative PCR (RT-qPCR) testing of peripheral blood and analyzed at a FTH designated 
central laboratory. The percent ratio of BCR-ABL transcripts versus control gene transcripts 
converted to IS will be calculated for each sample. 
RT-qPCR will be done on: 
 Screening 
 During second therapy (before treatment): 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab 
combination for first time. 
o Day 1 of cycles 4, 7, 10, and 13. 
 During third therapy: 
o Day 1 of cycles 17, 20 and 23.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 70 of 100 
12.15 Laboratory Evaluations  
Local laboratories will be used for analysis of hematology specimens collected and for analysis 
of biochemistry and serology specimens collected. 
12.15.1 
Complete Blood Count (CBC) With Differential 
CBC with differential is defined as peripheral blood total white blood cell (WBC) count, 
hemoglobin, hematocrit, platelet count, red blood cell count, leucocytes, absolute neutrophil 
count (ANC), and WBC differential, reported individually for each cell type. Hematologic 
assessments must be obtained at: 
 Screening 
 During first therapy: 
o Day 1 of cycle 1 (before treatment). 
o Day 15 of cycle 1. 
 During second therapy (before treatment): 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab combination 
for first time. 
o Day 1 of cycles 4, 7, 10, and 13. 
 During third therapy: 
o Day 1 of cycle 14. Before the patient takes bosutinib 400 mg/day in monotherapy, for 
the first time again for the treatment of CML. 
o Day 1 of cycles 17, 20 and 23.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 
o At the End of Study, (visit EOS or follow up): 28 days after the last dose. 
12.15.2 
Chemistry 
Serum chemistry consists of a peripheral blood draw with the following assessments: sodium, 
potassium, blood urea nitrogen (BUN) or urea, fasting glucose, albumin, creatinine, total 
cholesterol, triglycerides, total bilirubin (direct and indirect, only if total bilirubin is out normal 
range), GOT, GPT, GGT,  alkaline phosphatase, LDH, magnesium, phosphorous and calcium. 
Amylase and lipase determinations will be added only in screening and during bosutinib plus 
atezolizumab combination treatment. 
The chemistry assessments must be obtained at: 
 Screening 
 During first therapy (before treatment): 
o Day 1 of cycle 1 (visit 1/D1). 
 During second therapy (before treatment): 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab combination 
for first time. 
o Day 1 of cycles 4, 7, 10, and 13. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 71 of 100 
 During third therapy: 
o Day 1 of cycle 14. Before the patient takes bosutinib 400 mg/day in monotherapy, for 
the first time again for the treatment of CML. 
o Day 1 of cycle 20.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 
o At the End of Study, (visit EOS or follow up): 28 days after the last dose. 
12.15.3 
Serology 
At the time of screening, blood serum must be tested for Hepatitis B serology (Hepatitis B 
surface antigen, Hepatitis B core antibody, and Hepatitis B surface antibody) hepatitis C and 
HIV, in all patients. 
12.16 Bone Marrow Analysis and Cytogenetics 
Bone marrow aspiration will be performed at screening and every three months until Complete 
Cytogenetic Response (CCyR) is reached or after suspected disease progression.  
Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone 
marrow and is defined as the following (a review of a minimum of 20 metaphases is 
convenient): 
 Complete (CCyR) 0% Ph+ metaphases 
 Partial (PCyR) - >0 to 35% Ph+ metaphases 
 Minor (mCyR) - >35 to 65% Ph+ metaphases 
 Minimal - >65 to 95% Ph+ metaphases 
 None - >95 to 100% Ph+ metaphases 
These exams will be performed and analyzed locally. Quantification of the percentage of Ph+ 
chromosome metaphases, number of metaphases, number of positive for Ph chromosome, 
additional chromosomal abnormalities, if applicable, will be collected.  
Fluorescent In-situ hybridization (FISH) analysis will not be accepted. If the sample cannot be 
quantified, the extraction must be repeated as soon as possible. 
12.17 Pregnancy Test 
The pregnancy test must be a beta-human chorionic gonadotropin (β-HCG) test, using either 
urine or serum. Women who are not of childbearing potential (status post- hysterectomy, 
status post-bilateral oophorectomy, or postmenopausal [defined as amenorrhea for at least 12 
months]) do not need to have the test performed. If the test is deemed necessary, it must be 
performed in screening visit or during visit 1 before the first dose of study drug and known to 
be negative prior to drug administration. Women of childbearing potential at study start must 
also complete the pregnancy test each month during the study, at the end-of-treatment visit 
and at the end-of-study visit. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 72 of 100 
12.18 Inmunological Studies 
Samples: whole blood (30 ml in EDTA tubes) from all patients treated with bosutinib. 
Maximum number of samples per patient: 6 (180 ml of blood in total in two years).  
Blood samples for exploratory imunological and virological analysis will be measured at: 
 Screening 
 During second therapy (before treatment): 
o Day 1 of cycle 2. Before the patient takes the bosutinib plus atezolizumab combination 
for first time. 
o Day 1 of cycle 13. 
 During third therapy: 
o Day 1 of cycle 14. Before the patient takes bosutinib 400 mg/day in monotherapy, for 
the first time again for the treatment of CML.  
o At the End of Treatment: Day 29 (Last dose) of cycle 25. 
o At the End of Study, (visit EOS or follow up): 28 days after the last dose. 
12.19 Adverse Events and Concomitant Medications 
AEs and concomitant medications will be recorded continuously throughout the study, starting 
on the date of the first administration of the study medication, and, at least, up to the 28-day 
follow-up visit after the last dose of treatment. New and updated AEs and concomitant 
medications will be reported within the treatment period; ongoing AEs thought to be at least 
possibly study-drug related; and all ongoing SAEs should be followed at least every 4 weeks 
until they resolve to baseline (or to NCI CTCAE, v5.0 grade ≤ 1), stabilize, or are considered to 
be chronic/irreversible (see section 13 Adverse Events reporting, for more information). Those 
relevant events that start before the first administration of the study drug will be recorded in 
the clinical history of the subject.  
A maximum discontinuation of 1 month is allowed for the treatment with bosutinib if required 
due to the onset of adverse events, investigator decision, of other major circumstances. If a 
subject discontinued treatment for more than one month he/she will be withdrawn from the 
study and the appropriate follow-up procedures will be conducted. Regarding atezolizumab 
treatment, fail to administrate up to 3 out of the 11 administrations scheduled will be allowed 
for a patient to continue in the study. If, for some reasons, atezolizumab could not be 
administered 4 or more times, during the course of the study, the subject will be withdrawn 
from the study and the appropriate follow-up procedures will be conducted. All deviations from 
the scheduled treatments regime shall be recorded in the patients’ clinical history and the eCRF 
and explained if required. 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 73 of 100 
12.20 End of Treatment or Early Termination Procedures 
The end of treatment for the early termination visit should be performed within 2 weeks (14 
days) of the patient’s last dose of study drug or the patient/investigator decision to discontinue 
treatment. Survival information, stem cell transplantation, TKI therapy status, as well as 
information on the status of the patient’s disease (i.e., disease progression to AP/BC according 
to protocol definition, or CML related death) will be collected, if applicable. The information 
may be collected from tests that were performed for the study or as part of the patient’s 
routine medical care.  
Patients that finished the study as per protocol will continue to receive treatment for CML, 
according to standard clinical practice.  For those patients who withdraw before the end of the 
study, their physician will decide the best course of treatment indicated, following the standard 
clinical practice and current guidelines for the treatment of CML. 
12.21 End of Study. Follow-up Safety Procedures 
All AEs ongoing or starting within 28 days after end of treatment must be recorded in the eCRF. 
After this time, ongoing AEs thought to be at least possibly study-drug related, as well as all 
ongoing SAEs, should be followed at least every 4 weeks until they resolve to baseline (or to 
NCI CTCAE, v5.0 grade ≤ 1), stabilize, or are considered to be chronic/irreversible. 
12.22 Biological Samples Treatment after the End of the Study 
During the clinical trial, the management of biological samples will be carried out in accordance 
with the following: 
The blood samples for the evaluation of the BCR-ABL transcript will be analyzed by the 
molecular biology hematology laboratory of the Doce de Octubre University Hospital, 
which since 2009 has the UNE-EN ISO9001: 2008 certification and since 2017: 
accredited by the UNE standard -EN ISO 15189: 2013, complying with all security and 
confidentiality regulations. 
The samples for the immunological study will be analyzed by the AIDS 
Immunopathology Unit of the National Center for Microbiology, complying with all 
safety and confidentiality regulations. 
The samples will be shipped the same day of the extraction to the corresponding 
central laboratories; they will not be stored in the centers. The samples will be used 
exclusively for the analysis foreseen in the protocol, and the surpluses will be 
destroyed after its completion. 
The provisions of Law 14/2007, of July 3, on Biomedical Research and Royal Decree 
1716/2011, of November 18, which establishes the basic requirements for 
authorization and operation of Biobanks with Biomedical research purposes and the 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 74 of 100 
treatment of biological samples of human origin, and the operation and organization 
of the National Registry of Biobanks for biomedical research is regulated. 
13 ADVERSE EFFECTS REPORTING 
13.1 AE Definition 
An AE is any untoward medical occurrence in a trial subject to whom a medicinal product is 
administered and which does not necessarily have a causal relationship with this treatment. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding),symptom, or disease temporally associated with the use of a medicinal product, 
whether or not that sign, symptom, or disease is considered related to the medicinal product. 
Adverse event is any worsening of a pre-existing condition that is temporally associated or not 
with the use of the study drug. 
The adverse events that occurs since the patient signs the ICF but before he/she takes the first 
bosutinib dose will be considered as part of the clinical history of the patient.  
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
AE. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0.  
AEs include: 
 Clinically significant abnormal test findings 
 Clinically significant changes in physical exam findings 
 Other untoward medical events, regardless of their relationship to the study drug, such as 
injury, events that require surgery, accidents, or apparently unrelated illnesses 
 Hypersensitivity 
Additionally, AEs may include signs or symptoms resulting from: 
 Drug overdose 
 Drug withdrawal 
 Drug abuse 
 Drug misuse 
 Drug interactions 
 Drug dependency 
 
Product complaint 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 75 of 100 
13.2 Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
 Test result is associated with accompanying symptoms that are considered clinically 
significant in the opinion of the investigator. 
 Test result requires additional diagnostic testing (other than merely repeating an 
abnormal test) or medical/surgical intervention. 
 Test result leads to a change in study drug dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy. 
 Test result is considered to be clinically significant by the investigator or sponsor. 
13.3 Performing AE Assessment 
All observed AEs, regardless of suspected causal relationship to the investigational product, 
will be reported as described in the following sections. 
For all AEs, the investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious 
adverse event (SAE) requiring immediate notification to FTH or its designated representative. 
13.4 Reporting Period 
The investigator shall report all SAEs and AESIs to FTH (farmacovigiliancia@ifth.es) and Pfizer 
without undue delay but not later than 24 hours from the time he/she has knowledge of these 
events. The investigator, where applicable, shall send a follow-up report to the sponsor to 
allow the sponsor to assess whether the serious adverse event has impact on the benefit-risk 
balance of the clinical trial. The initial and follow-up reports shall identify the trial subjects only 
by a subject identification code assigned in the trial, specific for each of them.  
For all screened patients, beginning at the time of the signature of the informed consent form 
and concluding 28 days after the last dose of the assigned study treatment or the 
investigator/patient decision to discontinue treatment or end of study (whichever occurs 
later), n-TEAEs, and AEs (both serious and non-serious) should be recorded on the eCRF.  
Adverse event monitoring should start when the patient takes the study treatment for first 
time, and continued for at least 28 days following the last dose of study treatment or the 
investigator/patient decision to discontinue treatment (whichever occurs later). 
AEs Ongoing after the Reporting Period: Any ongoing AE should be followed at least every 4 
weeks, until they resolve to baseline, stabilize, or are considered to be chronic/irreversible. 
SAEs starting after End of Study: SAEs occurring to a patient after the participation of that 
patient has ended should be reported to the sponsor if the investigator becomes aware of 
them. The investigator does not need to actively monitor subjects for AEs once the trial has 
ended. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 76 of 100 
13.5 AE Severity 
The severity of AEs will be assessed according to the NCI CTCAE, v5.0 (see Appendix C and the 
study Reference Manual). If the AE is not defined in the CTCAE, the investigator will determine 
its severity based on the following definitions: 
 Mild (grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity. 
 Moderate (grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy. 
 Severe (grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy. 
 Life-threatening (grade 4): The patient is at immediate risk of death. 
 Death (grade 5): The patient dies as a direct result of the complication or condition 
induced by the AE. 
13.6 Causality 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious). An investigator’s causality assessment is the determination of whether there is a 
reasonable possibility that the investigational product caused or contributed to the AE. 
In addition, if the investigator determines that a SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and on the SAE form. 
The investigator must report such assessment in accordance with the SAE reporting 
requirements. 
The investigator will use both medical consideration and the following categories of causality 
to determine the causal relationship of an AE to the study drug (based on the definitions 
below).  Not all criteria in each category of relatedness must be present. 
Definitely Not Related (Not Drug-Related) 
 The patient did not receive study drug, or 
 The temporal sequence of the AE onset, relative to the administration of study drug, is not 
reasonable, or 
 There is another obvious cause for the AE 
Probably Not Related (Not Drug-Related) 
There is evidence of exposure to study drug and one of the following: 
 There is another, more likely cause of the AE 
 Dechallenge (if performed) is negative or ambiguous 
 Rechallenge (if performed) is negative or ambiguous 
Possibly Related (Drug-Related) 
There is evidence of exposure to study drug and one of the following: 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 77 of 100 
 The temporal sequence of the AE onset, relative to administration of study drug, is reasonable 
 The AE could have been due to another equally likely cause 
 
Dechallenge (if performed) is positive 
Probably Related (Drug-Related) 
There is evidence of exposure to study drug and one of the following: 
 The temporal sequence of the AE onset, relative to administration of study drug, is reasonable 
 The AE is more likely explained by study drug than by another cause 
Definitely Related (Drug Related) 
There is evidence of exposure to study drug and one of the following: 
 The temporal sequence of the AE onset, relative to administration of study drug, is reasonable 
 Dechallenge is positive 
 The AE shows a pattern consistent with previous knowledge of the test drug or a test drug 
class 
13.7 Expectedness 
The current Clinical Investigator’s Brochures (CIB) will be used as the reference for 
determination of expectedness and risk assessment for bosutinib and atezolizumab. 
13.8 SAEs  
The definitions and reporting requirements of ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2A, as well as the Royal 
Decree 1090/2015, of 4 December, regulating clinical trials with medicinal products, Ethics 
Committees for Investigation with medicinal products and the Spanish Clinical Studies Registry will be 
followed. 
The investigator or sponsor may determine the seriousness of an AE based on the following. 
An AE is considered a SAE if at least one of these conditions applies: 
 Death: if the death occurs within the time of the first dose and the 28 days after the last 
dose and the cause of death is the event. 
 Life-threatening: An AE that places the patient, in the view of the investigator or the 
sponsor, at immediate risk of death from the event as it occurred (e.g., this does not include 
an event that, had it occurred in a more severe form, might have caused death) 
 Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 Inpatient hospitalization or prolongation of existing hospitalization: Hospitalization refers 
to admission of a patient into a hospital for any length of time. 
 A congenital anomaly/birth defect: A fixed, permanent impairment established at or before 
birth 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 78 of 100 
 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) 
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as serious adverse events SAES. 
13.9 Adverse Event of Special Interest (AESI) Definition 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not result in death, be life-
threatening, or require hospitalization. However, if it is determined that the event may 
jeopardize the patient and/or may require intervention to prevent one of the other outcomes 
listed in the definition above, that important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. 
13.9.1 Adverse Event of Special Interest 
AESIs require ongoing monitoring by investigators and rapid identification and communication 
by the investigator to the sponsor. All AESIs, whether they are SAEs or not, must be reported 
immediately (within 24 hours) to the sponsor. The sponsor has determined that the events 
listed below (whether considered serious or non-serious by investigators) should be 
considered AESIs, and should therefore be reported within 24 hours: 
1) In relation to bosutinib: 
A. Grade 3-4 diarrhea  
B. Grade 3-4 nausea  and vomiting  
C. Potential drug-induced liver injury showed by abnormal values in liver enzyme (ALT 
increased and AST increased) concurrent with abnormal elevation in total bilirubin 
that meet the criteria outlined below: 
a. Patients with AST or ALT and total bilirubin baseline values within the normal 
range who subsequently present with AST or ALT ≥3 times the upper limit of 
normal concurrent with a total bilirubin ≥2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase ≤2 X ULN or not available; 
b. For patients with preexisting ALT or AST or total bilirubin values above the 
upper limit of normal, the following threshold values should be used: 
i. For patients with pre-existing AST or ALT baseline values above the 
normal range: AST or ALT ≥2 times the baseline values and ≥3 X ULN, 
or ≥8 X ULN (whichever is smaller). 
ii. For patients with pre-existing values of total bilirubin above the 
normal range: Total bilirubin increased by one time the upper limit 
of normal or ≥3 times the upper limit of normal (whichever is 
smaller).  


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 79 of 100 
D. Myelosuppression (Anemia, Neutropenia, Leukopenia) considered clinically 
significant by the investigator. 
E. Hemorrhage considered clinically significant by the investigator 
F. Infection 
G. Skin disorders (Rash) considered clinically significant by the investigator 
H. Clinically significant immunological events (Hypersensitivity) 
I. Renal dysfunction (increased blood creatinine considered clinically significant by the 
investigator)  
J. Pleural effusions 
K. Clinically significant cardiac events (QT prolongation, atrial fibrillation, sinus 
bradycardia, tachycardia, supraventricular tachycardia, bradycardia, premature 
ventricular contractions, pericardial effusion, right bundle branch block, sinus 
tachycardia, or premature atrial contractions). 
2) In relation to atezolizumab: 
A. Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see EASL, 2019) 
B. Suspected transmission of an infectious agent by the study treatment, 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 study treatment is suspected. 
C. Systemic lupus erythematosus 
D. Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, macrophage activating syndrome, hemophagocytic lymphohistiocytosis 
E. Nephritis 
F. Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
G. Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
H. Vasculitis 
I. Autoimmune hemolytic anemia 
J. Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
13.10 Information to Be Provided by the Investigator for a SAE or AESI 
The following information about the patient and the event must be provided to the sponsor: 
 Investigator identification, 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 80 of 100 
 Patient identification (e.g., sex, age, date of birth, code),  
 Information on study drug (e.g., start/stop date, dose and frequency of study drug 
administered), 
 Description of event. 
In addition to the above information, the sponsor will require the investigator’s assessment of the 
following: 
 Severity of the SAE or AESI, 
 Relationship of the SAE or AESI to the study drug, 
 Outcome of the SAE or AESI. 
13.11 Follow-up Information on a SAE or AESI 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, should be instituted. Appropriate consultation and follow-up evaluations should be 
carried out until the event has resolved or is otherwise explained by the investigator. For all 
SAEs or AESIs, the investigator must pursue and provide information to the sponsor. In 
addition, an investigator may be requested by the sponsor to obtain specific information in an 
expedited manner. This information may be more detailed than that captured on the AE form. 
In general, this information will include a description of the AE, provided in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes, such as concomitant medication and 
illnesses, must also be provided. 
13.12 Required Follow-up for SAEs or AESIs 
Routine follow-up should be conducted through and including 28 days after the last 
administration of assigned study treatment in the trial or the investigator/patient decision to 
discontinue treatment, whichever occurs later, in all patients, in order to monitor the 
occurrence of SAEs or AESIs. After this time, ongoing AEs thought to be at least possibly study-
drug related, as well as all ongoing SAEs, should be followed at least every 4 weeks until they 
resolve to baseline (or to NCI CTCAE, v5.0 grade ≤ 1), stabilize, or are considered to be 
chronic/irreversible. The medical monitor may specify a longer follow-up period if required to 
assure the safety of the patient. 
13.13 Expedited Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Study sponsor, Fundación Zero LMC, is responsible for reporting suspected, unexpected, 
serious adverse reactions involving the study drug to all regulatory authorities and participating 
investigators in accordance with ICH Guidelines and/or local regulatory requirements, as 
applicable. 
The sponsor will notify investigators of all reportable SAEs. This notification will be in the form 
of an expedited safety report (ESR). Upon receiving such notices, the investigator must review 
and retain the notice with other study-related documentation. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 81 of 100 
Suspected serious adverse reactions and other significant safety issues reported from the 
investigational product development program will be reported by the sponsor or its designated 
representative—either as expedited safety reports and/or in aggregate reports—to the 
relevant, competent health authorities in all concerned countries. 
13.14 Contraception and Pregnancy 
Females of childbearing potential and fertile males will be informed of the potential risk of 
conception while participating in this study. Females of childbearing potential are required to 
use a highly effective form of contraception from recruitment through at least 4 months after 
the end of treatment (see inclusion criterion 7) 
A pregnancy test will be performed on each premenopausal female of childbearing potential 
within 7 days prior to first dose of bosutinib, and again each month during the study, at the 
end-of-treatment visit and at the end-of-study visit. A negative pregnancy test must be 
documented prior to administration of study drug. 
Females should be advised to take a pregnancy test if their period is late, and to inform their 
investigator of the result. 
If a patient is confirmed pregnant during the trial, study drug administration must be 
discontinued immediately.  The investigator must also immediately notify the sponsor medical 
monitor of this event and record the pregnancy on a pregnancy form. Initial information 
regarding a pregnancy must be immediately (in less than 24 hours) forwarded to FTH 
Pharmacovigilance and Risk Management or its designated representative. 
The investigator must immediately report follow-up information to the sponsor regarding the 
course of the pregnancy, including perinatal and neonatal outcomes, regardless of whether 
the patient has discontinued participation in the study. If the pregnancy results in the birth of 
a child, additional follow-up information may be requested. If the pregnancy results in 
spontaneous abortion or stillbirth, that event should be reported as a SAE. 
Pregnancy outcomes must also be collected for the female partners of any males who took 
study drug in this trial. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
13.15 Overdose, medication error, abuse, misuse 
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of 
study treatment that exceeds the dose described in the protocol. Overdoses are not 
considered AEs; however, all overdoses should be recorded and forwarded to FTH 
Pharmacovigilance and Risk Management or its designated representative within 24 hours. An 
overdose should be reported even if it does not result in an AE.  Overdoses do not need to be 
recorded on the eCRF; dosing information is recorded on the form. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 82 of 100 
Other special situations such as medication error (including intercepted or potential 
medication error), abuse and misuse are not considered AEs. However, they should be also 
recorded and forwarded to FTH within 24 hours.  
14 CO-TREATMENT AND TREATMENT SUPPLY 
14.1 Prior and Concomitant Treatment 
All concomitant medications administered from the time of informed consent signature until 
28 days after end of treatment (either the last dose of study drug or the investigator/patient 
decision to discontinue, whichever occurs later), are to be recorded in the patient’s eCRF. 
14.2 Permitted Treatment 
All routine and appropriate supportive care (including receipt of blood products and 
hematopoietic growth factors) will be allowed during this study, as clinically indicated, and in 
accordance with standard-of-care practices. Clinical judgment should be utilized in the 
treatment of any AE experienced by an individual patient. 
Information on all concomitant medications, administered blood products, and interventions 
occurring during the study must be recorded on each patient’s eCRF. Among other treatments 
for concurrent illnesses, the following therapies are allowed: 
 Rhu-EPO and G-CSF are allowed in case of anemia (Hb<12 g/dl) and/or neutropenia (ANC 
< 1000/mm3) 
 Diuretics are allowed in case of fluid retention 
 It 
may 
be 
necessary 
in 
some 
situations 
to 
administer 
corticosteroids, 
immunosuppressives, thyroid replacement hormone, anti-thyroid drug, insulin, 
antihistamine, anti-pyretic, epinephrine, bronchodilators, and oxygen in case of adverse 
events observed with atezolizumab. 
14.3 Prohibited Treatments/Therapy 
The following concurrent medications and treatments are prohibited: 
 Other anticancer therapies 
 Other investigational drugs or devices 
 Medications that prolong the QT interval (see Appendix A)  
 CYP3A inhibitors (including, but not limited to itraconazole, ketoconazole, posaconazole, 
voriconazole, 
clarithromycin, 
telithromycin, 
nefazodone, 
mibefradil, 
indinavir, 
lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, boceprevir, telaprevir, grapefruit 
products including grapefruit juice) or moderate CYP3A inhibitors (including, but not 
limited to fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, 
atazanavir, darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib), and 
strong CYP3A inducers (including, but not limited to carbamazepine, phenytoin, 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 83 of 100 
rifampicin, St. John's Wort), or moderate CYP3A inducers (including, but not limited to 
bosentan, efavirenz, etravirine, modafinil, nafcillin). 
15 PLANNED STATISTICAL ANALYSIS 
This is a phase Ib/II, single arm, open-label and dose-escalation study designed to determine 
the safety profile and the recommended phase III dose of bosutinib when administered in 
combination with atezolizumab in naïve patients with chronic myeloid leukemia in chronic 
phase. 
15.1 Analysis Sets 
15.1.1 Full Analysis Set 
The full analysis set (FAS) comprises all patients who complete the first three phases of 
treatment (combination of bosutinib and atezolizumab) successfully. 
15.1.2 Safety Set 
The safety set (SS) includes all patients who received at least one dose of study medication. 
Reporting and analysis of safety information for these patients will be split into subsets by study 
phases. 
15.1.3 Per-Protocol Set 
The per-protocol set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol (CSP). 
A compliance of 70% with bosutinib treatment will be necessary to be included in the PPS 
Protocol deviations leading to exclusion from the PPS will be detailed in the Clinical Study 
Report. 
15.2 Patient Demographics/other Baseline Characteristics 
Demographic and other baseline data will be summarized descriptively for both the SS and the 
FAS. Categorical data will be presented as frequencies and percentages. For continuous data, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
15.3 Primary Objective 
The primary objective is to evaluate the safety profile of bosutinib 400 mg daily in combination 
with atezolizumab as first line treatments in participants with chronic myeloid leukemia. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 84 of 100 
15.3.1 Analysis Set and Grouping for the Analyses 
The safety set population will be used for all safety analyses. Reporting of safety information 
for these patients will be split into subsets by first phase, second phase, third phase, and fourth 
phase. 
15.3.2 Adverse Events 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs (TEAEs). However, all safety data 
(including those from the pre-treatment period) will be listed and those collected during the 
pre-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of adverse event, causality relation to study treatment by the phases or subsets previously 
described. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and safety subset. 
Specific safety event categories will be considered. Such categories consist of one or more well-
defined safety events which are similar in nature and for which there is a specific clinical 
interest in connection with the study treatment(s). 
For each specified safety event category, number and percentage of patients with at least one 
event part of the safety set will be reported. Also AESI will be summarized and analyzed. 
15.3.3 Laboratory Abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 the study’s biostatistician and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned to all non-missing 
values not graded as 1 or higher. Grade 5 will not be used. 
In some cases, (e.g., white blood cell differentials) the lower limits of normal ranges used in 
CTCAE definition have to be replaced by a clinically meaningful limit expressed in absolute 
counts. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-safety subset summaries will be generated separately for hematology, and 
biochemistry tests: 
 number and percentage of patients with clinically significant laboratory abnormalities, 
by parameter and worst post-baseline CTCAE grade. Each patient will be counted only 
for the worst grade observed post-baseline, regardless of the baseline status 
 shift tables using CTCAE grades to compare baseline to the worst on-treatment value 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 85 of 100 
 for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high 
 classification to compare baseline to the worst on-treatment value. 
 listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges. 
15.3.4 Other Safety Data 
Other safety data collected (e.g., ECG, vital signs) will be listed and summarized using 
descriptive statistics as appropriate. Notable values will be flagged. Notable/Abnormal values 
for safety data will be further specified in the RAP. 
15.3.5 Immunological Analysis 
Treatment in vivo with TKI drugs may increase the cytotoxic response in CML patients, helping 
them to control the disease progression in the absence of treatment. The analysis of the 
progression of these patients will allow us to correlate the cytotoxic response developed by 
previous treatment with different TKIs with a CML relapse in order to describe new biomarkers 
that may predict a successful treatment interruption in these patients. 
15.3.5.1 Immunological Assays: 
1. Phenotypic Assays: 6 samples per patient 
a. Cell characterization: NK cells (CD3- CD56+; CD16+ CD56+; TNFα; IFNα; Granzyme b 
NK-LGL cells (CD56+ CD57+), T-LGL cells (CD3+ CD57+), CD8 TCRα/β, NK markers 
(NKG2D, KIR2DL2/DL3/DS2, KIR2DL5B). 
b. Differentiation and maturation (NKG2A/CD16) and proliferation (NK67) markers of 
NK cells. 
c. CD4+ T cells activation markers: CD25 CD69 HLA-DR. 
d. Predictive markers of CML relapse: T regs (CD4+ CD25int-hi CD127low), CD8+ T cells 
(PD-1/PD-L1) and plasmacytoid dendritic cells (CD86+). 
15.4 Secondary objectives 
15.4.1 Secondary efficacy variables: 
 To evaluate the Major Molecular Response (MMR) and Molecular Response (MR) rates at 3, 
6, 12 months and at the End of Treatment (EoT) visit. Based on: 
o MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio of <= 0.1% on 
the International Scale (IS) 
o Molecular Response (MR): As defined in section 4. Definition of Terms 
 Percentage of Participants Alive at Month 6, 12  at the EoT visit. 
 Number of confirmed MR4 and MR4.5. [at end of treatment] 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 86 of 100 
 The rate of confirmed MR4 and MR4.5 at the end of treatment. 
 Number of Complete Cytogenetic Responses (CCyR) [Time Frame: After one year from study 
entry] 
 The rate of Complete Cytogenetic Response (CCyR) at 1 year. 
 Number of days to response (CCyR, MMR, MR4, MR4.5). [Time Frame: at the EoT visit] 
 The median time to response and the overall estimated probability of response (CCyR, MMR, 
MR4, MR4.5). 
 Number of overall surviving patients [Time Frame: at the EoT visit] 
 Number of progression-free survival patients. [Time Frame: at the EoT visit] 
 Number of failure-free survival patients. [Time Frame at the EoT visit] 
 Number of event-free survival patients.[Time Frame: at the EoT visit] 
 Immunological Studies 
15.4.2 Analyses Methods for Secondary Objectives 
A descriptive analysis of the secondary objectives will be carried out. Qualitative variables will 
be summarized by counts and percentages. Quantitative variables will be summarized by 
means of mean, standard deviation, minimum, maximum and main quartiles. The 95% 
confidence intervals will also be calculated. 
The hypothesis of normality will be tested by the Shapiro-Wilk test. A repeated measurement 
ANOVA or its equivalent non-parametric test will be used depending on the result of this test. 
The qualitative variables will be analyzed by means of the Fisher Chi-square test/exact test or 
Cochran's Q test, as appropriate. 
Survival analysis will be performed using the Kaplan-Meier estimation method and the Log-rank 
test. A p-value of <0.05 will be considered statistically significant. 
15.5 Sample Size Calculation 
There will be no formal calculation of the sample size. The sample size is selected to allow 
sufficient data collection for the DLT and safety assessment. It is an exploratory study. The 
minimum number of patients for the DLT evaluation will be 10 if no DLT is observed. After MTD 
is calculated, 26 more patients will be recruited for the dose variation phase. 36 patients (both, 
a first group of 10 patients and a second of 26 patients) will receive bosutinib 400 mg/day in 
monotherapy during one cycle of treatment. According to previous experience (Tim H 
Brümmendorf et al, 2015; Jorge E. Cortes el al, 2018), we assume that, at most, 15% of the 
patients included will not enter the dose escalation phase after the first month of treatment 
with bosutinib, due to side effects. Consequently, a total of 30-31 patients will receive the 
combination of bosutinib plus atezolizumab. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 87 of 100 
16 QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor/CRO has implemented and maintains a quality assurance system with written 
SOPs to ensure that the trial is conducted and data are generated, documented and reported 
in compliance with the protocol, GCP and the applicable regulatory requirements. 
The sponsor performs quality control and assurance checks on all clinical studies that it 
sponsored. Before enrolling any patients into this study, the sponsor or its designee, as well as 
the investigator, will review the protocol, the Clinical Investigator's Brochure; the eCRF model 
and the instructions for its completion; the procedure for obtaining informed consent; and the 
procedure for reporting AEs.  A qualified representative of the sponsor will monitor the 
conduct of the study by both visiting the site and contacting it by telephone or email. During 
the visits, information recorded in the eCRFs will be verified against source documents. The 
sponsor’s medical monitor will review the data for safety information. The sponsor’s clinical 
research associates (CRAs) will review the data for legibility, completeness, and logical 
consistency. Additionally, the sponsor’s CRAs and quality control staff will identify missing data, 
selected protocol violations, out-of-range data, and other data inconsistencies. Requests for 
data clarification or correction will be added to the electronic database and reviewed by the 
investigational site for resolution. The sponsor may visit the investigational site and perform a 
quality check of the eCRFs against source documents. 
16.1 Investigators and Study Administrative Structure 
The investigator must provide the sponsor with the following documents before enrolling any 
patient: 
 A clinical trial agreement 
 Documentation of financial disclosure 
 Principal investigator’s curriculum vitae 
If any investigator retires, relocates, or otherwise withdraws from conducting the study, the 
responsibility for maintaining records shall be transferred to another person (e.g., sponsor, 
IRB/IEC, or other investigators) who accepts the responsibility. The sponsor must be notified in 
writing and agree to the change in advance. 
16.2 Study Monitoring 
This study will be monitored by representatives of the sponsor. Site visits will be made before 
the study begins, at regular intervals during the study, and at the study closeout. Communication 
by telephone, mail, and e-mail may be used, as needed, to supplement site visits. The investigator 
and the rest of the investigational team will cooperate with the sponsor, provide all appropriate 
documentation, and be available to discuss the study. Adequate time and space for these visits 
should be stablished in agreement with the investigator. The purpose of the site visits is to verify: 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 88 of 100 
 Adherence to the protocol (the investigator should document and explain any deviation from 
the approved protocol) 
 The completeness and accuracy of the data registered in the eCRFs and the dispensing and 
inventory records of the study medication and other study supplies 
 Compliance with regulations  
 These verifications will require comparison of the source documents to the eCRFs  
 The scope, frequency and relevant details regarding the study monitoring will be detailed in 
the monitoring plan 
17 ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with the ethical standards that have their origin in 
the Declaration of Helsinki and that are consistent with GCP guidelines and the applicable 
regulatory requirements. 
17.1 Institutional Review Board or Ethics Committee Approval 
The protocol and the ICF must have the approval of an IRB/IEC. The signed IRB/IEC approval 
letter must identify the documents approved (e.g., list the investigator’s name, the protocol 
number and title, the date of the protocol and informed consent document, and the date of 
approval of the protocol and the informed consent document).  Any advertisements used to 
recruit patients should also be reviewed by the IRB/IEC. The sponsor will not ship clinical 
supplies until a signed approval letter from the IRB/IEC has been received and a Clinical Trial 
Agreement has been signed by the sponsor and the clinical site. 
17.2 Patient Information and Consent 
Regulatory agencies have issued regulations to provide protection for human patients in 
clinical investigations and to describe the general requirements for informed consent. 
A copy of the study ICF should be submitted to the sponsor for review and comment before its 
submission to the IRB/IEC. The study should not begin until the ICF has been reviewed and 
approved by the sponsor, and must not begin until the document has been approved by the 
IRB/IEC.   
The ICF shall contain all the elements of the informed consent specified in the regulations. 
Some regulations may require the disclosure of additional information to the patient and/or 
inclusion of additional information in an informed consent document. 
Nothing in this protocol or the regulations is intended to limit the authority of a physician to 
provide emergency medical care under applicable regulations. In addition, the investigator 
should be aware that some regulations require that he/she permits regulatory agencies to 
conduct inspections and review records pertaining to this clinical investigation. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 89 of 100 
17.3 Patient Confidentiality 
The investigator must ensure anonymity of the patients; patients must not be identified by 
their names in any documents submitted to sponsor. Signed informed consent forms and 
identification patient enrollment log must be kept strictly confidential while allowing patient 
identification at the site. 
17.4 Publication of the Study Protocol and Results  
The sponsor ensures that the key design elements of this protocol will be posted in REec and 
any other publicly accessible database such as clinicaltrials.gov, if necessary in addition, upon 
study completion and finalization of the study report, the results of this study will be either 
submitted for publication and/or posted in REec and other public accessible database of clinical 
study results. 
In addition, the sponsor may also publish the results in conferences and medical journals when 
deemed appropriate. 
17.5 Study Documentation 
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 Fundación Zero 
LMC-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, inspections 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, but it will not be source of any of the data collected. The investigator 
should ensure the accuracy, completeness, legibility, and timeliness of the data recorded in the 
eCRFs and all other required reports. Data recorded in the eCRF should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 90 of 100 
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) must be retained for a period of not less than 
twenty-five (25) years from the completion of the Clinical Trial, or longer if required by 
applicable regulation or the sponsor  requires their retention for an additional period of time. 
17.6 Confidentiality of Study Documents 
All unpublished information that the sponsor provides to the investigator, as well as all 
information generated in connection with the study, must be kept confidential and must not 
be disclosed to a third party without the prior written consent of the sponsor. In addition, this 
information must not be published prior to the sponsor’s review, in accordance with the terms 
of the Clinical Trial Agreement. 
17.7 Audits and Inspections 
Source data/documents must be readily available and accessible, upon request, to the Sponsor, 
or its designee, or to the Health Authorities. 
17.8 Financial Disclosures 
Financial disclosures should be provided prior to the start of the study by study personnel who 
are directly involved in the treatment or evaluation of patients at the site. 
17.9 Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact the sponsor or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no unauthorized 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 
sponsor and approved by the IRB/IEC/REB it cannot be implemented except when necessary to 
eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical 
or administrative aspects of the trial. All significant protocol deviations will be recorded and 
reported in the CSR. 
17.10 Amendments to the Protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by sponsor and investigators. Protocol modifications that are considered 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 91 of 100 
substantial, must be approved by sponsor, investigators, Health Authorities, and the 
IRB/IEC/REB when required. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB 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 IRB/IEC and authorities at the study site 
should be informed according to local regulations. 
18 DATA HANDLING AND RECORD KEEPING 
18.1 Case Report Forms and Study Records 
Study-specific eCRF will be made available to the investigative sites. Study data, contained in 
source documentation, will be recorded into the eCRFs, that will not be source of any data, for 
all patients screened for the study. All pertinent data records will be submitted to the sponsor 
during and/or at completion or termination of the study. 
18.2 Access to Source Documentation: Data Confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require that all subjects recruited sign an authorization 
(ICF) that informs them about the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their protected 
health information (PHI). 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, will retain the ability to use all information collected prior to the revocation of the 
authorization. For subjects that have revoked authorization to collect or use PHI, reasonable 
attempts should be made to obtain permission to collect follow-up safety information (e.g., has 
the subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study (eCRD) 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. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 92 of 100 
18.3 Site Monitoring 
Before study initiation, the clinical monitor will review the protocol and eCRF model with the 
investigators and their staff, if apply. During the study, the clinical monitor will visit the site 
regularly to verify the source documents data entries on the eCRFs, the adherence to the 
protocol and to GCP, the progress of enrollment, and to verify that study treatments are being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the clinical 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 eCRFs 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 eCRF entries. The clinical monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
18.4 Data Collection 
The designated investigator staff will enter the data required by the protocol into an electronic 
case report form (eCRF). Investigator site staff will not be given access to the eCRF system until 
they have been trained in its use. Automatic validation checks for data discrepancies in the 
eCRFs will be implemented and, it will allow modification or verification of the entered data by 
the investigator staff while maintaining data traceability. 
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. 
18.5 Database Management and Quality Control 
The Sponsor or person to whom this function is delegated will review the data entered by 
investigational staff for completeness and quality. Electronic data queries stating the nature of 
the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the EDC system. Designated investigator site staffs are required to respond 
promptly to queries and to make any necessary changes to the data. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for Regulatory Activities (MedDRA) terminology. 
After database lock, the investigator will receive copies of the patient data, either in paper or 
in electronic format, for archiving at the investigational site. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 93 of 100 
18.6 Retention of Data 
Trial documents (including relevant correspondence related to this clinical study, patient 
records, source documents, eCRFs, study drug inventory records; IRB/IEC and sponsor 
correspondence pertaining to the study; and original patient, laboratory, and study drug 
inventory records relating to the study) should be retained for at least 25 years after the end 
of the study, or a longer period if required by applicable regulatory requirements, ICH or by 
agreement with the sponsor. Thereafter, records will not be destroyed without giving the 
sponsor prior written notice and the opportunity to further store such records, at the sponsor’s 
cost and expense. 
18.7 Termination of Study 
The sponsor may terminate the study or a study site at any time for any of the following 
reasons: 
 Failure to enroll patients 
 Protocol violations 
 Inaccurate or incomplete data 
 Unsafe or unethical practices 
 Questionable safety of the study drug 
 Suspected lack of efficacy of the study drug 
 Administrative decision 
In the event of the termination of the study, by either the sponsor or an investigator: 
 The investigator will return all study drugs, eCRFs, and related study materials to the 
sponsor. 
 A written statement describing why the study was terminated prematurely will be 
provided by either the sponsor or the investigator. 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 94 of 100 
19 REFERENCES 
Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: An update of concepts and 
management recommendations of European LeukemiaNet. J Clin Oncol 2009, 27: 6041-6051. 
Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the 
management of chronic myeloid leukemia. Blood, 2013, 122: 872-884. 
Bartram CR, deKlein A, Hagemeijer A, et al. Translocation of c-Abl correlates with the presence of a 
Philadelphia chromosome in chronic myelogenous leukemia. Nature, 1983, 306: 277-280. 
Bradeen HA, Eide CA, O'Hare T, et al. Comparison of imatinib, dasatinib (BMS-354825), and nilotinib 
(AMN107) in an n-ethyl-n-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug 
combinations. Blood, 2006, 108: 2332-2338. 
Branford S, Yeung DT, Prime JA, et al. BCR-ABL1 doubling times more reliably assess the dynamics of 
CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management. 
Blood, 2012, 119: 4264-4271. 
Cervantes C, Hughes T, Etienne G, et al. Nilotinib induces deeper molecular responses vs. continued 
Imatinib in patients with Ph+ Chronic Myeloid Leukemia (CML) with detectable disease after = 2 
years on imatinib: ENESTcmr 12-months results. 17th congress of European Hematology 
Association; 2012, Abstract 0586. 
Cortes J, Kantarjian H, Shah N, et al. Ponatinib in refractory philadelphia chromosome-positive 
leukemias. N Engl J Med 2012, 367: 2075-2088. 
Cortesa JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, 
Milojkovic D, le Coutre P, Garcia-Gutierrez V, Reilly L, Jeynes-Ellis A, Leip E, Bardy-Bouxin N, 
Hochhaus A, Brümmendorf TH. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid 
Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 2018 Jan 20;36(3):231-237. 
Cortesb JE, Apperley JF, DeAngelo DJ, Deininger MW, Kota VK, Rousselot P, Gambacorti-Passerini C. 
Management of adverse events associated with bosutinib treatment of chronic-phase chronic 
myeloid leukemia: expert panel review. J Hematol Oncol. 2018 Dec 27;11(1):143. 
Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the p 
210 bcr/Abl gene of the Philadelphia chromosome. Science 1990, 247: 824-830. 
CTFG (Clinical Trials Facilitation and Coordination Group). Recommendations related to 
contraception and pregnancy testing in clinical trials. Version 1.1. 21/09/2020 . 
European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; Clinical 
Practice Guideline Panel: Chair:; Panel members; EASL Governing Board representative:. EASL 
Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019;70(6):1222–1261. 
Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a 
scientific statement for healthcare professionals from the American Heart Association/American 
Stroke Council. Stroke, 2009, 40: 2276-2293. 
Enright H, McGlave P. Chronic myelogenous leukemia. In: Hoffman R, Benz EJ, Shattil SJ et al., eds. 
Hematology: Basic Principles and Practice, Third Edition. New York: Churchill-Livingstone, Inc. 
2000, 1155-1171. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 95 of 100 
Goh HG, Lin M, Fukushima T. Sensitive quantitation of minimal residual disease in chronic myeloid 
leukemia using nanofluidic digital polymerase chain reaction assay. Leukemia & Lymphoma, 2011, 
52: 896–904. 
Graham SM, Jorgensen HG, Allan E, Pearson C, et al. Primitive, quiescent, Philadelphia-positive stem 
cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002, 
99:319-25. 
Hasford J1, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and 
subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS 
score. Blood. 2011 Jul 21;118(3):686-92. 
Heisterkamp N, Stephenson JR, Groffen J, et al. Localization of the c-Abl oncogene adjacent to a 
translocation break point in chronic myelocytic leukemia. Nature, 1983, 306: 239-242. 
Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission following frontline nilotinib in patients 
with chronic myeloid leukemia in chronic phase: Results from the ENESTfreedom study. Leukemia, 
2017, 31(7): 1525-1531. 
Hughes TP, Cervantes F, Spector N, et al. Treatment-Free Remission eligibility in patients with chronic 
myeloid leukemia in chronic phase and residual disease on long-term imatinib who switched to 
second-line nilotinib. Blood, 2015, 126: 4029. 
Imagawa J, Tanaka H, Okada M, et al. Discontinuation of dasatinib in patients with chronic myeloid 
leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a 
multicentre phase 2 trial. Lancet Haematol, 2015, 2: e528-e535. 
James PA, Oparil S, Carter BL, et al. Evidence-based guideline for the management of high blood 
pressure in adults: report from the panel members appointed to the Eighth Joint National 
Committee (JNC 8). JAMA. 2014; 311(5):507-520. 
Jorge E. Cortes, Carlo Gambacorti-Passerini, Michael W. Deininger, Michael J. Mauro, Charles Chuah, 
Dong-Wook Kim, Irina Dyagil, Nataliia Glushko, Dragana Milojkovic, Philipp le Coutre, Valentin 
Garcia-Gutierrez, Laurence Reilly, Allison Jeynes-Ellis, Eric Leip, Nathalie Bardy-Bouxin, Andreas 
Hochhaus, and Tim H. Brümmendorf. Bosutinib Versus Imatinib for Newly Diagnosed Chronic 
Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 2018 Jan 20; 36(3): 
231–237. 
Kelliher MA, McLaughlin J, Witte ON, et al. Introduction of a chronic myelogenous leukemia-like 
syndrome in mice with v-Abl and BCR/ABL. Proc Natl Acad Sci USA, 1990, 87; 6649-6653. 
Larson RA, Hochhaus A, Hughes TP, et al.  Nilotinib vs imatinib in patients with newly diagnosed 
Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year 
follow-up. Leukemia, 2012, 26: 2197-2203. 
Lauseker M, Hanfstein B, Haferlach C, et al. Equivalence of BCR-ABL transcript levels <1% according 
to the international scale with complete cytogenetic response in chronic phase CML patients. 
Abstract 2495. Presented at the 54th American Society of Hematology annual meeting, 2012. 
Atlanta, GA. Dec 8-11. 
Lee SE, Choi SY, Bang JH, et al. Predictive factors for successful imatinib cessation in chronic myeloid 
leukemia patients treated with imatinib. Am J Hematol, 2013, 88 (6): 449-454. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 96 of 100 
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine 
release syndrome. Blood 2014; 124: 188-195 
Mahon FX, Etienne G. Deep Molecular Response in Chronic Myeloid Leukemia: The New Goal of 
Therapy? Clin Cancer Res, 2014, 15;20(2): 310-322. 
Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid 
leukemia who have maintained complete molecular response: update results of the STIM study. 
Blood (ASH Annual Meeting Abstracts), 2011, 118: Abstract 603. 
Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid 
leukaemia who have maintained complete molecular remission for at least 2 years: the 
prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol, 2010, 11: 1029-1035. 
Marin D. Patient with chronic myeloid leukemia in complete cytogenetic response: what does it 
mean, and what does one do next? J Clin Oncol, 2014, 32: 379-384. 
Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only 
requirement for predicting outcome for patients with chronic myeloid leukemia treated with 
tyrosine kinase inhibitors. J Clin Oncol, 2012, 30: 232-238. 
Matsuki E, Ono Y, Sakurai M, et al. Discontinuation of imatinib in patients with CML and sustained 
complete molecular response (CMR) for over 2 years in the Japanese population – An interim 
analysis of KEIO STIM study. Blood, 2011, 118: 3765. 
Maude SL, Barrett D, Teachey DT, et al. Managing cytokine release syndrome associated with novel 
T cell-engaging therapies. Cancer J. 2014;20:119-122. 
Mori S, Vagge E, le Coutre P, et al. Age and dPCR can predict relapse in CML patients who discontinued 
imatinib: the ISAV study. Am J Hematol, 2015, 90: 910-914. 
National Comprehensive Cancer Network (2012). NCCN clinical practice guidelines in oncology. 
Available at:. Version 2.2018. 
Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science, 
1960, 132: 1497-1501. 
O'Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid 
leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer 
Cel, 2009, 16: 401-412. 
Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients 
with stable undetectable minimal residual disease: results from the TWISTER study. Blood, 2013, 
122: 515-522. 
Rousselot P, Charbonnier A, Cony-Makhoul P, et al. Loss of major molecular response as a trigger for 
restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous 
leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol, 2014, 32: 
424-430. 
Rousselot P, Makhoul PC, Rea D, et al. Fluctuating values of molecular residual disease (MRD) without 
molecular progression after imatinib discontinuation in patients (pts) with chronic myeloid 
leukemia (CML) who have maintained complete molecular response: implications for re- 
treatment criteria and role of prior interferon therapy. A pilot study of the French CML group 
(FILMC). Blood (ASH Annual Meeting Abstracts), 2011, 118: Abstract 3781. 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 97 of 100 
Rowley JD. A new consistent abnormality in chronic myelogenous leukemia identified by quinacrine, 
fluorescence and Giemsa staining. Nature, 1973, 243: 290-293. 
Saglio, G et al. EHA21 st 2016 meeting LB 618 
Saglio G, Kantarjian H, Shah N, et al. Early response (molecular and cytogenetic) and long-term 
outcomes in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): exploratory 
analysis of DASISION 3-year data. 54th American Society of Hematology annual meeting (Atlanta, 
GA), 2012, Abstract 1675.  
Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in "good-risk" chronic granulocytic 
leukemia. Blood. 1984 Apr;63(4):789-99. 
Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab 
treatment related to abnormal macrophage activation and ameliorated with cytokine-directed 
therapy. Blood. 2013;121:5154-5157 
Thygesen K, Alpert JS, Jaffe AS. Third universal definition of myocardial infarction. Circulation, 2012, 
126: 2020-2035. 
Tim H Brümmendorf, Jorge E Cortes, Cármino Antonio de Souza, Francois Guilhot, Ladan Duvillié, 
Dmitri Pavlov, Karïn Gogat, Athena M Countouriotis, and Carlo Gambacorti-Passerini. Bosutinib 
versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-
month follow-up of the BELA trial. Br J Haematol. 2015 Jan; 168(1): 69–81. 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 98 of 100 
APPENDIX A: Drug-induced QT prolongation and Torsades de Pointes 
Four categories of QT-prolonging drugs that may be used as a guide for this protocol can be accessed 
at http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs. Categories include “Drugs 
with Known TdP Risk,” “Drugs with Possible TdP Risk,” “Drugs with Conditional TdP Risk,” and “Drugs 
to be Avoided by Congenital Long QT Patients.”  The investigator site should register (under the “For 
Healthcare Providers” tab) to access these categories. If the investigator site does not wish to 
register, a composite list, including all categories, is available. 
Drugs with a known risk of torsades de pointes are listed in the table below, and are the only category 
of QT-prolonging drugs that are prohibited in this study. 
Note: The website and table are only to be used as a guideline and are not comprehensive. It is the 
investigator’s responsibility to ensure that any drugs under consideration have not been newly 
identified as causing torsades de pointes. 
Table A-1: Drugs generally accepted by the QTDrugs.org Advisory Board of the Arizona CERT to 
have a known risk of causing torsades de pointes; prohibited in this study 
Generic name 
Brand names 
Class / Clinical use 
Amiodarone 
Cordarone®, Pacerone®, Nexterone® 
Antiarrhythmic/abnormal heart rhythm 
Arsenic trioxide 
Trisenox® 
Anticancer/Leukemia 
Astemizole 
Hismanal® 
Antihistamine/Allergic rhinitis 
Azithromycin 
Zithromax®, Zmax® 
Antibiotic/bacterial infection 
Bepridil 
Vascor® 
Antianginal/heart pain 
Chloroquine 
Aralen® 
Antimalarial/malaria infection 
Chlorpromazine 
Thorazine®, Largactil®, Megaphen® 
Antipsychotic/Antiemetic/schizophrenia, 
nausea 
Cisapride 
Propulsid® 
GI stimulant/heartburn 
Citalopram 
Celexa®  
Antidepressant/depression 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic/bacterial infection 
Cocaine 
Cocaine 
Local anesthetic/topical anesthetic 
Disopyramide 
Norpace® 
Antiarrhythmic/abnormal heart rhythm 
Dofetilide 
Tikosyn® 
Antiarrhythmic/abnormal heart rhythm 
Domperidone 
Motilium®, Motillium®, Motinorm®, Costi®, Nomit® 
Antinausea/nausea 
Dronedarone 
Multaq® 
Antiarrhythmic/atrial fibrillation 
Droperidol 
Inapsine®, Droleptan®, Dridol®, Xomolix®  
Sedative; 
antinausea/anesthesia 
adjunct, 
nausea 
Erythromycin 
Erythrocin®, E.E.S. ®, Robimycin®, Erymax®, Ery-
Tab®, Eryc Ranbaxy®, Erypar®, Eryped®, Erythrocin 
Stearate 
Filmtab®, 
Erythrocot®, 
E-Base®, 
Erythroped®, Ilosone®, MY-E®, Pediamycin®, 
Zineryt®, Abboticin®, Abboticin-ES®, Erycin®, PCE 
Dispertab®, Stiemycine®, Tiloryth® 
Antibiotic; GI stimulant/bacterial infection; 
increase GI motility 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 99 of 100 
Generic name 
Brand names 
Class / Clinical use 
Escitalopram 
Cipralex®, Lexapro®, Nexito®, Anxiset-E®, Exodus®, 
Esto®, Seroplex®, Elicea®, Lexamil®, Lexam®, Entact®, 
Losita®, Reposil®, Animaxen®, Esitalo®, Lexamil® 
Antidepressant/major 
depression, 
anxiety 
disorders 
Flecainide 
Tambocor®, 
Almarytm®, 
Apocard®, 
Ecrinal®, 
Flécaine® 
Antiarrhythmic/abnormal heart rhythm 
Halofantrine 
Halfan® 
Antimalarial/malaria infection 
Haloperidol 
Haldol®, 
Aloperidin®, 
Bioperidolo®, 
Brotopon®, 
Dozic®, 
Duraperidol®, 
Einalon 
S®, 
Eukystol®, 
Halosten®, Keselan®, Linton®, Peluces®, Serenace®, 
Serenase®, Sigaperidol® 
Antipsychotic/schizophrenia, agitation 
Ibutilide 
Corvert® 
Antiarrhythmic/abnormal heart rhythm 
Levomethadyl 
Orlaam® 
Opiate 
agonist/pain 
control, 
narcotic 
dependence 
Mesoridazine 
Serentil® 
Antipsychotic/schizophrenia 
Methadone 
Dolophine®, Symoron®, Amidone®, Methadose®, 
Physeptone®, Heptadone® 
Opiate 
agonist/pain 
control, 
narcotic 
dependence 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
Antibiotic/bacterial infection 
Ondansetron 
Zofran®, Anset®, Ondemet®, Zuplenz®, Emetron®, 
Ondavell®, 
Emeset®, Ondisolv®, Setronax® 
Somatostatin analog/nausea and vomiting 
Pentamidine 
Pentam®, NebuPent® 
Antiinfective/pneumocystis pneumonia 
Pimozide 
Orap® 
Antipsychotic/Tourette's tics 
Probucol 
Lorelco® 
Antilipemic/Hypercholesterolemia 
Procainamide 
Pronestyl®, Procan® 
Antiarrhythmic/abnormal heart rhythm 
Quinidine 
Quinaglute®, Duraquin®, Quinact®, Quinidex®, Cin-
Quin®, Quinora® 
Antiarrhythmic/abnormal heart rhythm 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general/anesthesia 
Sotalol
 
Betapace®, Sotalex®, Sotacor® 
Antiarrhythmic/abnormal heart rhythm 
Sparfloxacin 
Zagam® 
Antibiotic/bacterial infection 
Terfenadine 
Seldane® 
Antihistamine/Allergic rhinitis 
Thioridazine
 
Mellaril®, Novoridazine®, Thioril® 
Antipsychotic/schizophrenia 
Vandetanib 
Caprelsa® 
Anticancer/thyroid cancer 
 
 


Clinical Trial Protocol 
Protocol number: ZEROLMC-01 
EudraCT:  2020-000166-41 
Date: 05/May/2021 
Version 2.0 
 
 
Confidential 
 
Page 100 of 100 
APPENDIX B: National Cancer Institute Common Terminology Criteria for Adverse 
Events 
The United States of America (USA) National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 5.0 (NCI CTCAE, v5.0) can be found on the following website: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
This version of CTCAE is compatible at the AE term level where each CTCAE term is a Medical 
Dictionary for Regulatory Activities Terminology Lowest Level Term (MedDRA LLT). CTCAE version 5.0 
includes 837 AE terms. Each AE term is associated with a 5-point severity scale. 

SAP_001.pdf: 
ZEROMLC-01 
 
April 06, 2021 
 
Page 1 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
Multicenter, open-label, Phase Ib/II trial to evaluate safety and efficacy for the 
combination of bosutinib plus atezolizumab in newly diagnosed chronic myeloid 
leukemia patients 
 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 2 
 
Table of contents 
 
1. Administrative Information: .................................................................................. 4 
1.1. Title and trial registration: ......................................................................................... 4 
1.2. Statistical Analysis Plan version: ................................................................................ 4 
1.3. Protocolversion: ........................................................................................................ 4 
1.4. StatisticalAnalysis Plan revisions: ............................................................................... 5 
1.5. StatisticalAnalysis Plan contributors: ......................................................................... 5 
2. Abbreviations ....................................................................................................... 6 
3. Introduction ........................................................................................................ 10 
3.1. Background: ............................................................................................................ 10 
3.2. Objectives: .............................................................................................................. 12 
4. Study Methods ................................................................................................... 14 
4.1. Trial design:............................................................................................................. 14 
4.2. Randomization: ....................................................................................................... 16 
4.3. Sample size: ............................................................................................................ 16 
4.4. Statistical interim analysis and stopping guidance: ................................................... 16 
4.5. Timing of final analysis: ........................................................................................... 17 
5. Trial Population .................................................................................................. 17 
5.1. Screening data and recruitment ............................................................................... 17 
5.2. Eligibility criteria ..................................................................................................... 18 
5.3. Withdrawal/follow-up ............................................................................................. 21 
6. Statistical Principles ............................................................................................ 22 
6.1. General features ..................................................................................................... 22 
6.2. Analysis Populations................................................................................................ 22 
6.3. Baseline patient characteristics ................................................................................ 23 
6.4. Outcome definitions ................................................................................................ 24 
6.5. Analysis methods .................................................................................................... 25 
6.6. Missing data ............................................................................................................ 26 
6.7. Sensitivity analysis .................................................................................................. 26 
6.8. Subgroup analysis ................................................................................................... 26 


ZEROMLC-01 
 
April 06, 2021 
 
Page 3 
6.9. Safety data analysis ................................................................................................. 26 
6.10. References ............................................................................................................ 29 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 4 
1. Administrative Information: 
 
1.1. Title and trial registration: 
 
Title: 
 
 
 
 
 
Multicenter, open-label, Phase Ib/II trial to 
evaluate safety and efficacy for the combination 
of 
bosutinib 
plus 
atezolizumab 
in 
newly 
diagnosed chronic myeloid leukemia patients 
Protocol Number: 
ZEROLMC-01 
 
 
Study phase: 
 
Ib/II 
 
Product Name: 
 
Bosutinib (Bosulif®, Pfizer) and Atezolizumab 
(Tecentriq®, Roche Registration GMBH) 
 
 
EudraCT Number: 
 
2020-000166-41 
 
Sponsor: 
 
 
 
 
Fundación ZeroLMC (Fundación Española para 
la curación de la Leucemia Mieloide Crónica) 
Plaza San Francisco, S/N, portal 13, planta 1, 
puerta 5 
50006 Zaragoza 
 
 
1.2. Statistical Analysis Plan version: 
 
Version: SAP version 1.0 
SAP Issue Date: April 06, 2021 
 
 
1.3. Protocol version: 
 
Version1.2 


ZEROMLC-01 
 
April 06, 2021 
 
Page 5 
 
1.4. Statistical Analysis Plan revisions: 
 
Revision Date 
Justification 
N/A 
N/A 
 
 
 
 
 
 
 
1.5. Statistical Analysis Plan contributors: 
 
Names 
Affiliations 
Role of contributor 
Pedro Zapater 
Universidad Miguel Hernández Coordinator 
José Vicente Segura 
Universidad Miguel Hernández Biostatistician 
María de los Ángeles Pena 
Universidad Miguel Hernández Collaborator 
 
 
 
 
Signatures 
 
 
 
Pedro Zapater 
 
 
 
José Vicente Segura 
 
 
 
María de los Ángeles Pena 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 6 
2. Abbreviations 
 
Abbreviation 
Definition 
2GTKIs  
2nd Generation Tyrosine Kinase Inhibitors  
ABL  
Abelson leukemia oncogene 
AC  
Accelerated Phase 
ACTH  
Adrenocorticotropic Hormone  
AE  
Adverse Event 
AEMPS  
Agencia Española de Medicamentos y Productos Sanitarios  
AESI  
Adverse Event of Special Interest  
ALT  
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT  
ANC  
Absolute Neutrophil Count 
AP  
Accelerated Phase 
AST  
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT  
AUC  
Area Under the Curve  
BAL  
Bronchoalveolar lavage 
BC  
Blast Crisis  
BCR  
Break point Cluster Region 
BCR-ABL  
BCR-ABL oncoprotein product of BCR-ABL fusion gene  
BM  
Bone Marrow 
BP  
Blast Phase 
BUN  
Blood Urea Nitrogen 
CBC  
Complete blood count 
CCAA  
Comunidades Autónomas (Autonomous Communities)  
CCyR 
Complete Cytogenetic Response  
CEIm 
Ethics committees for investigation with medicinal products.  
CHF  
Congestive Heart Failure 
CHR  
Complete Hematologic Response  
CIB  
Clinical Investigator’s Brochure 
CML  
Chronic Myeloid Leukemia 
CMR  
Complete Molecular Response  
CP  
Chronic Phase 
CP-CLM  
Chronic phase Chronic Myeloid Leukemia  
CRA  
Clinical Research Associate 
CRF  
Case Report/Record Form; the term CRF can be applied to either EDC or paper  
CRO  
Clinical Research Organisation 
CRP  
C-Reactive Protein 
CSP  
Clinical Study Protocol 
CSR  
Clinical Study Report 
CT  
Computed Tomography 
CTA  
Clinical Trial Assistant 
CTCAE  
NCI Common Terminology Criteria for Adverse Events  
CV  
Coefficient of Variation 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 7 
Abbreviation 
Definition 
CYP3A4  
Cytochrome 3A4  
CyR 
Cytogenetic Response  
DLT  
Dose-Limiting Toxicity 
EC  
European Commission 
eCFR 
Electronic Case Report Form 
ECG  
Electrocardiogram 
ECHO  
Echocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report/record Form  
EDC  
Electronic Data Capture  
ELN  
European Leukemia Net  
EMA  
European Medicines Agency  
EOS  
End of Study 
EOT  
End of Treatment 
ESR  
Expedited Safety Report 
FAS  
Full Analysis Set  
FDA  
Food and Drug Administration (USA)  
FISH  
Fluorescent In-Situ Hybridization 
FPFV  
First Patient First Visit 
FTH  
Fundación Teófilo Hernando  
GCP  
Good Clinical Practice 
GELMC  
Grupo Español de Leucemia Mieloide Crónica  
GGT  
Gamma-glutamil transpeptidase 
ICF  
Informed Consent form 
ICH  
International Council of Harmonization 
IEC  
Independent Ethics Committee 
IFN  
Interferon 
IL-2  
Interleukin-2  
IM  
Imatinib  
IMP  
Investigational Medicinal Product 
IRB  
Institutional Review Board 
IRR  
Infusion-Related Reaction 
IS  
International Scale 
IUD  
Intra Uterine Device 
IUS  
Intra Uterine System 
IV  
Intravenous 
IVIG  
Intravenous Immunoglobulin 
Kg  
Kilogram 
LFT  
Liver Function Test  
LN  
Lymph Node 
LPLV  
Las Patient Last Visit 
LVEF  
Left Ventricular Ejection Fraction 
 
 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 8 
Abbreviation 
Definition 
MCyR 
Major Cytogenetic Response  
MCyR 
Minor Cytogenetic Response  
MDSC  
Myeloid Derived Suppressor Cells 
MedDRA  
Medical Dictionary for Regulatory Activities  
mg  
milligram 
MMR  
Major Molecular Response  
MR  
Molecular Response  
MR4  
Molecular Response 4.0 log reduction from baseline  
MR4.5  
Molecular Response 4.5 log reduction from baseline  
MRI  
Magnetic Resonance Imaging 
MTD  
Maximum Tolerated Dose 
N/A  
Not Applicable 
NCCN  
National Comprehensive Cancer Network  
n-TEAE  
No Treatment Emerged Adverse Event  
NYHA  
New York Heart Association 
OD  
Once Daily 
OS  
Overall Survival 
PCR  
Polymerase Chain Reaction 
PCyR 
Partial Cytogenetic Response  
PD-L1  
Programmed Death-ligand 1  
PFS  
Progression Free Survival 
Ph+  
Philadelphia chromosome 
PHI  
Protected Health Information 
PPS  
Per-Protocol Set  
Pts 
Patients 
Q2WK  
Every 2 weeks 
QD  
Once a Day  
QT  
QT interval; a measure of the time between the start of the Q wave 
and the end of the T wave in the heart's electrical cycle  
QTcF 
QT interval corrected (Fridericia)  
REB  
Research Ethics Board 
REec 
Registro Español de Estudios Clínicos  
RP3D  
Recommended Phase III Dose 
RR  
Relative Risk 
RT-qPCR 
Real Time-Quantitative Reverse Transcription PCR  
SAE  
Serious Adverse Event 
SD  
Standard Deviation 
SOP  
Standard Operating Procedure 
SS  
Safety Set  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
TBil 
Total Bilirubin 
TEAE  
Treatment Emerged Adverse Event 
 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 9 
Abbreviation 
Definition 
TFR  
Treatment-Free Remission 
TFS  
Treatment-Free Survival 
TKI  
Tyrosine Kinase Inhibitor 
Treg 
Regulatory T cells 
TSH  
Thyroid Stimulating Hormone  
ULN  
Upper Limit of Normal  
VAD  
Ventricular Assist Device 
VOE  
Vascular Occlusive Event 
WBC  
White Blood Cell  
WHO  
World Health Organization 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 10 
3. Introduction 
 
3.1. Background: 
 
Chronic Myeloid Leukemia (CML) is a haematological stem cell disorder 
associated with a specific chromosomal translocation known as the Philadelphia 
(Ph) chromosome; it is found in 95% of patients. The translocation consists in 
the fusion of the ABL proto-oncogene with the BCR gene, resulting in the 
production of an activated form of the ABL protein-tyrosine kinase. Expression 
of the BCR-ABL protein causes leukemia in mice, suggesting this protein is 
linked to disease pathogenesis. 
Clinically, CML progresses through three distinct phases of increasing 
refractoriness to therapy: chronic phase (CP) (median duration 3-4 years; 
median survival up to 10 years with allogenic bone marrow transplant and 5-6 
years with interferon (IFN), accelerated phase (AP) (median duration 3-9 
months; median survival 8-18 months), and blast crisis (BC) (median survival 3-
6 months). Most patients suffer the CP form, which is characterized by 
splenomegaly and leukocytosis with generally few symptoms. 
National Comprehensive Cancer Network (NCCN) guideline on CML 
(NCCN guideline v1.2019) and European Leukemia Net (ELN) recommend 
continuing tyrosine kinase inhibitor (TKI) treatment (i.e., imatinib, nilotinib, 
dasatinib, ponatinib, bosutinib) indefinitely in all responding patients. Treatment 
discontinuation may be considered in individual patients, also outside studies, if 
proper, high-quality, and certified monitoring can be ensured at monthly 
intervals. 
Imatinib (IM) rapidly became the gold standard therapy in CML that 
dramatically changed the prognosis of the disease. More potent second-
generation tyrosine-kinase inhibitors (TKI) have been consecutively developed 
to counteract resistance to IM in a substantial proportion of patients such as 
dasatinib, nilotinib, bosutinib and ponatinib. Efficacy of second and third 
generation TKIs was first shown in second-line therapy for patients intolerant or 
resistant to IM. Superiority of dasatinib and nilotinib over IM was thereafter 
demonstrated in first-line therapy (DASISION and ENESTnd phase III trials), in 
terms of achievement of complete cytogenetic response (CCyR) at 12 months 


ZEROMLC-01 
 
April 06, 2021 
 
Page 11 
and an increased rates of major molecular responses (MMR) and deep 
molecular responses.  
Bosutinib is an oral, once-daily, second-generation tyrosine kinase 
inhibitor, with a manageable and distinct safety profile. Bosutinib exhibits dose-
proportional increases in exposure between 200 and 600 mg, and its absorption 
increases with food. It has extensive tissue distribution, is highly bound to 
plasma proteins, and is primarily metabolized in the liver by cytochrome P450 
(CYP) 3A4. Hepatic and renal impairment increases the exposure to bosutinib. 
Metabolic drug–drug interactions of bosutinib are limited in scope to CYP3A 
inhibitors and inducers but are significant in their extent. Co-administration of 
bosutinib with strong or moderate CYP3A inhibitors or inducers should be 
avoided. 
Bosutinib is used for the treatment of chronic phase (CP), accelerated 
phase (AP), and blast phase (BP) Philadelphia chromosome-positive chronic 
myelogenous leukaemia (Ph+ CML) previously treated with one or more 
tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib 
are not considered appropriate treatment options. 
Atezolizumab is a monoclonal antibody targeting programmed death 
ligand 1 (PD-L1 or CD274 antigen). PD-L1 is thought to play an important role 
in suppressing the immune system triggered by disease, by reducing the 
proliferation of antigen specific CD8+ T-cells and controlling the accumulation of 
foreign antigen-specific T-cells. Up-regulation of PD-L1 has been suggested as 
a mechanism used by cancer cells to evade the host immune system. 
Since the introduction of imatinib and subsequent second-generation 
tyrosine kinase inhibitors (2GTKIs), the prognosis of chronic-phase Chronic 
Myeloid Leukemia (CP-CML) has improved greatly. Initially considered to be a 
lethal disease with a median estimated overall survival (OS) of 3.2 years, CP-
CML is now regarded as a chronic disease with a life expectancy similar to that 
of the healthy population. However, CML patients, despite their treatment 
response, cannot be considered cured and should take the treatment 
indefinitely. 
Recently, data from different clinical trials have shown how a minority of 
patients who achieve a deep molecular response with imatinib and maintain the 
response, could stop treatment safety. Therefore, treatment free remission 


ZEROMLC-01 
 
April 06, 2021 
 
Page 12 
(TFR) has been established as a new goal for CML patients. However, 
currently, TFR is only available for a small group of patients since deep 
molecular response is achieved by 5 years only in approximately 20% of 
patients treated with imatinib, and unfortunately, 50% of patients will eventually 
relapse. In addition, recent data have shown a time exposure to imatinib longer 
than 7 years as a prognostic factor for TFR. Starting treatment with 2GTKIS 
(dasatinib, nilotinib and bosutinib) have demonstrated higher probabilities of 
deep molecular responses. 
We know how PD-1 is expressed at diagnosis in CML patients on T cells, 
and that its expression considerable decreases after achieving deep molecular 
response. The combination of TKI plus interferon has translated into higher 
probabilities of deep molecular responses compared to TKI monotherapy in 
several clinical trials. Atezolizumab is engineered to eliminate binding to Fc 
receptors and to prevent Fc-effector function. This modification eliminates 
antibody-dependent cell mediated cytotoxicity and thus avoids potential loss of 
PD-L1-expressing T-effector cells and reduced anticancer immunity. 
The combination of bosutinib plus atezolizumab in first line CML chronic 
phase patients would increase molecular responses and therefore TFR 
probabilities in newly diagnosed CML patients. 
 
3.2. Objectives: 
 
Primary Objective: 
The primary objective is to evaluate the safety profile of bosutinib 400mg/day in 
combination with atezolizumab as a first line treatment in participants with 
chronic phase-chronic myeloid leukemia. 
Key Secondary Objectives: 
 To evaluate the Major Molecular Response (MMR) and Molecular 
Response (MR) rates at 3, 6, 12 months and at the End of Treatment 
(EoT) visit. Based on: 
◦ MMR is defined as ≥ 3-log reduction in BCR-ABL transcripts or a ratio 
of ≤ 0.1% on the International Scale (IS) 


ZEROMLC-01 
 
April 06, 2021 
 
Page 13 
◦ Molecular Response (MR): defined as 
▪ MMR – BCR-ABL ≤ 0.1% (IS). 
▪ MR4 – BCR-ABL ≤ 0.01% (IS). 
▪ MR4.5 ≤ 0.0032% (IS). 
▪ UNDETECTABLE. 
 Percentage of participants alive at months 6 and 12 and at the EoT visit. 
 Number of confirmed MR4 and MR4.5 at end of treatment. 
 The rate of confirmed MR4 and MR4.5 at the end of treatment. 
 Number of Complete Cytogenetic Responses (CCyR) at 1 year] 
 The rate of Complete Cytogenetic Response (CCyR) at 1 year. 
 Number of days to response (CCyR, MMR, MR4, MR4.5). [Time Frame: 
at the EoT visit] 
 The median time to response and the overall estimated probability of 
response (CCyR, MMR, MR4, MR4.5). 
 Number of overall surviving patients [Time Frame: at the EoT visit] 
 Number of progression-free survival patients.[Time Frame: at the EoT 
visit] 
 Number of failure-free survival patients. [Time Frame at the EoT visit] 
 Number of event-free survival patients. [Time Frame: at the EoT visit] 
 Immunological Studies  
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 14 
4. Study Methods 
 
4.1. Trial design: 
This is a phase Ib/II, two arms, open-label and dose-escalation study designed 
to determine the safety profile and the recommended phase III dose (RP3D) of 
bosutinib when administered in combination with atezolizumab in naïve patients 
with chronic myeloid leukemia in chronic phase. This study has two groups of 
patients. 
First therapy 
All patients included, both the first 10 patients and the next 26 patients, will 
receive bosutinib 400 mg/day in monotherapy during one cycle of treatment. All 
patients who tolerate this cycle of bosutinib treatment will continue to the 
second therapy (bosutinib plus atezolizumab). 
Second Therapy  
Group 1: The first 10 patients 
Only for the first ten patients included in the study, atezolizumab will be 
introduced at a dose of 840 mg every two weeks combined with 400 mg/day of 
bosutinib for 2 cycles (8 weeks). These patients will be closely monitored for 
safety issues. 
If dose-limiting toxicities (DLTs) appear in 2 or more patients the study will end. 
A DLT would include either of the following adverse events that occurred during 
bosutinib therapy in combination with atezolizumab, if it is considered at least 
possibly related to bosutinib and/or atezolizumab: 
• Grade 4 neutropenia (<500/l) persisting for > 7 day duration or Grade 4 
white cell count decrease for >7 day duration (<1000/l). 
• Febrile neutropenia (ANC<1000/l and fever ≥38.5°C). 
• Grade 4 thrombocytopenia > 48 hour duration or with bleeding requiring 
platelet transfusion. 
• Any Grade 3 or 4 clinically evident non-hematological toxicity. 


ZEROMLC-01 
 
April 06, 2021 
 
Page 15 
• Any ≥Grade 3 toxicity that requires >14 days to resolve (to ≤Grade 1 
despite optimal medical therapy). 
DTLs will be graded according to the NCI CTCAE, v5.0. 
If no relevant safety issue, regarding the combination is detected the study will 
continue. 
These initial 10 patients will cross-over from bosutinib 400 mg/day plus 
atezolizumab 840 mg every 2 weeks to bosutinib 400 mg/day plus atezolizumab 
1680 mg every 4 weeks for 10 cycles (40 weeks). 
Group 2: The next 26 patients 
After receiving bosutinib 400 mg/day in monotherapy for one cycle (1st 
therapy), the last 26 patients included will receive bosutinib 400 mg/day plus 
atezolizumab 1680 mg every 4 weeks for 12 cycles. 
Patients will continue to be closely monitoring. If DLTs appear in 2 or more 
patients at a dose of 1680 mg of Atezolizumab every 4 weeks, the dose of 
atezolizumab will be reduced for all patients to an 840 mg Atezolizumab every 2 
weeks dose. 
Third Therapy 
All patients completing 12 treatment cycles (48 weeks) will begin the last 
therapy of study. 


ZEROMLC-01 
 
April 06, 2021 
 
Page 16 
 
 
 
4.2. Randomization: 
Randomization does not apply. 
 
4.3. Sample size: 
There will be no formal calculation of the sample size. The sample size is 
selected to allow sufficient data collection for the DLT and safety assessment. It 
is an exploratory study. The minimum number of patients for the DLT evaluation 
will be 10 if no DLT is observed. After MTD is calculated, 26 more patients will 
be recruited for the dose variation phase. 36 patients (both, a first group of 10 
patients and a second of 26 patients) will receive bosutinib 400 mg/day in 
monotherapy during one cycle of treatment. According to previous experience, 
we assume that, at most, 15% of the patients included will not enter the dose 
escalation phase after the first month of treatment with bosutinib, due to side 
effects. Consequently, a total of 30-31 patients will receive the combination of 
bosutinib plus atezolizumab. 
4.4. Statistical interim analysis and stopping guidance: 
There are no interim analyses planned. 


ZEROMLC-01 
 
April 06, 2021 
 
Page 17 
 
4.5. Timing of final analysis: 
Primary outcome, adverse events, will be recorded continuously throughout the 
study, starting on the date of the first administration of the study medication, 
and, at least, up to the 28-day follow-up visit after the last dose of treatment. 
 
5. Trial Population 
5.1. Screening data and recruitment 
The target population of this study includes naïve adult patients of both genders 
with chronic myeloid leukemia in chronic phase. 
Written informed consent must be obtained before performing any study specific 
medical procedures. The screening visit will take place at study days -28 to 
zero.  
The screening RT-qPCR blood sample will be analyzed by a Sponsor 
designated central laboratory. In case the BCR-ABL1 status cannot be 
determined on this sample (e.g., due to technical or logistical issues) another 
blood sample for RT-qPCR is to be collected immediately and submitted to the 
central laboratory for determination of the BCR-ABL1 status. 
Laboratory baseline assessments (including hematology and chemistry), 
physical examination including performance status, height, weight, ECG and 
vital signs must be performed within 28 days prior to Cycle 1/study Day 1, 
before the first IMP dose. As long as a patient that has signed the IC fulfil all 
inclusion criteria and none of the exclusion criteria, he/she could be included in 
this study. 
 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 18 
5.2. Eligibility criteria 
Inclusion Criteria -Patients eligible for inclusion in this study have fulfil the 
following criteria: 
1. Male or female patient ≥ 18 years of age. 
2. Evidence of a personally signed and dated informed consent document 
indicating that the patient (or a legal representative) has been informed 
of all pertinent aspects of the study. 
3. Patients who are willing and able to comply with scheduled visits, 
treatment plan, laboratory tests, and other study procedures 
4. Newly Patient with Philadelphia chromosome positive chronic phase 
CML and BCR-ABL1 transcript detected at diagnosis. 
5. ECOG Performance Status of 0, 1, or 2. 
6. Adequate hepatic, renal and pancreatic function defined as: 
a. Total bilirubin within normal range or Direct bilirubin ≤ 1.5 x ULN, 
b. Aspartate 
aminotransferase 
(AST)/Alanine 
aminotransferase 
(ALT) ≤2.5 x upper limit of normal (ULN) or ≤5 x ULN if attributable 
to liver involvement of leukemia, 
7. Have a negative pregnancy test documented prior to enrolment (for 
females of childbearing potential). A woman is considered of childbearing 
potential, i.e., fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilization methods 
include 
hysterectomy, 
bilateral 
salpingectomy 
and 
bilateral 
oophorectomy (CTFG, 21/09/2020). These women must have a negative 
serum or urine pregnancy test before initiation of study treatment and 
must also use highly effective methods of contraception while enrolled in 
the study. The use of highly effective contraception should continue for at 
least 14 days after the last dose of study treatment. Acceptable forms of 
highly effective contraception methods include (CTFG, 21/09/2020): 
a. Total abstinence [when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception] 
b. Male/female sterilization. These defined as: 


ZEROMLC-01 
 
April 06, 2021 
 
Page 19 
i. Female 
sterilization 
(have 
had 
surgical 
bilateral 
oophorectomy with or without hysterectomy) or tubal 
ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed and documented 
by follow-up hormone level assessment. 
ii. Male sterilization (at least 6 months prior to screening). For 
female patients on the study, study participation assumes 
the vasectomised male partner is the sole partner for that 
patient. 
c. Contraceptive methods: 
i. Combined 
(estrogen 
and 
progestogen 
containing) 
hormonal contraception associated with inhibition of 
ovulation: oral, intravaginal, or transdermal. 
ii. Progestogen-only hormonal contraception associated with 
inhibition of ovulation: oral, injectable, or implantable. 
iii. Placement of an intrauterine device (IUD) or intrauterine 
system (IUS). 
Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy with or without hysterectomy or tubal ligation 
at least six weeks prior to enrolling. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment is she 
considered not of child bearing potential. 
If a study patient gets pregnant or is suspected of being pregnant 
during the study or within 30 days as part of safety evaluations after 
the final dose of bosutinib, the study Doctor needs to be informed 
immediately and any ongoing study treatment with bosutinib has to 
be stopped immediately. 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 20 
 
Exclusion Criteria - Patients eligible for this study must not fulfil the following 
criteria: 
1. Pregnant or lactating women, 
2. Participation in another clinical trial with any investigational drug within 
30 days prior to study enrolment, 
3. Any prior medical treatment for CML including tyrosine kinase inhibitors 
(TKIs) with the exception of hydroxyurea, 
4. Period of time since CML diagnosis longer than 6 months, 
5. Hypersensitivity to the active substances or to any of the excipients of 
the bosutinib and/or atezolizumab formulations, 
6. Major surgery or radiotherapy within 14 days of enrolment, 
7. Known clinically significant liver disease, including active viral, alcoholic, 
or other hepatitis, cirrhosis, and inherited liver disease, 
8. Concomitant use of or need for medications known to prolong the QT 
interval, 
9. Concomitant 
use 
with 
strong 
CYP3A 
inhibitors 
(ketoconazole, 
itraconazole, clarithromycin), moderate CYP3A inhibitors (erythromycin, 
fluconazole, 
diltiazem), 
or 
strong 
CYP3A 
inducers 
(rifampin, 
carbamazepine, phenytoin), 
10. History of clinically significant or uncontrolled cardiac disease, including: 
a. Stage II to IV congestive heart failure (CHF) as determined by the 
New York Heart Association (NYHA) classification system for 
heart failure, 
b. Myocardial infarction within the previous 6 months, 
c. Symptomatic cardiac arrhythmia requiring treatment, 
d. Diagnosed or suspected congenital or acquired prolonged QT 
history or prolonged QTc. (QTcF should not exceed 500 msec), 
11. Grade III or IV fluid retention, 
12. Uncontrolled 
hypomagnesemia 
or 
uncorrected 
symptomatic 
hypokalemia, due to potential effects on the QT interval, 
13. Uncontrolled or symptomatic hypercalcemia, 


ZEROMLC-01 
 
April 06, 2021 
 
Page 21 
14. Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. 
Crohn's Disease, Ulcerative Colitis or prior total or partial gastrectomy, 
15. Autoimmune or infectious active disease that require treatment, 
16. CML patient not in chronic phase at diagnosis, 
17. Patients with known atypical transcript. An atypical transcript is defined 
by the presence of any transcript in the absence of the major transcripts 
b3a2 (e14a2) and b2a2 (e13a2) or p210 protein, 
18. Patients with known resistant mutation(s) (T315I, E255K/V, Y253H, 
F359C/V). It is not necessary to perform mutation tests on the patient to 
be included in the study if they were not previously performed, 
19. Individuals with an active malignancy, 
20. Known seropositivity to human immunodeficiency virus (HIV), current 
acute or chronic hepatitis B (hepatitis B surface-antigen positive) and/or 
hepatitis C, 
21. Any other disease, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding that contraindicates the use of an 
investigational drug, 
22. Patients with severe renal impairment. 
 
 
5.3. Withdrawal/follow-up 
Patients may suspend their participation in the study whenever they wish, 
based on his/her own judgement and opinion, without giving any explanation, 
although the investigator may investigate the reasons of a voluntary dropout. 
The investigator may also decide to withdraw a patient from the trial if he/she 
does not comply with the protocol, due to AEs or treatment inefficacy or toxicity. 
Patients who do not comply with at least 70% of the scheduled doses of 
bosutinib or that, in 4 or more times, the administration of atezolizumab is 
cancelled, will be withdrawn from the study. 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 22 
6. Statistical Principles 
6.1. General features 
 
Principal features of this analysis have been specified in the protocol according 
to ICH E3 (“Structure and content of clinical study reports”) and ICH E9 
(“Statistical Principles for Clinical Trials” and addendum Draft R1). 
This is a phase Ib/II, single arm, open-label and dose-escalation study designed 
to determine the safety profile and the recommended phase III dose of bosutinib 
when administered in combination with atezolizumab in naïve patients with 
chronic myeloid leukemia in chronic phase. 
The investigator should document and explain any deviation from the approved 
protocol. All significant protocol deviations will be recorded and reported in the 
Clinical Study Report. 
 
6.2. Analysis Populations 
All data will be received from the sponsor duly anonymized. All analyzes carried 
out and results of software applications will be duly dated and stored. 
 
Full Analysis Set: The full analysis set (FAS) comprises all patients who 
complete the first three phases of treatment (combination of bosutinib and 
atezolizumab) successfully. 
Safety Set: The safety set (SS) includes all patients who received at least one 
dose of study medication. Reporting and analysis of safety information for these 
patients will be split into subsets by study phases. 
Per-Protocol Set: The per-protocol set (PPS) consists of a subset of the 
patients in the FAS who are compliant with requirements of the clinical study 
protocol (CSP).A compliance of 70% with bosutinib treatment will be necessary 
to be included in the PPS. Protocol deviations leading to exclusion from the 
PPS will be detailed in the Clinical Study Report. 
 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 23 
6.3. Baseline patient characteristics 
Demographic and other baseline data will be summarized descriptively for both 
the SS and the FAS. The list of baseline patient characteristics to be 
summarized is: 
 
Variables 
Type of variables 
Medical/Surgical History:  
Diagnoses. Medical and surgical treatments.  
Categorical nominal 
Recent Medication Prior to 
First Dose of IMP 
The relevant medication at the time of the IC 
signature will be obtained from each patient at the 
time of screening and before the first IMP dose.  
Categorical nominal 
Demographic information 
Gender 
Age 
Race 
Categorical nominal 
Continuous 
Categorical nominal 
Leukemia Diagnosis and 
Prior Cancer Therapy 
Initial leukemia diagnosis. Screening diagnosis 
Categorical nominal 
Sokal Risk Score 
Sokal risk score 
Continuous 
ECOG 
ECOG Performance Status(0, 1, 2, 3, 4, 5) 
Categorical ordinal  
Vital signs 
Temperature. Pulse. Respiratory rate. Blood 
pressure 
Continuous 
Weight and Height 
Height (cm). Body weight (Kg; 1 decimal) 
Continuous 
Physical Examination and 
Extra-medullary Leukemia 
Involvement 
Examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, 
vascular and neurological. Findings on physical 
examination 
consistent 
with 
extra-medullary 
leukemic involvement will be recorded (e.g., lymph 
nodes, liver, and spleen size). 
Categorical nominal 
Blood Samples for BCR-
ABL Molecular Response 
Assessment 
Percent ratio of BCR-ABL transcripts versus 
control gene transcripts converted to IS 
Continuous 
Complete Blood Count with 
Differential 
Peripheral 
total 
white 
blood 
cell 
count, 
hemoglobin, hematocrit, platelet count, red blood 
cell count, leucocytes, absolute neutrophil count 
(ANC), and WBC differential 
Continuous 
Serum chemistry 
sodium, potassium, blood urea nitrogen (BUN) or 
urea, fasting glucose, albumin, creatinine, total 
cholesterol, triglycerides, total bilirubin (direct and 
indirect, only if total bilirubin is out normal range), 
GOT, GPT, GGT, alkaline phosphatase, LDH, 
magnesium, phosphorous and calcium. Amylase 
and lipase determinations will be added only in 
screening and during bosutinib plus atezolizumab 
combination treatment. 
Continuous 
Serology 
Hepatitis B serology (Hepatitis B surface antigen, 
Hepatitis B core antibody, and Hepatitis B surface 
antibody) hepatitis C and HIV 
Categorical nominal 
Bone Marrow Analysis and 
Cytogenetics 
Percentage of Ph+ metaphases in the bone 
marrow and is defined as complete, partial, minor, 
minimal and none 
Continuous 
Categorical nominal 
Pregnancy Test 
hCG laboratory test 
Categorical nominal 
12-Lead Electrocardiogram 
QTcF interval 
Continuous 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 24 
6.4. Outcome definitions 
The primary objective is to evaluate the safety profile of bosutinib 400 mg 
daily in combination with atezolizumab as first line treatments in 
participants with chronic myeloid leukemia. The safety set population will 
be used for all safety analyses. For a detailed description of safety 
variables analysis see the 6.9 Safety Data Analysis section. 
 
 Secondary variables: 
o Major Molecular Response (MMR) and Molecular Response (MR) 
rates at 3, 6, 12 months and at the End of Treatment (EoT) visit. 
o Percentage of participants alive at months 6 and 12 and at the 
EoT visit. 
o Number of confirmed MR4 and MR4.5 at end of treatment. 
o The rate of confirmed MR4 and MR4.5 at the end of treatment. 
o Number of Complete Cytogenetic Responses (CCyR) at 1 year] 
o The rate of Complete Cytogenetic Response (CCyR) at 1 year. 
o Number of days to response (CCyR, MMR, MR4, MR4.5). [Time 
Frame: at the EoT visit] 
o The median time to response and the overall estimated probability 
of response (CCyR, MMR, MR4, MR4.5). 
o Number of overall surviving patients [Time Frame: at the EoT visit] 
o Number of progression-free survival patients.[Time Frame: at the 
EoT visit] 
o Number of failure-free survival patients. [Time Frame at the EoT 
visit] 
o Number of event-free survival patients. [Time Frame: at the EoT 
visit] 
o Immunological Studies: phenotypic Assays: 
 Cell characterization: NK cells (CD3- CD56+; CD16+ 
CD56+; TNFα; IFNα; Granzyme b NK-LGL cells (CD56+ 
CD57+), T-LGL cells (CD3+ CD57+), CD8 TCRα/β, NK 
markers (NKG2D, KIR2DL2/DL3/DS2, KIR2DL5B). 
 b. Differentiation and maturation (NKG2A/CD16) and 
proliferation (NK67) markers of NK cells. 


ZEROMLC-01 
 
April 06, 2021 
 
Page 25 
 c. CD4+ T cells activation markers: CD25 CD69 HLA-DR. 
 d. Predictive markers of CML relapse: T regs (CD4+ 
CD25int-hi CD127low), CD8+ T cells (PD-1/PD-L1) and 
plasmacytoid dendritic cells (CD86+). 
 
6.5. Analysis methods 
Descriptive statistics are presented using mean and standard deviations for 
continuous variables and count and percentages for categorical variables. The 
95% confidence interval (CI) for a proportion will be reported for the primary 
efficacy variable. The Shapiro-Wilks test will be used to test the normality of the 
distribution of continuous variables. Statistical differences between groups were 
analyzed using the chi-square test for categorical data and the Student’s t test 
for quantitative data. Quantitative data showing non-normal distribution were 
analyzed using the Mann–Whitney U test. The Kaplan-Meier method is used to 
study survival. A p-value of <0.05 was considered statistically significant. All 
analyses were carried out with the free statistical program R (https://cran.r-
project.org/). 
 
Primary Objective: 
Frequency and percentage of adverse events will be summarized by system 
organ class and/or preferred term, severity (based on CTCAE grades), type of 
adverse event and causality relation to study treatment by the study 
phases.95% confidence intervals of the proportion of adverse events will be 
computed using the exact binomial distribution. 
Secondary Objectives: The rates of molecular responses at certain time points 
as well as the percentages will be presented together with an exact 95% 
binomial confidence interval.  
All time to event endpoints will be analyzed using the Kaplan-Meier method and 
will be presented by Kaplan-Meier method plots. 


ZEROMLC-01 
 
April 06, 2021 
 
Page 26 
 
6.6. Missing data 
For time to event endpoints, a Last Observation Carried Forward & Next 
Observation Carried Backward statistical approach will be performed to the 
analysis of longitudinal repeated measures data where some follow-up 
observations may be missing.  
 
6.7. Sensitivity analysis 
A sensitivity analysis employing only participants with complete data will be 
performed in order to demonstrate that study conclusions are invariant to 
assumptions, the particular model, and methods of handling missing data.  
 
6.8. Subgroup analysis 
No subgroup analysis is planned 
 
6.9. Safety data analysis 
Reporting of safety information will be split into subsets by first phase, second 
phase, third phase, and fourth phase. 
Adverse Events: Summary tables for adverse events (AEs) have to include only 
AEs that started or worsened during the on-treatment period, the treatment-
emergent AEs (TEAEs). However, all safety data (including those from the pre-
treatment period) will be listed and those collected during the pre-treatment 
period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from 
baseline) will be summarized by system organ class and/or preferred term, 
severity (based on CTCAE grades), type of adverse event, causality relation to 
study treatment by the phases or subsets previously described. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed 
by patient and tabulated by type of adverse event and safety subset. 


ZEROMLC-01 
 
April 06, 2021 
 
Page 27 
Specific safety event categories will be considered. Such categories consist of 
one or more well-defined safety events which are similar in nature and for which 
there is a specific clinical interest in connection with the study treatment(s). 
For each specified safety event category, number, and percentage of patients 
with at least one event part of the safety set will be reported. Also, AESI will be 
summarized and analyzed. 
Laboratory abnormalities: For laboratory tests covered by the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 the study’s 
biostatistician and reporting team will grade laboratory data accordingly. For 
laboratory tests covered by CTCAE, a Grade 0 will be assigned to all non-
missing values not graded as 1 or higher. Grade 5 will not be used. 
In some cases, (e.g., white blood cell differentials) the lower limits of normal 
ranges used in CTCAE definition have to be replaced by a clinically meaningful 
limit expressed in absolute counts. 
For laboratory tests where grades are not defined by CTCAE, results will be 
graded by the low/normal/high classifications based on laboratory normal 
ranges. 
The following by-safety subset summaries will be generated separately for 
hematology, and biochemistry tests: 
 number and percentage of patients with clinically significant laboratory 
abnormalities, by parameter and worst post-baseline CTCAE grade. 
Each patient will be counted only for the worst grade observed post-
baseline, regardless of the baseline status 
 shift tables using CTCAE grades to compare baseline to the worst on-
treatment value 
 for laboratory tests where CTCAE grades are not defined, shift tables 
using the low/normal/high 
 classification to compare baseline to the worst on-treatment value. 
 listing of all laboratory data with values flagged to show the 
corresponding CTCAE grades and the classifications relative to the 
laboratory normal ranges. 


ZEROMLC-01 
 
April 06, 2021 
 
Page 28 
Other Safety Data: other safety data collected (e.g., ECG, vital signs) will be 
listed and summarized using descriptive statistics as appropriate. Notable 
values will be flagged. Notable/Abnormal values for safety data will be further 
specified in the RAP. 
The list of safety data will be summarized as: 
Variables 
Data 
Laboratory (hematology, 
biochemistry, urinary and 
others), Vital signs, changes in 
physical exam findings  and 
Electrocardiogram abnormalities 
Number and percentage 
Description (mapped to MedDRA thesaurus terms) 
Time of appearance in relation to study’s drug 
administration/data of onset (n-TEAE or TEAE, days/hours) 
End date or ongoing until recovery or stability 
Severity-CTCAE grades (from 0 to 5 or low/normal/high for 
laboratory tests or according to study protocol) 
Seriousness (according to definitions of study protocol) 
SAE (yes or not) 
Causality (Definitely Not Related, Probably Not Related, 
Possibly Related, Probably Related or  Definitely Related) 
Expectedness (according to Clinical Investigator’s Brochure) 
Outcome/evolution 
Any medication used to treat the AE or concomitant medication 
(yes or not, an specify active substance name, dose, and 
frequency) 
If it requires further exams/test(yes or not, an specify) 
 
Other untoward medical events 
(such as injury, events that 
require surgery, accidents, or 
apparently unrelated illnesses) 
 
Hypersensitivity 
 
Adverse 
Event 
of 
Special 
Interests (AESI): 
1. Myocardial infarction  
2. Angina  
3. Coronary artery disease  
4. Cerebrovascular 
ischemic 
disease 
5. New onset or worsening of 
peripheral artery occlusive 
disease  
6. Retinal 
vascular 
thrombosis, 
both 
venous 
and arterial. 
7. Venous 
thromboembolism 
that 
could 
result 
in 
significant compromise of 
organ 
function 
or 
other 
significant consequences  
8. Any other event considered 
important 
by 
the 
investigator  
 
Pregnancy 
 
All variables will be recorded, ongoing or starting within 28 days after end of 
treatment/patient decision to discontinue treatment (pos-treatment). 
 


ZEROMLC-01 
 
April 06, 2021 
 
Page 29 
 
6.10. References 
 ICH Harmonised Tripartite Guideline: Structure and Content of Clinical 
Study Reports E3. Step 4, 30 November 1995. Available from: 
http://www.ich. 
org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3
_Guideline.pd 
 ICH topic E9: Note for guidance on statistical principles for clinical trials 
(CPMP/ICH/363/96). September 1998.Draft ICH E9 (R1) addendum on 
estimands and sensitivity analysis in clinical trials to the guideline on 
statistical principles for clinical trials (EMA/CHMP/ICH/436221/2017), 
step 2b – Revision 1. August 2017. 
 Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Doré C, 
Williamson PR, Altman DG, Montgomery A, Lim P, Berlin J, Senn S, Day 
S, Barbachano Y, Loder E. Guidelines for the Content of Statistical 
Analysis Plans in Clinical Trials. JAMA. 2017 Dec 19; 318 (23):2337-
2343. doi: 10.1001/jama.2017.18556. 
 Introduction to Statistical Methods for Clinical Trials, by T.D. Cook and 
D.L. DeMets, Boca Raton: Chapman & Hall/CRC, 2008, ISBN: 1-58488-
027-1, xxiii + 439 pp.