Conditions: Polycythemia Vera
Keywords: chronic myeloproliferative neoplasms Polycythemia Vera Essential Thrombocythemia Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis Givinostat
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: no

Brief summary:
This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, Maximum Tolerated Dose and preliminary efficacy of Givinostat in patients with JAK2V617F positive Polycythemia Vera. Part A is the dose finding part while Part B is assessing the preliminary efficacy. Patients will be enrolled either in Part A or Part B and transition from one part to the other is not allowed.

Eligible patients for this study will have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria. Only if the enrolment in Part A is slow (i.e. \< 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with chronic myeloproliferative neoplasms.

Study therapy will be administered in 28 day cycles (4 weeks of treatment). Disease response will be evaluated according to the European LeukemiaNet criteria after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess the clinico-haematological response.

The study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in a long-term study.

Safety will be monitored at each visit throughout the entire duration of the study. Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

Detailed description:
This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, MTD and preliminary efficacy of Givinostat in patients with JAK2V617F positive PV.

Part A is the dose escalation portion of the study and, once the MTD has been established, Part B will commence where the preliminary efficacy of Givinostat in PV patients will be established. Patients will be enrolled either in Part A or Part B and transition from one part to the other is not allowed. Only PV patients from Part A assigned to the dose selected for Part B (MTD) may be counted towards the efficacy assessment in Part B.

Eligible patients for this study will have a confirmed diagnosis of PV according to the revised WHO criteria and the JAK2V617F positivity. Only if the enrolment in Part A is slow (i.e. \< 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with cMPN.

After providing informed written consent before undertaking any protocol-related procedure, a unique patient identification code (i.e. patient screening ID which will be a combination of his/her site ID, study part ID and patient screening number, e.g. IT01-A01) will be assigned to each patient and it will identify the patient within his/her enrolment confirmation by Italfarmaco S.p.A. or its designee and never be reused in case of screening failure. After the enrolment confirmation and the assignation of the dose level before the first drug intake, a unique patient identification code (i.e. patient ID which will be a combination of patient screening number ID and dose level ID, e.g. IT01-A01-DL1) will be assigned to each patient and it will identify the patient throughout his/her participation in the study and never be reused in case of premature drop-out.

Study therapy will be administered in 28 day cycles. In fact, the "cycle" is defined as 4 weeks of treatment.

Disease response will be evaluated according to the clinico-haematological ELN criteria after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess the clinico-haematological response.

The study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in a long-term study (Study N.: DSC/11/2357/44).

Safety will be monitored at each visit throughout the entire duration of the study. Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

Arms:
arm 1: In Part A patients will treated in dose levels at the following daily doses of Givinostat:

* 50 mg b.i.d.,
* 100 mg b.i.d.;
* 150 mg b.i.d.,
* 200 mg b.i.d.;
* 150 mg t.i.d.;
* 200 mg t.i.d.. Intermediate dose levels and, consequently, additionally dose levels may be used to establish the Maximum Tolerated Dose.

In Part B patients will be treated at the Maximum Tolerated Dose established in Part A.

The product will be supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each.

Interventions: intervention 1: Givinostat
Intervention descriptions: intervention 1: In Part A patients will treated in dose levels at the following daily doses of Givinostat:

* 50 mg b.i.d.,
* 100 mg b.i.d.;
* 150 mg b.i.d.,
* 200 mg b.i.d.;
* 150 mg t.i.d.;
* 200 mg t.i.d.. Intermediate dose levels and, consequently, additionally dose levels may be used to establish the Maximum Tolerated Dose.

In Part B patients will be treated at the Maximum Tolerated Dose established in Part A. The product will be supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each.

Protocol document:
Prot_001.pdf: 
 ITALFARMACO S.p.A.
                                 Study N.:
DSC/12/2357/45
                                                                                              EudraCT N.:
2013-000860-27
Clinical Study Protocol  
Version 3.0 – 29th  July 2015 
SOP 2 final version 12.09 
Page 1of 142 
Confidential
STUDY N.: DSC/12/2357/45  
EUDRACT N.:  2013-000860-27
A two-part study to assess the safety and preliminary efficacy 
of Givinostat in patients with JAK2V617F positive Polycythemia 
Vera
 
 
Document type: 
Clinical Study Protocol 
Development Phase: 
Phase Ib/II 
Document status: 
Version 3.0 
including Amendment 2 (version 1.0, 
29th July 2015) 
Release: 29th July 2015 
Number of pages:  
142 
Sponsor:
ITALFARMACO S.p.A. 
Via dei Lavoratori, 54
20092 Cinisello Balsamo (MI), Italy
Tel.:
Fax:
Property of Italfarmaco 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Italfarmaco   
PPD
PPD


 ITALFARMACO S.p.A.
                                 Study N.:
DSC/12/2357/45
                                                                                              EudraCT N.:
2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
Page 2 of 142 
Confidential
EMERGENCY SAFETY PROCEDURES 
Any SAE (see chapter “Adverse Events” for definition and details), that occurs after a 
patient has signed the Informed Consent Form and up to the follow-up visit (regardless 
of relationship to study drug) must be reported by the Investigators to Italfarmaco 
S.p.A. within 24 hours of learning of its occurrence. 
Related SAEs MUST be collected and reported even if the study has been closed.  
The Investigator must notify the SAE to the Drug Safety Unit (hereinafter “DSU”) of 
Italfarmaco S.p.A. by sending the SAE Form, according with the procedures described 
in the study manual and within 24 hours of learning of its occurrence. 
The details of the DSU are specified below: 
Italfarmaco S.p.A.  
Drug Safety Unit Via dei Lavoratori, 54  
20092 Cinisello Balsamo (MI), Italy  
Phone:  
 
Fax:   
 
Fax (back-up): 
Mobile:  
 
e-mail:  
 
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PPD
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 ITALFARMACO S.p.A.
                                 Study N.:
DSC/12/2357/45
                                                                                              EudraCT N.:
2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
Page 5 of 142 
Confidential
CRO SIGNATURES 
   
Senior Biostatistician  
Quintiles S.r.l. 
Cassina Plaza  
Via Roma, 108 - Edificio F, Scala 2 
Cassina De’ Pecchi (MI), Italy 
Phone: 
Mobile: 
Fax: 
e-mail: 
                 Signature  
       Date 
Medical Director 
Hematology & Oncology  
Medical Strategy & Science 
Therapeutic Science & Strategy Unit 
(TSSU) 
Quintiles S.r.l. 
Cassina Plaza  
Via Roma, 108 - Edificio F, Scala 2 
Cassina De’ Pecchi (MI), Italy  
Phone:
Mobile: 
Fax: 
e-mail: 
                 Signature  
       Date 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 6 of 142 
Confidential
CENTRE SIGNATURE 
Compound name: 
            Givinostat 
Study number: 
 
DSC/12/2357/45 
EudraCT number: 
 
2013-000860-27 
I have read and understood this clinical study protocol (version 3.0, 29th July 2015) that 
includes the Amendment 2 (version 1.0, 29th July 2015), and agree to conduct this trial 
in accordance with all stipulations of the clinical study protocol (version 3.0, 29th July 
2015) that includes the Amendment 2 (version 1.0, 29th July 2015), and in accordance 
with the Good Clinical Practice. 
_________________________  
Principal Investigator’s Name 
_________________________  
Centre address 
_________________________  
Phone number 
_________________________  
Fax number 
_________________________  
e-mail 
                  Signature  
       Date 
 
 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 7 of 142 
Confidential
TABLE OF CONTENTS 
EMERGENCY SAFETY PROCEDURES 
2 
SIGNATURE PAGES 
3 
GLOSSARY OF ABBREVIATIONS 
12 
STUDY SYNOPSIS 
15 
1. INTRODUCTION 
36 
1.1 Medical indication and current treatments 
36 
1.2 Rationale 
38 
1.3 Preclinical rationale 
38 
1.4 Clinical studies 
39 
1.4.1 Givinostat in chronic myeloproliferative neoplasms 
39 
1.5 Rationale for a phase Ib/II study 
40 
2. STUDY OBJECTIVES 
40 
2.1 Primary objectives 
40 
2.2 Secondary objectives 
40 
2.3 Exploratory objectives 
41 
3. STUDY ENDPOINTS 
41 
3.1 Primary endpoints 
41 
3.2 Secondary endpoints 
42 
3.3 Exploratory endpoints 
42 
4. INVESTIGATIONAL PLAN 
43 
4.1 Overall study design 
43 
4.1.1 Part A
44 
4.1.1.1 Definition of Dose Limiting Toxicity (DLT) 
44 
4.1.1.2 Study team definition 
45 
4.1.1.3 Dose Levels (DLs) and dose escalation scheme 
45 
4.1.1.4 Dose escalation rules 
46 
4.1.1.5 Definition of MTD 
47 
4.1.2 Part B
48 
4.2 Trial organization 
48 
4.3 Patient population 
48 
4.3.1 Inclusion criteria 
49 
4.3.2 Exclusion criteria 
51 
4.3.3 Criteria for dose modifications, treatment interruption and treatment 
discontinuation 
52 
4.3.3.1 Dose modification criteria in Part A 
52 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 8 of 142 
Confidential
4.3.3.2 Dose modification criteria in Part B 
54 
4.3.3.2.1 Dose adjustments for safety reasons in Part B 
55 
4.3.3.2.2 Dose increase for inadequate efficacy in Part B 
58 
4.3.3.3 Treatment interruption and treatment discontinuation in Parts A and B 60 
4.4 Treatments 
62 
4.4.1 Investigational Medicinal Product (IMP) 
62 
4.4.1.1 Dosage and administration 
62 
4.4.2 Treatment assignment 
63 
4.4.3 Patient numbering and screening 
64 
4.4.4 Blinding 
65 
4.4.5 Concomitant therapy 
65 
4.4.6 Treatment compliance 
66 
4.4.7 Drug supply 
66 
4.4.7.1 Packaging 
66 
4.4.7.2 Labelling 
66 
4.4.7.3 Storage 
67 
4.4.7.4 IMP dispensing 
68 
4.4.7.5 IMP accountability 
68 
4.5 Study Procedures 
68 
4.5.1 Laboratory evaluations and vital signs assessment 
69 
4.5.2 Physical examination 
70 
4.5.3 Spleen evaluation, PK and PD characterization, molecular examinations 
and bone marrow histological evaluation 
70 
4.5.3.1 Spleen evaluation 
70 
4.5.3.2 PK characterization 
70 
4.5.3.3 PD characterization 
71 
4.5.3.4 JAK2V617F characterization 
72 
4.5.3.5 Molecular examinations 
72 
4.5.3.6 Bone marrow histological evaluation 
73 
4.5.4  Visit schedule 
73 
4.5.4.1 Part A
74 
4.5.4.1.1 Pre-treatment evaluations (up to 4 weeks: -28 to Day -1) 
74 
4.5.4.1.2 Cycle 1 
75 
4.5.4.1.3 Cycles 2, 3, 4, 5 and 6 
80 
4.5.4.2 Part B
84 
4.5.4.2.1 Pre-treatment evaluations (up to 4 weeks: -28 to Day -1) 
85 
4.5.4.2.2 Day 1 of Cycle 1 
87 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 9 of 142 
Confidential
4.5.4.2.3 Day 28 of Cycles 1, 2, 4 and 5 
87 
4.5.4.2.4 Day 28 of Cycles 3 and 6 
88 
4.5.4.2.5 End of study 
89 
4.5.4.3 Information to be collected on screening failures  
91 
4.6 Efficacy assessments 
91 
4.6.1 Criteria for assessing clinico-haematological improvement 
91 
4.6.2 Criteria for determination of MTD 
94 
4.6.3 Criteria for characterization of PK 
94 
4.6.4 The Efficacy Population 
94 
4.7 Safety assessments 
94 
4.7.1 Laboratory evaluations 
95 
4.7.2 Clinical safety assessments 
96 
4.7.3 Adverse events 
96 
4.8 Exploratory parameters 
97 
4.8.1 Evaluation of the effects of Givinostat on each single parameter of the clinico-
haematological ELN response criteria 
97 
4.8.2 Evaluation of the effects of Givinostat on PD markers 
97 
4.8.3 Spleen size assessment 
97 
4.8.4 Improvement of constitutional symptoms 
98 
4.8.5 Reduction of the JAK2V617F allele burden 
98 
4.8.6 Reduction of the symptomatic treatment of pruritus in term of dosage and/or 
days of treatment 
98 
4.8.8 Evaluation of the effects of Givinostat on each single parameter of the revised 
ELN response criteria 
100 
4.9 Definition of end of the study 
100 
5. ADVERSE EVENTS 
100 
5.1  Definitions 
101 
5.1.1 Adverse Event (AE) 
101 
5.1.2 Adverse Drug Reaction (ADR) 
101 
5.1.3 Unexpected Adverse Drug Reaction 
102 
5.1.4 Serious Adverse Event (SAE) 
102 
5.2 AE Reporting 
103 
5.2.1 Abnormal laboratory findings and other objective measurements 
104 
5.2.2  Baseline medical conditions 
104 
5.3 SAE Reporting 
105 
5.3.1 Over-dosage  and other situations putting the patient at risk of adverse 
reaction 
106 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 10 of 142 
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5.3.2 Pregnancy 
106 
6. STATISTICAL METHODS 
107 
6.1 Experimental design 
107 
6.2 Statistical methods to be employed 
107 
6.2.1 Analysis Sets 
108 
6.2.2 Background and demographic characteristics 
109 
6.2.3 IMP 
109 
6.2.4 Prior and Concomitant medications and prior and concomitant significant 
non-drug therapies 
109 
6.2.5 Primary Efficacy and Safety evaluation 
110 
6.2.5.1 Part A
110 
6.2.5.2 Part B
111 
6.2.6 Secondary Efficacy and Safety evaluation 
112 
6.2.6.1 Part A
112 
6.2.6.2 Part B
113 
6.2.7 Exploratory evaluations 
115 
6.2.7.1 Parts A and B
115 
6.2.8 Other Safety evaluation 
115 
6.2.9 Interim analyses 
116 
6.3 Sample size and power considerations 
116 
7. ETHICS AND GOOD CLINICAL PRACTICE 
117 
7.1 Institutional Review Board/Ethics Committee 
117
7.2 Informed consent 
117 
8. ADMINISTRATIVE PROCEDURES 
118 
8.1 Changes to the protocol 
118 
8.2 Monitoring procedures 
118 
8.3 Recording of data and retention of documents 
119 
8.4 Auditing procedures 
119 
8.5 Handling of study medication 
120 
8.6 Ownership of data, disclosure and confidentiality 
120 
8.7 Study discontinuation 
121 
9. REFERENCE LIST 
122 
10. APPENDICES 
125 
10.1 Appendix A: Flow-chart 
126 
10.1.1 Flow-chart of Part A
126 
10.1.1.1 Flow-chart of Cycle 1 
126 
10.1.1.2 Flow-chart of Cycle 2 and beyond 
130 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 11 of 142 
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10.1.2 Flow-chart of Part B
133 
10.2 Appendix B: ECOG Performance Status* 
137 
10.3 Appendix C: Drugs at risk of causing TdP 
138 
10.4 Appendix D: Bazett’s correction formula 
140 
10.5 Appendix E: JAK2V617F genotyping and quantification in granulocytes 
141 
10.6 Appendix F: Conversion formula (from Urea to BUN) 
142 
 
 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 12 of 142 
Confidential
GLOSSARY OF ABBREVIATIONS 
 
 
ADR 
Adverse Drug Reaction 
AE 
ALP 
Adverse Event 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
ATC 
Aspartate aminotransferase 
Anatomical Therapeutical Classification 
BED 
b.i.d. 
Biologically Effective Dose 
Bis In Die (twice daily) 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CHMP 
CIs 
Committee for Medicinal Products for Human Use 
Confidence Intervals 
Cl 
Chloride 
cMPN 
CR 
Chronic Myelo-Proliferative Neoplasms 
Complete Response 
CRF 
Case Report Form 
CRO 
CMO 
Contract Research Organization 
Contact Manufacturing Organization 
CT 
Computerized Tomography 
CTCAE 
DSU 
Common Terminology Criteria for AE 
Drug Safety Unit 
DLT 
ECG 
Dose Limiting Toxicity 
Electrocardiogram 
ECOG 
ELN 
EMA 
Eastern Cooperative Oncology Group 
European LeukemiaNet 
European Medicinal Agency 
ET 
EU 
EUMNET 
Essential Thrombocytopenia 
European Union 
European Myelofibrosis Network  
GCP 
Good Clinical Practice 
Hb  
Haemoglobin 
HBV 
HCT 
Hepatitis B Virus 
Haematocrit 
HCV 
Hepatitis C Virus 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 13 of 142 
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HDACs 
HDPE 
HGF 
Histone deacetylases 
High-density Polyethylene 
Haematopoietic Growth Factor 
HIV 
IC50 
ICH 
IF 
Human Immunodeficiency Virus 
50% Inhibitory Concentration 
International Conference on Harmonization 
Investigator’s File 
IMP 
Investigational Medicinal Product 
IRB/EC 
ITT 
Institutional Review Board/Ethics Committees 
Intent-to-treat 
JAK2 
Janus Kinase 2 
JAK2V617F 
Janus Kinase 2 mutated at position 617 
K 
Potassium 
LCM 
Left Costal Margin 
LDH 
LDPP 
Lactate Dehydrogenase 
Low Denier Polypropylene 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
MedDRA 
Mean Corpuscular Volume 
Medical Dictionary for Regulatory Activities 
MF 
mg 
Myelofibrosis 
Milligram 
Mg 
MPN-SAF 
MRI 
msec 
Magnesium 
Myeloproliferative Neoplasm Symptom Assessment Form  
Magnetic Resonance Imaging 
Millisecond 
MTD 
Na 
Maximum Tolerated Dose 
Sodium 
NCI 
National Cancer Institute 
nM 
Nanomolar 
NR 
No Response 
NYHA 
New York Heart Association 
o.d. 
Once Daily 
PB 
Peripheral Blood 
PD 
Pharmacodynamic 
PLT 
Platelets 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 14 of 142 
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PMF 
PP 
PR 
PRV-1 
PT 
Primary Myelofibrosis 
Per-protocol 
Partial Response 
Polycythemia Rubra Vera Receptor 1 
Preferred Term  
PV 
PK 
QOL 
qRT-PCR 
Polycythemia Vera  
Pharmacokinetics 
Quality Of Life 
Quantitative Real Time Polymerase Chain Reaction 
QTc 
QT interval corrected 
RBC 
Red Blood Cell (count) 
RT-PCR 
Real Time Polymerase Chain Reaction 
RR 
Response Rate 
SAE 
SAP 
SAS 
SOC 
SOP 
Serious Adverse Event 
Statistical Analysis Plan 
Statistical Analysis System 
System Organ Class 
Standard Operative Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction
STAT5 
TdP 
TEAE 
Signal Transducers and Activators of Transcriptase 5 
Torsades de Pointes  
Treatment-Emergent Adverse Event 
t.i.d. 
Ter In Die (three times daily) 
TMF 
Trial Master File 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell (count) 
WHO 
World Health Organization 
WHO-DRL 
World Health Organization-Drug Reference List 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 15 of 142 
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STUDY SYNOPSIS 
STUDY TITLE 
A two-part study to assess the safety and preliminary efficacy of 
Givinostat in patients with JAK2V617F positive Polycythemia Vera. 
STUDY NUMBER  
DSC/12/2357/45 
EUDRACT No. 
2013-000860-27 
STUDY TYPE 
International  
CLINICAL PHASE 
Ib/II 
DISEASE 
Patients with JAK2 positive chronic myeloproliferative neoplasms 
(cMPN), particularly Polycythemia Vera (PV). 
STUDY RATIONALE 
In recent years several reports have documented that histone 
deacetylases (HDACs) inhibitors induce neoplastic cells to undergo 
growth arrest, differentiation and/or apoptotic cell death.  
Among these agents, Givinostat (ITF2357) has most recently 
demonstrated effects on haematological parameters as well as 
constitutional parameters in patients with PV.  
Preliminary signs of clinical activity in patients with JAK2 mutant 
cMPN, have been observed in two studies with Givinostat (Studies N. 
DSC/07/2357/28 and DSC/08/2357/38). In these studies, the maximum 
administered dose of Givinostat was 150 mg per day which was 
generally well tolerated. Assuming a linear relationship between dose 
and efficacy, greater clinical efficacy can be expected with increased 
doses of Givinostat. 
Since the MTD of Givinostat has not been defined previously, the first 
aim of the current study is, therefore, to determine the maximum 
tolerated dose of Givinostat in patients with PV. This study will 
investigate the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) activity of Givinostat monotherapy. As such, 
the study will characterize Dose Limiting Toxicities (DLTs) and 
Maximum Tolerated Dose (MTD) of Givinostat.  
The second aim of this study is to characterize the clinical efficacy of 
Givinostat at the MTD. 
PRIMARY 
OBJECTIVES 
Part A 
•
To characterize the safety, tolerability and MTD of Givinostat 
in patients with PV.  
Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD 
after 3 cycles according to the clinico-haematological European 
LeukemiaNet (ELN) response criteria. 
•
To determine the safety and tolerability of Givinostat at the 
MTD after 3 cycles. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 16 of 142 
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SECONDARY 
OBJECTIVES 
Part A 
•
To evaluate the preliminary efficacy of Givinostat after 3 and 6  
cycles of treatment according to the clinico-haematological 
ELN response criteria. 
•
To characterize PK. 
Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD 
after 6 cycles according to the clinico-haematological ELN 
response criteria. 
•
To determine the safety and tolerability of Givinostat at the 
MTD after 6 cycles. 
•
To characterize PK. 
EXPLORATORY 
OBJECTIVES 
Parts A and B  
•
To evaluate the effect of Givinostat on single parameters of the 
clinico-haematological ELN response criteria. 
•
To evaluate the effects of Givinostat on PD markers. 
•
To evaluate the effects of Givinostat on spleen size (by MRI or 
CT scan) in patients with confirmed splenomegaly at baseline. 
•
To evaluate the effects of Givinostat on disease-related quality 
of life. 
•
To evaluate the effect of Givinostat on JAK2V617F allele burden. 
•
To evaluate the reduction of the symptomatic treatment of 
pruritus. 
Part B  
•
To evaluate the preliminary efficacy of Givinostat after 6  
cycles of treatment according to the “new” ELN response 
criteria (i.e. the revised ELN response criteria). 
•
To evaluate the effect of Givinostat on single parameters of the 
the “new” ELN response criteria (i.e. the revised ELN response 
criteria). 
PRIMARY ENDPOINTS Part A 
•
Safety and tolerability evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse 
events, graded according to Common Terminology Criteria 
for Adverse Events (CTCAE v. 4.03, 14th June 2010). 
•
Determination of the MTD of Givinostat based on cycle 1 
DLT’s. 


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Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial 
Response (PR) - of Givinostat at the MTD after 3 cycles; the 
response will be evaluated according to the clinico-
haematological ELN response criteria. 
•
Safety and tolerability of Givinostat at the MTD  after 3 cycles
evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse 
events, graded according to CTCAE v. 4.03. 
SECONDARY 
ENDPOINTS 
Part A 
•
Overall response rate - i.e. Complete Response (CR) and Partial 
Response (PR) - of Givinostat at the MTD after 3 and 6 cycles; 
the response will be evaluated according to the clinico-
haematological ELN response criteria. 
•
Individual Givinostat concentrations tabulated by dose cohort 
along with descriptive statistics. 
Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial 
Response (PR) - of Givinostat at the MTD after 6 cycles; the 
response will be evaluated according to the clinico-
haematological ELN response criteria. 
•
Safety and tolerability of Givinostat at the MTD after 6 cycles
evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse 
events, graded according to CTCAE v. 4.03. 
•
Individual Givinostat concentrations tabulated with descriptive 
statistics. 
EXPLORATORY 
ENDPOINTS 
Part A and Part B  
•
To evaluate the effect of Givinostat on each single response 
parameter according to the clinico-haematological ELN 
response criteria. 
•
To evaluate the effects of Givinostat on PD markers by mRNA 
analysis. 
•
To evaluate the effects of Givinostat on spleen size (by MRI or 
CT scan) in patients with confirmed splenomegaly at baseline. 
•
Improvement of constitutional symptoms evaluated according 
to MPN-SAF QOL questionnaire. 
•
Reduction of the JAK2V617F allele burden, tested by quantitative 
RT-PCR. 


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•
Reduction of the symptomatic treatment of pruritus in term of 
dosage and/or days of treatment. 
Part B  
•
Overall response rate - i.e. Complete Remission and Partial 
Remission - of Givinostat at the MTD after 6 cycles; the 
response will be evaluated according to the “new” ELN 
response criteria (i.e. the revised ELN response criteria). 
•
To evaluate the effect of Givinostat on each single response 
parameter according to the “new” ELN response criteria (i.e. 
the revised ELN response criteria). 
STUDY DESIGN 
Two-part, multicenter, open label, non-randomized, phase Ib/II study. 
NUMBER OF 
PATIENTS 
About 52 evaluable patients, approximately 24 in Part A and 28 in Part 
B. 
TEST PRODUCT, 
DOSE AND MODE OF 
ADMINISTRATION 
Givinostat is a histone-deacetylases inhibitor.  
The product will be supplied as hard gelatine capsules for oral 
administration at the strength of 50 mg and/or 75 mg and/or 100 mg 
each.  
In Part A patients will treated in Dose Levels (DLs) at the following 
daily doses of Givinostat:  
•
50 mg b.i.d.; 
•
100 mg b.i.d.; 
•
150 mg b.i.d.; 
•
200 mg b.i.d.; 
•
150 mg t.i.d.; 
•
200 mg t.i.d.. 
Intermediate Dose Levels (IDLs) and, consequently, additionally DLs 
may be used to establish the MTD. 
In Part B patients will be treated at the MTD established in Part A. 
TREATMENT PLAN 
This is a two-part, multicenter, open label, non-randomized, phase Ib/II 
study to assess the safety and tolerability, MTD and preliminary 
efficacy of Givinostat in patients with JAK2V617F positive PV. Part A is 
the dose finding part while Part B is assessing the preliminary efficacy. 
Patients will be enrolled either in Part A or Part B and transition from 
one part to the other is not allowed. 
Eligible patients for this study will have a confirmed diagnosis of PV 
according to the revised WHO criteria and the JAK2V617 positivity. 
Only if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 
months), eligibility for this part of the study may be expanded to all 
patients with cMPN.  


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Study therapy will be administered in 28 day cycles (4 weeks of 
treatment). 
Disease response will be evaluated according to the ELN criteria after 
3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with 
Givinostat for both parts of the study. All phlebotomies performed in 
the first 3 weeks of treatment will not be counted to assess the clinico-
haematological response. 
The study will last up to a maximum of 24 weeks of treatment. 
However, after completion of the trial, all patients achieving clinical 
benefit will be allowed to continue treatment with Givinostat (at the 
same dose and schedule) in a long-term study (Study N.: 
DSC/11/2357/44), provided that the long-term study has already 
received all necessary approvals in that specific country and site, and 
the study has been already initiated in that particular site. 
Safety will be monitored at each visit throughout the entire duration of 
the study. Treatment will be administered on an outpatient basis and 
patients will be followed regularly with physical and laboratory tests, 
as specified in the protocol; in case of hospitalization, the treatment 
will be continued or interrupted according to the Investigators’ 
decision. 
Part A
Part A is the dose escalation part of this study, evaluating the safety 
and tolerability and MTD of Givinostat in patients with JAK2V617F
positive PV. 
Approximately 24 patients will be enrolled in this part of the study. 
In Part A, Dose Limiting Toxicity (DLT) is defined as the following 
drug-related toxicity: 
•
Grade 4 haematological toxicities, or
•
Grade 3 febrile neutropenia, or
•
Grade  3 non-haematological toxicities with exception of:
a) Grade 3 diarrhoea without adequate supportive care lasting 
less than 3 days, and 
b) Grade 3 nausea or vomiting without adequate supportive 
care lasting  less than 3 days, or
•
Any drug-related SAE, or
•
Any toxicity that is clearly not related to disease progression or 
intercurrent illness requiring interruption of dosing for more 
than 3 days during the first cycle. 
The severity of the above mentioned events will be graded according to 
CTCAE v. 4.03.  
Dose escalation will be conducted according to a standard 3+3 design, 


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adopting a modified Fibonacci escalation schema. Patients will be 
enrolled in cohorts of 3 new patients (up to a maximum of 6) in rising 
dose levels.  
Givinostat 
daily dose  
Givinostat dose 
level (DL) 
DL used primarily to asses 
50 mg b.i.d. 
DL0 
Safety, PK, PD* 
100 mg b.i.d. 
DL1 
MTD, PK, PD 
150 mg b.i.d. 
DL2 
MTD, PK, PD 
200 mg b.i.d. 
DL3 
MTD, PK, PD 
150 mg t.i.d. 
DL4 
MTD, PK, PD 
200 mg t.i.d. 
DL5 
MTD, PK, PD 
* DL previously demonstrated as safe. 
The DL0 (i.e. 50 mg b.i.d.) has been previously shown to be well 
tolerated in several disorders and also in cMPN patients (Study N. 
DSC/07/2357/28 and Study N. DSC/08/2357/38). Therefore, it is 
preferred to assign patients to the highest available dose level (i.e. 
DL1, DL2, DL3, DL4 and DL5) before assigning patients to DL0. 
Intermediate Dose Levels (IDLs) and, consequently, additionally DLs 
may be introduced to more accurately define the MTD. 
In Part A each patient will receive study drug at a specific DL. Once 
the first 3 patients of the first DL (i.e. DL1) have been treated for 1 
cycle, tolerability data will be evaluated and a decision to escalate to 
the next dose will be made. 


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                                                                                              EudraCT N.:     2013-000860-27
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N. of patients 
with DLT at a 
given DL 
Action 
0 out of 3 
Enter 3 patients at the next dose level.
1 out of 3 
Enter at least 3 more patients at this dose level 
and 
•
if 0 of these 3 new patients experiences 
DLT, proceed to the next dose level; 
•
if  1 of this group suffer DLT (for a total 
of  2/6 patients with a DLT), this dose 
exceeds the MTD and dose escalation is 
stopped. To further assess tolerability, 3 
additional patients will be entered at the 
next lowest dose level if only 3 patients 
were treated previously at that dose. Upon 
determination of the MTD, the study 
proceeds directly to Part B. 
 2 
Dose escalation will be stopped. This dose 
exceeds the MTD. To further assess tolerability, 3 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose and the study will proceed 
directly to Part B of the study.
At any time, if  2/3 or  2/6 patients at a given dose level develop a 
DLT, it is acceptable to de-escalate to an intermediate, not previously 
studied dose, if evaluation of toxicity at such a dose is desired, in lieu 
of proceeding directly to Part B of the study. If this approach is taken, 
3 patients should be enrolled at the intermediate dose, and the 
aforementioned rules should be used to determine enrolment at this 
dose. If the decision is made to proceed directly to the efficacy portion 
of the study (i.e. Part B), the efficacy part will start at the next lower 
dose below where  2/3 or  2/6 DLTs were observed (i.e. the MTD 
dose level). 
If 2 or more patients per dose level experience a DLT, dose escalation 
will terminate and the MTD is the next lower dose level if no more 
than one out of 6 patients had a DLT at that level. Once all patients 
enrolled in Part A have been treated for at least 1 cycle, the study team 
will determine the MTD to be used in Part B based on the safety and 
tolerability profile of Givinostat observed as well as the PK and PD 
data, if applicable.  


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                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
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No intra-patient dose escalation will be permitted prior to determining 
the MTD. At that time, patients on treatment at lower dose levels may 
be allowed to escalate their Givinostat dose up to the MTD the 
remainder of the study (Part A) at the discretion of the Investigator 
and after the written authorization of Italfarmaco S.p.A.. Of note, 
patients initially dosed at lower dose levels that are allowed to escalate 
their Givinostat dose up to the MTD for the remainder part of the study 
(Part A), will follow the dose modification rules of Part B.  
Only PV patients from Part A assigned to the dose selected for Part B
(MTD) may be counted towards the efficacy assessment in Part B.  
Part B
Part B is a multicenter, open label, non-randomized, phase II, cohort 
expansion study to assess the preliminary clinical efficacy of 
Givinostat at the MTD in patients with JAK2V617F positive PV. 
Approximately twenty eight patients will be enrolled in Part B at the 
MTD defined in Part A, according to an optimized Simon’s 2-stage 
design. 
The dose of Givinostat will be modified for protocol specified 
toxicities.  
INCLUSION CRITERIA 1. Patients must be able to provide informed consent and be willing to 
sign an informed consent form; 
2. Patients must have an age 18 years; 
3. Patients must have a confirmed diagnosis of PV according to the 
revised WHO criteria; 
4. Patients must have JAK2V617F positive disease; 
5. Patients must have an active/not controlled disease defined as  
a) HCT  45% or HCT <45% in need of phlebotomy, and
b) PLT counts > 400 x109/L, and
c) WBC > 10 x109/L; 
6. Patients must have an Eastern Cooperative Oncology Group 
(ECOG) performance status  1 in Part A, ECOG performance 
status  2 in Part B within 7 days of initiating study drug; 
7. Female patient of childbearing potential has a negative serum or 
urine pregnancy test within 72 hours of the first dose of study 
therapy; please note that a borderline urine pregnancy test must be 
followed with a serum pregnancy test; 
8. Use of an effective means of contraception for women of 
childbearing potential and men with partners of childbearing 
potential;  


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9. Adequate and acceptable organ function within 7 days of initiating 
study drug; 
10. Willingness and capability to comply with the requirements of the 
study. 
Note that if the enrolment in Part A is slow (i.e. < 5 patients 
enrolled in 3 months), eligibility for this part of the study may be 
expanded to all patients with cMPN. In this case, the inclusion 
criterion n. 5 will be modified as following only for Part A:
5. Patients must have an active/not controlled disease defined as: 
a) ET patients: PLT counts > 600 x109/L; 
b) MF patients: no response according to EUMNET criteria.
Note that an effective means of contraception for women of 
childbearing potential and men with partners of childbearing potential 
(i.e. inclusion criterion n. 5) is defined as following described based on 
different subject subgroups:   
A. Female subjects of childbearing potential: acceptable non-
hormonal, contraceptive methods must be used from the 28 days 
before first dose of study drug through 3 months after the last dose 
of study drug and include the following: 
•
True abstinence (absence of any sexual intercourse), when 
in line with the preferred and usual lifestyle of the subject. 
Periodic 
abstinence 
(e.g., 
calendar, 
ovulation, 
symptothermal, postovulation methods) and withdrawal are 
not acceptable methods of contraception. 
•
Double barrier contraception such as diaphragm or a barrier 
method of contraception in conjunction with spermicidal 
jelly such as for example cervical cap with spermicide jelly 
and the male partner must use a condom with spermicide. 
•
Intra-uterine device (non-hormone-releasing) in place for at 
least 90 days previously and the male partner must use a 
condom with spermicide. 
•
Tubal ligation at least 6 months previously and 1 additional 
acceptable contraception method. 
•
Vasectomy of the male partner (with a negative sperm post-
vasectomy semen analysis) at least 6 months previously and 
1 additional acceptable contraception method. 
B. Female subjects of non-childbearing potential must meet at least 
1 of the following criteria: 
•
Postmenopausal: Female subjects, less than 60 years of age, 
who have been amenorrheic for at least 2 years and have a 


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                                 Study N.:       DSC/12/2357/45
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serum FSH level within the laboratory’s reference range for 
postmenopausal females. Female subject who are 60 years 
of age or older who are amenorrheic for greater than 2 years 
will be assume to be postmenopausal. 
•
Documented hysterectomy or bilateral oophorectomy or 
both all other female subjects (including subjects with tubal 
ligations and subjects that do not have a documented 
hysterectomy) will be considered to be of childbearing 
potential. 
C. Male Subjects, acceptable contraceptive methods must be used 
from Screening Visit through 3 months after the last dose of study 
drug, and include the following: 
•
True abstinence (absence of any sexual intercourse), when 
in line with the preferred and usual lifestyle of the subject. 
Periodic 
abstinence 
(e.g. 
calendar, 
ovulation, 
symptothermal, postovulation methods) and withdrawal are 
not acceptable methods of contraception. 
•
Condom with spermicide and the female partner must use 
an acceptable method of contraception, such as an oral, 
transdermal, 
injectable 
or 
implanted 
steroid-based 
contraceptive, or a diaphragm or a barrier method of 
contraception in conjunction with spermicidal jelly such as 
for example cervical cap with spermicide jelly. 
•
Vasectomy (with a negative sperm post-vasectomy semen 
analysis) at least 6 months previously and 1 additional 
acceptable contraception method.  
•
Male subjects must not donate sperm from the Screening Visit 
through 3 months after the last dose of study drug.
Note also that  
–
Male condom cannot be used with female condom due to risk 
of tearing. 
–
The use of birth-control methods does not apply if the female 
partner has a bilateral oophorectomy, hysterectomy, or is 
postmenopausal (as defined above). 
EXCLUSION 
CRITERIA 
1. Active bacterial or mycotic infection requiring antimicrobial 
treatment; 
2. Pregnancy or nursing;   
3. A clinically significant QTc prolongation at baseline (e.g. repeated 
demonstration of a QTc interval  450 msec); 
4. Use of concomitant medications known to prolong the QT/QTc 
interval;  
5. Clinically significant cardiovascular disease including:  


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a) Uncontrolled 
hypertension 
despite 
medical 
treatment, 
myocardial infarction, unstable angina within 6 months from 
study start; 
b) New York Heart Association (NYHA) Grade II or greater 
congestive heart failure;  
c) History of any cardiac arrhythmia requiring medication 
(irrespective of its severity);   
d) A history of additional risk factors for TdP (e.g. heart failure, 
hypokalemia, family history of Long QT Syndrome);  
6. Known positivity for HIV; 
7. Known active HBV and/or HCV infection; 
8. Platelet count < 100 x 109/L within 14 days before enrolment (i.e. 
the receipt of the Patient ID); 
9. Absolute neutrophil count < 1.2 x 109/L within 14 days before 
enrolment (i.e. the receipt of the Patient ID); 
10. Serum creatinine > 2 x ULN; 
11. Total serum bilirubin > 1.5 x ULN except in case of Gilbert’s 
disease; 
12. Serum 
aspartate 
aminotransferase/alanine 
aminotransferase 
(AST/ALT) > 3 x ULN; 
13. History of other diseases (including active tumours), metabolic 
dysfunctions, physical examination findings, or clinical laboratory 
findings giving reasonable suspicion of a disease or condition that 
contraindicates use of an investigational drug or that might affect 
interpretation of the results of the study or render the subject at 
high risk from treatment complications; 
14. Prior treatment with a JAK2 or HDAC inhibitor or participation in 
an interventional clinical trial for cMPN, including PV, ET or MF; 
15. Systemic treatment for cMPN other than aspirin/cardio aspirin;  
16. Hydroxyurea within 28 days before enrolment (i.e. the receipt of 
the Patient ID); 
17. Interferon alpha within 14 days before enrolment (i.e. the receipt of 
the Patient ID); 
18. Anagrelide within 7 days before enrolment (i.e. the receipt of the 
Patient ID); 
19. Any other investigational drug or device within 28 days before 
enrolment (i.e. the receipt of the Patient ID); 
20. Patient with known hypersensitivity to the components of study 
therapy. 


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Of note, a repeated demonstration of a QTc interval  450 msec (i.e. 
exclusion criterion n. 3) means that, if the first ECG evaluation 
demonstrates a prolonged QTc interval (i.e. a QTc interval  450 
msec), two additional ECG evaluations over a brief period of time (i.e. 
5 minutes between each recording) must be performed. The averaged 
value of these three ECG evaluations has to be used for the evaluation 
of the QTc interval requested by the exclusion criterion n. 3. In the 
CRF all the performed ECG evaluations have to be entered as well as 
the average value of multiple ECG evaluation, if necessary.
Note that an any other investigational drug or device (i.e. exclusion 
criterion n. 19) includes any investigational drug or device not already 
mentioned and detailed in the exclusion criteria n. 14, 15, 16 17 and/or 
18.
DURATION OF 
TREATMENT  
The study (both Part A and Part B) will last up to a maximum of 24 
weeks of treatment.  
However, after completion of the trial, all patients achieving clinical 
benefit will be allowed to continue treatment with Givinostat (at the 
same dose and schedule) in a long-term study (Study N.: 
DSC/11/2357/44), provided that the long-term study has already 
received all necessary approvals in that specific country and site, and 
the study has been already initiated in that particular site.
CONCOMITANT 
TREATMENT 
Patients must NOT receive the following treatments during the study:
a) Other investigational drugs while on this study; 
b) Cytotoxic agents, interferons or other approved treatment for 
cMPN other than aspirin/cardio-aspirin; 
c) Any drug known to provoke TdP. 
Other concomitant medications (e.g. symptomatic treatment of 
pruritus) and significant non-drug therapy (e.g. phlebotomy, blood 
transfusion) are permitted.  
CRITERIA FOR 
RESPONSE 
Criteria for assessing clinico-haematological improvement 
Disease response will be evaluated according to the following clinico- 
haematological ELN criteria after 3 and 6 cycles of treatment with 
Givinostat both in Part A (secondary endpoints) and in Part B (primary 
and secondary endpoints, respectively).  
•
Complete response:  
1.
HCT<45% without phlebotomy, and
2.
platelets  400 x109/L, and
3.
WBC 10 x109/L, and
4.
Normal spleen size, and
5.
no disease-related systemic symptoms (i.e. pruritus, 
headache, microvascular disturbances). 


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                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
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•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1.
HCT <45% without phlebotomy, or  
2.
response in 3 or more of the other criteria. 
•
No response: any response that does not satisfy  partial 
response.
As an exploratory endpoint, disease response will be evaluated also 
according to the following “new” ELN criteria (i.e. the revised ELN 
response criteria) after 6 cycles of treatment with Givinostat in Part B. 
•
Complete remission:  
1. Durable resolution of disease-related signs including 
palpable hepato-splenomegaly improvement, and large 
symptoms improvement, and
2. Durable peripheral blood count remission, defined as HCT < 
45% without phlebotomies, and PLT count  400 x109/L, 
and WBC count < 10 x109/L, and
3. No progressive disease, and absence of any hemorrhagic or 
thrombotic event, and
4. Bone marrow histological remission defined as the presence 
of age-adjusted normo-cellularity, and disappearance of tri-
linear hyperplasia, and absence of grade > 1 reticulin 
fibrosis. 
•
Partial remission:  
1. Durable resolution of disease-related signs including 
palpable 
hepato-splenomegaly, 
and 
large 
symptoms 
improvement, and
2. Durable peripheral blood count remission, defined as HCT <
45% without phlebotomies, and PLT count  400 x109/L, 
and WBC count < 10 x109/L, and
3. No progressive disease, and absence of any hemorrhagic or 
thrombotic event, and
4. No bone marrow histological remission defined as 
persistence of tri-linear hyperplasia. 
•
No response: any response that does not satisfy  partial 
remission.
•
Progressive Disease: transformation into post-PV myelofibrosis, 
myelodysplastic syndrome or acute leukemia (according to the 
IWG-MRT criteria for the diagnosis of post-PV myelofibrosis 
and according to WHO criteria for the diagnosis of 
myelodysplastic syndrome and acute leukemia).


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                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
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Please note that according to the “new” ELN criteria (i.e. the revised
ELN response criteria): 
1) Molecular response is not required for assignment as Complete 
Remission or Partial Remission. Molecular response evaluation 
requires analysis in peripheral blood granulocytes. Complete 
response is defined as eradication of a pre-existing abnormality. 
Partial response applies only to patients with at least 20% 
mutant allele burden at baseline. Partial response is defined as 
 50% decrease in allele burden. 
2) “Durable” is defined as lasting at least 12 weeks. 
3) “Large symptom improvement” is defined as  10 points of 
decrease in MPN-SAF Total Symptom Score. 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled 
in 3 months) and the eligibility for this part of the study may be 
expanded to all patients with cMPN, disease response for this part of 
the study will be evaluated according to the ELN and EUMNET 
criteria after 3 and 6 cycles of treatment with Givinostat, in ET and MF 
patients, respectively. 
For ET (from the clinico-hematological ELN response criteria): 
•
Complete response:  
1.
platelets  400 x109/L, and
2.
no disease related systemic symptoms (i.e. pruritus, 
headache, microvascular disturbances), and
3.
normal spleen size, and
4.
WBC 10 x109/L. 
•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1.
Platelet count < 600 x 109/L, or 
2.
Platelet count decrease > 50% from baseline. 
•
No response: any response that does not satisfy  partial 
response.
In all cases, both for PV and ET patients, all phlebotomies performed 
in the first 3 weeks of treatment will not be counted to assess the 
clinico-haematological response. 


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                                 Study N.:       DSC/12/2357/45
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For MF (from EUMNET response criteria)  
•
Complete 
response: 
complete 
response 
in 
anemia, 
splenomegaly, constitutional symptoms, platelet and leukocyte 
count.
1.
Complete response in anaemia: Haemoglobin  12 g/dL 
for transfusion-independent patients or  11 g/dL for 
transfusion-dependent patients (applicable only for patients 
with baseline haemoglobin level of < 10 g/dL); 
2.
Complete response in splenomegaly: Spleen not palpable; 
3.
Complete response in constitutional symptoms: Absence of 
constitutional symptoms (fever, drenching night sweats, or 
 10% weight loss); 
4.
Complete response in platelet count: Platelet count 150-
400 x109/L; 
5.
Complete response in leukocyte count: Leukocyte count 4-
10 x109/L. 
•
Major response: Any response in both anaemia and 
splenomegaly without progression in constitutional symptoms 
or complete response in anaemia without progression in 
splenomegaly or partial response in anaemia in a baseline 
transfusion-dependent patient combined with response in 
constitutional symptoms without progression in splenomegaly 
or any response in splenomegaly combined with response in 
constitutional symptoms without progression in anaemia.
1.
Partial response in anaemia: Increase of Hb > 2 g/dL 
(but Hb < 12 g/dL) for non-RBC transfusion –dependent 
patients; or reduction > 50% of transfusion requirement 
for RBC transfusion-dependent patients. 
2.
Partial response in splenomegaly: Either  50% 
decrease in spleen size if baseline  10 cm from left 
costal margin (LCM) or  30% decrease if baseline > 10 
cm from LCM. 
3.
Partial response in platelet count: A  50% decrease in 
platelet count if baseline > 800 x109/L or platelet count 
increase by   50% x 109/L if baseline < 100 x109/L. 
4.
Partial response in leukocyte count: A  50% decrease 
in leukocyte count of baseline >  20 x109/L or leukocyte 
count increase by  1 x109/L if baseline < 4 x109/L 
5.
Progression in anaemia: A hemoglobin decrease of  2 
g/dL  or  a 50% increase in transfusion requirement or
becoming transfusion dependent 
6.
Progression in splenomegaly: A  50% increase in 
spleen size if baseline  10 cm from LCM or a  30% 


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increase if baseline > 10 cm from LCM. 
7.
Progression in constitutional symptoms: Appearance of
constitutional symptoms. 
•
Moderate response: Complete response in anaemia with 
progression in splenomegaly or partial response in anaemia 
without progression in  splenomegaly or any response in 
splenomegaly without progression in   anaemia and 
constitutional symptoms.  
•
Minor response: Any leukocyte- or platelet-based response 
without 
progression 
in 
anaemia, 
splenomegaly, 
or
constitutional symptoms.
•
No response: Any response that does not qualify at least as 
minor response.
In all cases (PV, ET and MF patients), the disease-related systemic 
symptoms will be evaluated directly by patients according to MPN-
SAF QOL questionnaire.  
Criteria for determination of MTD  
Once all patients enrolled in Part A have been treated for at least 1 
cycle, the study team will determine the MTD to be used in Part B
based on the safety and tolerability profile of Givinostat observed as 
well as the PK and PD data, if applicable. No intra-patient dose 
escalation will be permitted prior to determining the MTD.  
At that time, patients on treatment at lower dose levels may be allowed 
to escalate their Givinostat dose up to the MTD for the remainder part 
of the study (Part A) at the discretion of the Investigator and after the 
written authorization of Italfarmaco S.p.A.. Of note, patients initially 
dosed at lower dose levels that are allowed to escalate their Givinostat 
dose up to the MTD for the remainder part of the study (Part A), will 
follow the dose modification rules of Part B.
Criteria for characterization of PK 
Plasma concentrations from Parts A and B will be evaluated by dose 
and time point for all patients and time points with at least 1 PK 
assessment.  
DOSE 
MODIFICATIONS 
RULES, TREATMENT 
INTERRUPTION AND 
TREATMENT 
DISCONTINUATION 
For patients who do not tolerate the protocol-specified dosing schedule, 
dose adjustments are permitted in order to allow the patients to 
continue the treatment with the study drug. 
Dose modification criteria in Part A  
In the Cycle 1 of Part A dose modifications will not be allowed. 
Patients receiving subsequent cycles of treatment in Part A may have 
up to two dose modifications for drug related DLT’s. The first dose 


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modification should be one dose level below the current dose, the 
second modification should be two dose levels below. Study drug may 
be resumed at lower dose level once the event resolves to at least grade 
1 or baseline values. If toxicities meeting modification criteria occur 
after the second dose reduction, therapy must be discontinued.  
Patients with unresolved toxicities lasting 2 weeks or longer will not 
be permitted to continue on study.  
Patients experiencing Grade 3 or 4 unmanageable toxicity will require 
immediate dose interruption and notification to the Sponsor. Treatment 
for each new cycle will be delayed until dose limiting toxicities that are 
clearly not related to disease progression have resolved to at least 
Grade 1 or the patient’s baseline.  
Dose modification criteria in Part B   
Dose adjustments are permitted for patients who do not tolerate the 
protocol-specified dosing schedule, in order to allow to these patients 
to continue the treatment with Givinostat. The objective of the 
Givinostat dose adjustment rules is to optimize the response for each 
individual patient, avoiding specific drug-related toxicities. Therefore, 
dose reductions or interruptions will be mandatory for specific 
toxicities and dose increases after an initial dose reduction will be 
allowed in the case of inadequate efficacy at the reduced dosage in 
absence of specific toxicities.  
The severity of the above mentioned events will be graded according to 
NCI Common Terminology Criteria for AE (CTCAE v. 4.03, 14th June 
2010). 
Each dose modification has to be recorded on the CRF.    
Patients initially dosed at lower dose levels in Part A that, after the 
definition of MTD, are allowed to escalate their Givinostat dose up to 
the MTD for the remainder part of the study (Part A) at the discretion 
of the Investigator and after the written authorization of Italfarmaco 
S.p.A., will follow the dose modifications criteria for Part B. 
Total daily dose may never exceed the MTD defined in Part A (i.e. 100 
mg b.i.d.). 
Treatment interruption and treatment discontinuation in Parts A
and B  
In some circumstances, it may be necessary to temporarily interrupt 
treatment as a result of adverse experiences that may have an unclear 
relationship to study drug. Study drug may be withheld by the 
Investigator at any time if there is concern about patient safety and for 
all aspects of the conduct of the protocol, since the safety of the 


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individual patient is paramount. Treating Investigator may employ any 
means necessary to ensure patient safety, particularly in medical 
circumstances not anticipated by this protocol.  
Dose adjustments are permitted for patients who do not tolerate the 
protocol-specified dosing schedule, in order to allow to these patients 
to continue the treatment with Givinostat. The objective of the 
Givinostat dose adjustment rules is to optimize the response for each 
individual patient, avoiding specific drug-related toxicities.  
If the patient inadvertently misses a drug dose, no additional trial 
medication should be taken that day or in the next days in the effort to 
replace the material that has been missed.  
If vomiting occurs, no additional trial medication should be taken that 
day in an effort to replace the material that has been vomited. 
If the study drug is interrupted for any reason for more than 4 weeks 
continuously, dosing may be not be restarted.  
Patients have the right to withdraw from the study at any time for any 
reason. The Investigator has the right to withdraw patients from the 
study due to medical reasons according to his/her discretion.  
If a pregnancy occurs, the patient will be replaced and another patient 
in that DL should be recruited. 
If the patient discontinues the study because of an adverse event 
whether or not drug related, he/she must be followed until resolution or 
stabilization of the event, whichever occurs first.
In case of lack of compliance or in case the patient is found not 
eligible, the patient discontinuation have to be discussed between 
Investigator and Sponsor.    
If the patient discontinues for any reason (including discontinuation for 
pregnancy), with drug related adverse event ongoing at study end, 
he/she must be followed until resolution or stabilization of the event or 
until it is reasonable to consider the event not drug related any more or 
until the start of a new treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications 
included in list of “Drugs with risk of Torsades de Pointes”, the 
treatment with Givinostat is to be promptly discontinued and the 
patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for 
toxicity), “adverse events” should be indicated as the primary reason 
whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be 
included on the CRF. 
A complete end of study visit must be performed by 7 days after the 
last drug intake for any patient permanently discontinuing study 
treatment. Should any drug-related AE still be ongoing beyond the last 
scheduled visit, this must be followed at subsequent follow-up visits 
until recovery. If a patient does not return for a scheduled visit, every 


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effort should be made to contact the patient. In any circumstance every 
effort should be made to complete and report the observations as 
thoroughly as possible. All relevant information related to the reason 
for treatment discontinuation including contributory factors must be 
included on the CRF.  
STATISTICAL 
METHODS 
This is a two-part, multicenter, open label, non-randomized, phase Ib/II 
study. 
A standard 3+3 design adopting a modified Fibonacci escalation 
schema will be used  in Part A.  
Sample size for Part B was discussed for the primary endpoint defined 
as the Overall Response Rate after 3 cycles. A Simon’s 2-stage design 
will be employed enrolling up to 28 patients in Part B with the aim of 
testing the “null hypothesis” that RR  0.50 versus the “alternative” 
that RR  0.75. Response rate will be assessed as defined in the 
Criteria for Response section. Overall up to 28 patients will need to be 
recruited, 12 patients being enrolled in Stage-1. Futility will be 
assessed after 12 patients enrolled (Stage 1). Please note that PV 
patients enrolled at the MTD in Part A may be counted towards Stage 
1. Under the “null hypothesis” (if RR = 0.50), the expected total 
sample size is of 18.2 patients, the probability of early termination at 
the end of Stage-1 is 0.613 and the probability of rejecting the “null 
hypothesis” is 0.081 (the target for the type-I error being 0.100). Under 
the “alternative hypothesis” (if RR = 0.75), the probability of rejecting 
the “null hypothesis” in favour of the “alternative” is 0.902 (the type-II 
error being 0.098). After testing the treatment on 12 patients in Stage-
1, if 6 or fewer patients respond to the treatment the trial will be 
terminated rejecting the “alternative” that RR  0.75. Otherwise, the 
trial goes on to Stage-2 enrolling further 16 patients to a total of 28 
patients. If at the end of Stage-2, a total of 17 or fewer patients respond 
to the treatment the “alternative hypothesis” that RR  0.75 will be 
rejected; alternatively, if 18 or more patients respond, the “null 
hypothesis” that RR  0.50 will be rejected. Estimations are obtained 
from proprietary software (based on SAS ® 9.2) according to the 
algorithm proposed by R. Simon. 
Summary statistics will be calculated for all variables. For each 
continuous variable, the mean, standard deviation, median, minimum 
value and maximum value will be computed. For each discrete variable 
the number of patients in each category with non-missing values in 
relation to all patients with non-missing values of that variable will be 
provided. Results will be displayed within each cohort and overall, 
where applicable. Statistical calculations will be carried-out by 
resorting to SAS version 9.2 (or later). Both continuous and categorical 
data will be summarized and tabulated in 2-way tables (variable-by-
visit).  
The main purpose of this phase Ib/II study consists in providing 


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accurate estimates of clinically relevant variables and measures. From 
the statistical viewpoint this translates in estimating confidence 
intervals (CIs) with adequate precision where precision represents the 
degree of uncertainty. 
The two tailed 95% CIs of the sample estimates will be computed 
using parametric approaches if deemed appropriate. Otherwise the 
StatXact-4 
software 
will 
be 
used 
in 
order 
to 
compute 
Exact/Nonparametric 95% CIs.      
Sub-groups analyses will be performed mainly for exploratory 
purposes. Since these analyses will be used to promote  hypothesis 
rather than confirm them, no adjustment for type I error inflation due to 
multiplicity of the tests will be considered. Moreover post-hoc and 
data-driven analyses will be carefully considered and ranked according 
to their biological plausibility. 
The following analysis sets will be defined:  
- Safety analysis set (SAF): The Safety analysis set will include all 
recruited patients who receive at least one dose of study 
medication. All safety analyses will be conducted on this 
population. 
- Intent-to-treat analysis set (ITT): The Intent-to-treat analysis set 
will include all recruited patients who receive at least one dose of 
study medication and from whom at least one post-baseline 
efficacy measurement is obtained. All efficacy analyses will be 
conducted on this population and they will be based on the 
effective/actual DL/daily doses of Givinostat at which each patient 
has been treated.   
- Per Protocol analysis set (PP): In order to assess the robustness of 
the efficacy analysis, the analysis of the efficacy endpoints could be 
repeated in the Per Protocol (PP) analysis set. The Per-protocol 
analysis set will include all ITT patients who receive at least 14 
daily doses without interruptions, and without any major deviation 
from the protocol procedures.  
- MTD analysis set: The MTD analysis set will include all patients 
who experienced a DLT in Cycle 1 or received at least 90% of the 
doses of study medication in cycle 1. The first cycle data from this 
analysis set will be used to determine MTD. Patients who didn’t 
experience a DLT and missed more than 10% of the doses in Cycle 
1 of Part A will be replaced.  
- PK Analysis set: will consist of all SAF patients who with at least 1 
PK assessment. This analysis set will be used for PK analysis. 
The number and percentage of the patients included in the analysis 
populations will be reported in a table showing the reason of exclusion 
for all patients enrolled into the study. A listing of reasons of exclusion 
from analysis population will be provided. 


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Italfarmaco S.p.A. will perform a preliminary analysis of data after the 
completion of the first cycle of treatment from all patients recruited in 
Part A, in order to assess the MTD to be used for Part B.  Moreover, a 
preliminary analysis will be performed on the 12 patients of the stage I 
(Part B). If six or fewer responses will be observed during the first 
stage then the study will be stopped. If seven or more  responses will 
be observed in stage I, further 16 patients will be enrolled in Part B. In 
this case, a final statistical analysis will be performed considering all 
patients enrolled in the two study phases. In addition, Italfarmaco 
S.p.A. can perform a preliminary analysis of data in case of necessary 
safety and efficacy updates (e.g. to update regulatory documents and/or 
the drug safety profile, to revise the development program). 
This study is registered in the EudraCT database and in Clinicaltrial.gov database.


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1. INTRODUCTION 
1.1 Medical indication and current treatments  
Polycythemia Vera (PV), also termed Polycythemia rubra vera, together with Essential 
Thrombocythemia (ET) and Myelofibrosis (MF) belongs to a distinct group of Ph-
chromosome-negative chronic myeloproliferative neoplasms (cMPN) characterized by 
clonal proliferation of multipotent haematopoietic stem cells leading to thrombocytosis, 
leukocytosis, erythrocytosis and bone marrow fibrosis [1, 2]. PV is characterized by a 
tri-lineage expansion of morphologically normal red cells, white cells, and platelets [3]. 
Generally, in PV it is possible to recognise two phases: (a) an initial proliferative 
polycythaemic phase, associated with increased red cell mass, which results in an 
increased propensity to thromboembolic events leading to significant morbidity and 
mortality, and (b) a “spent”, or post-polycythaemic phase, in which cytopenias, 
including anaemia, are associated with ineffective haematopoiesis, bone marrow 
fibrosis and hypersplenism. The course of the disease is associated with a tendency to 
transform to myelofibrosis and leukaemia, events which may be influenced by treatment 
[4].  
In 2005 the acquired mutation of the JAK2 kinase (JAK2V617F) was discovered in PV 
patients [5, 6, 7, 8]. The JAK2 kinase, through its association with cytokine receptors 
and receptor tyrosine kinases, play a central role in cytokine signalling and signal 
transduction. The JAK2V617F mutation, that is present in about 90-95% of PV patients, 
results in expression of a constitutively activated JAK2 tyrosine kinase that confers 
growth factors independence and hypersensitivity to blood cell lines [5, 6, 8, 9].  
PV is diagnosed in asymptomatic patients during the routine blood cell count analysis 
or, more commonly, on the basis of skin and mucous membrane redness or 
splenomegaly. Pruritus (aquagenic or not), fatigue, headache, vision disturbances, 
paraesthesia, erythromelalgia (acral dysesthesia and erythema) are the most common 
disease symptoms, that are present in the majority of patients and often severely 
deteriorate their quality of life [10, 11].  
The long-term prognosis of PV patients is variable. Particularly without treatment, 
about half of the people who have PV with symptoms die in less than 2 years, while 
with treatment, median survival in PV is 15 years. The 10-year risk of developing either 
myelofibrosis (MF) or acute myeloid leukaemia (AML) is 10% and 6%, respectively. 
The primary causes of morbidity and mortality in PV patients are thrombosis, 
haematological transformation, and haemorrhage, responsible for 41%, 13% and 4% of 
deaths, respectively [12].  
The first step in PV patient management is risk-stratification. The main two factors to 
be considered for risk-stratification are an age > 60 years and/or a history of thrombosis. 
Other factors, such as haematocrit, leukocytes and/or platelets counts and generic 
cardiovascular risk factors, are taken into account for risk stratification but their 
significance is still controversial. 


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In low risk patients, it is recommended to control the erythrocytosis by phlebotomy and, 
when no contraindication exists, to administer low-dose aspirin [2, 13]. In patients with 
intermediate risk of thrombosis, phlebotomy should be offered to keep the haematocrit 
below appropriate values and in general it is recommended to add a low daily dose of 
aspirin. When platelet counts are > 1000 x 109/L, additional myelosuppressive treatment 
should be considered. High-risk PV patients require cytoreductive therapy, even if the 
first step in the disease management is always phlebotomy plus low-dose aspirin [2]. 
Standard front-line therapy for high risk PV is hydroxycarbamide (formerly known as 
hydroxyurea, HU), the first choice cytoreductive agent [10, 13] authorised for PV 
therapy (both in Europe than in USA). Hydroxycarbamide is an antimetabolite that 
inhibits the enzyme ribonucleotide diphosphate reductase which has a rate-limiting role 
in DNA synthesis. It controls blood counts and reduces the rate of thromboembolic 
events. In general, hydroxycarbamide is well tolerated and has good clinical effect [4, 
10], but its use is burdened by a not negligible rate of neoplastic transformation of the 
disease [14, 15].  
In addition to hydroxycarbamide, PV patients can be also treated with alkylating agents 
(pipobroman and busulfan) authorised in Europe for treatment of PV. Pipobroman is a 
piperazine derivative and is available for clinical use in some European countries 
(France and Italy). The role of pipobroman in inducing the neoplastic transformation of 
PV has been recently emphasized as it appears to be even greater than that of 
hydroxycarbamide [14, 15]. Busulphan has been reported to be effective in controlling 
blood counts in PV since the 50’s, but an extensive use of the drug is limited by its 
leukemogenic potential [4, 16]. In current clinical practice, pipobroman and busulfan 
are considered as second line therapies in hydroxycarbamide-intolerant or refractory 
cases [2].  
Further to cytoreductive and anti-thrombotic therapy, very often patients are candidate 
to receive symptomatic treatments to control systemic symptoms, such as pruritus, 
headache, microvascular disturbances and fatigue, which can severely impair the 
patients’ quality of life. 
Recently, a JAK inhibitor was authorized both in Europe (i.e. Jakavi, INN: ruxolitinib) 
and in US (Jakafi, INN: ruxolitinib) for the treatment of adult patients with PV who are 
resistant to or intolerant of hydroxyurea.   
The clinical course of PV and ET is marked by significant thrombotic complications 
and a variable risk to evolve into myelofibrosis and eventually to acute myeloid 
leukemia. Randomized clinical trials performed in USA and Europe have shown that 
cytoreductive treatment of blood hyperviscosity, chemotherapy and low-dose aspirin 
have dramatically reduced the number of thrombo-hemorrhagic episodes and 
substantially improved survival.  
As compared to PV and ET, MF has the worst prognosis with a median survival or 3-5 
years. A prognostic score system was developed where the presence of leukocytosis, 
leukopenia or anaemia was used to identify three groups of patients with different 
survival, from 1 to 8 years. Conventional therapies in this disease were palliative and 
include many drugs in addition to supportive therapy to improve anaemia, 
thrombocytopenia and progressive splenomegaly.  


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Recently, a JAK inhibitor was authorized for the treatment of disease-related 
splenomegaly or symptoms in adult patients with MF in Europe (i.e. Jakavi, INN: 
ruxolitinib) and to treat intermediate or high-risk MF patient in US (i.e. Jakafi, INN: 
ruxolitinib). 
1.2 Rationale  
Polycythemia Vera (PV) is a myeloproliferative disorder which is considered to be a 
clonal disease derived from a transformed pluripotent hematopoietic stem cell. This cell 
is thought to lead to overactive hematopoiesis, driven by a constitutively active JAK-
STAT signalling pathway, caused by V617F mutations within exons 12 and 14 of the 
JAK2 gene [17]. The clinical course of PV is marked by significant thrombotic 
complications with an estimated incidence of 18x1000 person-years, accounting for 
45% of all deaths; myelofibrosis and transformation into AML may occur in a small 
percentage of cases (5x1000 person-years) [18].  
The mainstay of current therapy is aimed at reducing the number of these disease 
related complications by reducing blood hyperviscosity. Cytoreductive agents have 
been proven efficacious in this regard, but concerns regarding acceleration of disease 
transformation remain, thereby substantiating the need for novel therapies [2].  
Recently, small molecule inhibitors of the JAK2 kinase have at least partially validated 
the importance of this molecule in the clinical setting and several JAK2 inhibitors are 
currently under clinical development in PV. Recently, a JAK inhibitor was authorized 
both in Europe (i.e. Jakavi, INN: ruxolitinib) and in US (Jakafi, INN: ruxolitinib) for the 
treatment of adult patients with PV who are resistant to or intolerant of hydroxyurea.   
Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin 
and play a key role in the epigenetic regulation of gene expression.  
Givinostat (ITF2357) is a potent, orally available small molecule inhibitor of HDACs 
and it has shown to interfere with the JAK/STAT signalling pathway in preclinical 
studies.  
1.3 Preclinical rationale
Completed and updated data following described are reported in the Section 5 “Non-
clinical studies” of the current Investigator Brochure Dossier related to ITF2357.  
Givinostat has an anti-proliferative effect for tumor cells. Its efficacy in  hematological 
tumors bearing the JAK2V617F mutation is remarkable, showing an IC50 of 95 nM for 
SET-2 and 175 nM for HEL cell lines which are hetero- and homozygous for the mutant 
protein, respectively. These values are two- to three-fold lower than the ones observed 
for a JAK2 wild type tumor cell such as the erythroleukemic cell line K562, for which 
the IC50 is 350 nM [19, 20]. Combination benefit of Givinostat and hydroxyurea was 
observed in in-vitro cytotoxicity assays conducted in HEL and UKE cells. 


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1.4 Clinical studies
Completed and updated data following described are reported in the Section 6 “Effects 
in humans” of the current Investigator Brochure Dossier related to ITF2357. 
Givinostat has been tested in a number of clinical studies. Three major indications have 
been explored with Givinostat, inflammatory disease, neuromuscular disorders and 
oncology. The most common AEs observed were thrombocytopenia as well as 
gastrointestinal toxicities. AEs were generally mild to moderate and reversible upon 
discontinuation of study drug. The maximum administered dose was a single dose of 
600 mg in healthy volunteers and up to 400 mg once per week in patients with multiple 
myeloma. Doses up to approximately 100 mg b.i.d. were generally very well tolerated. 
At higher doses of Givinostat transient reduces haematological parameters (particularly 
platelets) and diarrhoea as well as nausea and vomiting were observed.  
1.4.1 Givinostat in chronic myeloproliferative neoplasms  
Givinostat is an HDACi and, as such, it has been investigated for its inhibitory activity 
on the autonomous proliferation of cells obtained by PV and ET patients carrying the 
JAK2V617F mutation and to elucidate the mechanism of action of this inhibition. Cells 
obtained from PV or ET patients carrying the JAK2V617F mutation are sensitive in 
colony assays to a 100-500 lower dose of Givinostat as compared to cells bearing un-
mutated JAK2. Moreover, Givinostat promotes the outgrowth of normal colonies over 
that of JAK2V617F mutated cells in vitro and induces down-modulation of the JAK2V617F
but not JAK2 wild type protein. JAK2V617F inhibition by Givinostat takes place at the 
post-transcriptional level and is followed by down-modulation of the phosphorylated 
STAT5 protein and PRV-1 gene expression.  
Two phase II study were conducted in patients with JAK2V617F positive cMPN. A phase 
II of Givinostat monotherapy, was completed with positive results in patients with 
JAK2V617F positive PV, ET and MF (Study N.: DSC/07/2357/28) [22]. Another phase II 
study combining Givinostat with hydroxyurea, was recently completed with positive 
results in patients with JAK2V617F positive PV not responding to the maximum tolerated 
dose of hydroxyurea monotherapy (Study N. DSC/08/2357/38); a total of 44 PV 
patients received Givinostat doses of either 50 or 100 mg per day and were treated for 
up to 24 weeks [23]. The ELN response criteria [21] were used to assess the primary 
endpoint after 12 weeks of treatment. Complete or partial responses were observed in 
approximately 50% of patients across both dose levels. 
At the time being, a multicenter, open label, long-term study testing the long term 
safety, tolerability and efficacy of Givinostat in patients with cMPN following core 
protocols and/or patient-named compassionate use program is ongoing (Study N. 
DSC/11/2357/44).  
After completion of this current trial (Study N. DSC/12/2357/45), all patients achieving 
clinical benefit will be allowed to continue treatment with Givinostat (at the same dose 
and schedule) in the above mentioned long-term study (Study N.: DSC/11/2357/44), 


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provided that the long-term study has already received all necessary approvals in that 
specific country and site and the study was initiated in that particular site. 
1.5 Rationale for a phase Ib/II study  
Preliminary signs of clinical activity in patients with JAK2 mutant cMPN as described 
above, have been observed in two studies with Givinostat. In these studies, the 
maximum administered dose of Givinostat was 150 mg per day which was generally 
well tolerated. Assuming a linear relationship between dose and efficacy, greater 
clinical efficacy can be expected with increased doses of Givinostat. 
Since the MTD of Givinostat has not been defined previously, the first aim of the 
current study is therefore, to determine the maximum tolerated dose of Givinostat in 
patients with PV. This study will investigate the safety, tolerability, pharmacokinetic 
(PK), and pharmacodynamic (PD) activity of Givinostat monotherapy. As such, the 
study will characterize Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose 
(MTD) of Givinostat. The second aim of this study is to characterize the clinical 
efficacy of Givinostat at the MTD. 
2. STUDY OBJECTIVES 
2.1 Primary objectives  
Part A 
•
To characterize the safety, tolerability and MTD of Givinostat in patients with 
PV.  
Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD after 3 cycles  
according to the clinico-haematological European LeukemiaNet (ELN) response 
criteria [21] (see paragraph 4.6.1). 
•
To determine the safety and tolerability of Givinostat at the MTD after 3 cycles. 
2.2 Secondary objectives  
Part A 
•
To evaluate the preliminary efficacy of Givinostat after 3 and 6  cycles of 
treatment according to the clinico-haematological ELN response criteria [21] 
(see paragraph 4.6.1). 
•
To characterize PK. 


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Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD after 6 cycles  
according to the clinico-haematological ELN response criteria [21] (see 
paragraph 4.6.1). 
•
To determine the safety and tolerability of Givinostat at the MTD after 6 cycles. 
•
To characterize PK. 
2.3 Exploratory objectives  
Parts A and B  
•
To evaluate the effect of Givinostat on single parameters of the clinico-
haematological ELN response criteria [21] (see paragraph 4.6.1). 
•
To evaluate the effects of Givinostat on PD markers. 
•
To evaluate the effects of Givinostat on spleen size (by MRI or CT scan) in 
patients with confirmed splenomegaly at baseline. 
•
To evaluate the effects of Givinostat on disease-related quality of life. 
•
To evaluate the effect of Givinostat on JAK2V617F allele burden. 
•
To evaluate the reduction of the symptomatic treatment of pruritus. 
Part B  
•
To evaluate the preliminary efficacy of Givinostat after 6 cycles of treatment 
according to the “new” ELN response criteria (i.e. the revised ELN response 
criteria) [33] (see paragraph 4.8.7). 
•
To evaluate the effect of Givinostat on single parameters of the “new” ELN 
response criteria (i.e. the revised ELN response criteria) [33] (see paragraph 
4.8.7). 
3. STUDY ENDPOINTS 
3.1 Primary endpoints  
Part A 
•
Safety and tolerability evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse events, graded 
according to Common Terminology Criteria for Adverse Events (CTCAE v. 
4.03, 14th June 2010). 
•
Determination of the MTD of Givinostat based on cycle 1 DLT’s. 


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Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - 
of Givinostat at the MTD after 3 cycles; the response will be evaluated 
according to the clinico-haematological ELN response criteria [21] (see 
paragraph 4.6.1). 
•
Safety and tolerability of Givinostat at the MTD after 3 cycles evaluated as 
following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse events, graded 
according to CTCAE v. 4.03. 
3.2 Secondary endpoints   
Part A 
•
Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - 
of Givinostat at the MTD after 3 and 6 cycles; the response will be evaluated 
according to the clinico-haematological ELN response criteria [21] (see 
paragraph 4.6.1). 
•
Individual Givinostat concentrations tabulated by dose cohort along with 
descriptive statistics. 
Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - 
of Givinostat at the MTD after 6 cycles; the response will be evaluated 
according to the clinico-haematological ELN response criteria [21] (see 
paragraph 4.6.1). 
•
Safety and tolerability of Givinostat at the MTD after 6 cycles evaluated as 
following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse events, graded 
according to CTCAE v. 4.03. 
•
Individual Givinostat concentrations tabulated with descriptive statistics. 
3.3 Exploratory endpoints  
Part A and Part B  
•
To evaluate the effect of Givinostat on each single response parameter according 
to the clinico-haematological ELN response criteria [21] (see paragraph 4.6.1). 
•
To evaluate the effects of Givinostat on PD markers by mRNA analysis. 


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•
To evaluate the effects of Givinostat on spleen size (by MRI or CT scan) in 
patients with confirmed splenomegaly at baseline. 
•
Improvement of constitutional symptoms evaluated according to MPN-SAF 
QOL questionnaire [24, 32]. 
•
Reduction of the JAK2V617F allele burden, tested by quantitative RT-PCR. 
•
Reduction of the symptomatic treatment of pruritus in term of dosage and/or 
days of treatment. 
Part B  
•
Overall response rate - i.e. Complete Remission and Partial Remission - of 
Givinostat at the MTD after 6 cycles; the response will be evaluated according 
to the “new” ELN response criteria (i.e. the revised ELN response criteria [33], 
see paragraph 4.8.7). 
•
To evaluate the effect of Givinostat on each single response parameter according 
to the “new” ELN response criteria (i.e. the revised ELN response criteria [33], 
see paragraph 4.8.7). 
4. INVESTIGATIONAL PLAN 
4.1 
Overall study design 
This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess 
the safety and tolerability, MTD and preliminary efficacy of Givinostat in patients with 
JAK2V617F positive PV.  
Part A is the dose escalation portion of the study and, once the MTD has been 
established, Part B will commence where the preliminary efficacy of Givinostat in PV 
patients will be established. Patients will be enrolled either in Part A or Part B and 
transition from one part to the other is not allowed. Only PV patients from Part A
assigned to the dose selected for Part B (MTD) may be counted towards the efficacy 
assessment in Part B.  
Eligible patients for this study will have a confirmed diagnosis of PV according to the 
revised WHO criteria and the JAK2V617F positivity. Only if the enrolment in Part A is 
slow (i.e. < 5 patients enrolled in 3 months), eligibility for this part of the study may 
be expanded to all patients with cMPN.  
After providing informed written consent before undertaking any protocol-related 
procedure, a unique patient identification code (i.e. patient screening ID which will be 
a combination of his/her site ID, study part ID and patient screening number, e.g. IT01-
A01) will be assigned to each patient and it will identify the patient within his/her 
enrolment confirmation by Italfarmaco S.p.A. or its designee and never be reused in 
case of screening failure. After the enrolment confirmation and the assignation of the 
dose level before the first drug intake, a unique patient identification code (i.e. patient 
ID which will be a combination of patient screening number ID and dose level ID, e.g. 
IT01-A01-DL1) will be assigned to each patient and it will identify the patient 


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throughout his/her participation in the study and never be reused in case of premature 
drop-out. 
Study therapy will be administered in 28 day cycles. In fact, the “cycle” is defined as 4 
weeks of treatment. 
Disease response will be evaluated according to the clinico-haematological ELN criteria 
[21] after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with 
Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks 
of treatment will not be counted to assess the clinico-haematological response. 
The study will last up to a maximum of 24 weeks of treatment. However, after 
completion of the trial, all patients achieving clinical benefit will be allowed to continue 
treatment with Givinostat (at the same dose and schedule) in a long-term study (Study 
N.: DSC/11/2357/44), provided that the long-term study has already received all 
necessary approvals in that specific country and site, and the study has been already 
initiated in that particular site. 
Safety will be monitored at each visit throughout the entire duration of the study. 
Treatment will be administered on an outpatient basis and patients will be followed 
regularly with physical and laboratory tests, as specified in the protocol (see Appendix 
A and paragraph 4.5.4); in case of hospitalization, the treatment will be continued or 
interrupted according to the Investigators’ decision.  
4.1.1 Part A
Part A is the dose escalation part of this study, evaluating the safety, tolerability and 
MTD of Givinostat in patients with JAK2V617F positive PV. 
Approximately 24 patients will be enrolled in Part A. 
In this part of the study the first cycle of treatment will be used to assess the safety and 
tolerability of Givinostat as well as PK/PD.  
After the completion of the first cycle, the patients will be treated for an additional 5 
cycles.  
Only PV patients from Part A assigned to the dose selected for Part B (MTD) may be 
counted towards the efficacy assessment in Part B.  
4.1.1.1 Definition of Dose Limiting Toxicity (DLT) 
Dose Limiting Toxicity (DLT) is defined as the following drug-related toxicity: 
•
Grade 4 haematological toxicities, or
•
Grade 3 febrile neutropenia, or
•
Grade  3 non-haematological toxicities with exception of:
a) Grade 3 diarrhoea without adequate supportive care lasting  less than 3 days, 
and 


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b) Grade 3 nausea or vomiting without adequate supportive care lasting less 
than 3 days, or
•
Any drug-related SAE, or
•
Any toxicity that is clearly not related to disease progression or intercurrent 
illness requiring interruption of dosing for more than 3 days during the first 
cycle.  
The severity of the above mentioned events will be graded according to NCI Common 
Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010). 
Only Dose Limiting Toxicities (DLTs) experienced during the first cycle of treatment 
will be considered for dose escalation decisions. DLTs include all AEs that are clearly 
not related to disease progression or intercurrent illnesses. 
Patients who didn’t experience a DLT and missed more than 10% of the doses in Cycle 
1 of Part A will be replaced (see paragraph 4.6.4). 
4.1.1.2 Study team definition 
The study team will include: selected Principal Investigator/s (i.e. Chairman and/or 
Principal Investigator/s who recruited the patients under discussion), the CRO Medical 
Monitor, Italfarmaco Medical Expert/s, Italfarmaco Clinical Scientist and any other 
additional personnel, if necessary. 
4.1.1.3 Dose Levels (DLs) and dose escalation scheme  
Dose escalation will be conducted according to a standard 3+3 design, adopting a 
modified Fibonacci escalation schema [25, 26, 27]. Patients will be enrolled in cohorts 
of 3 new patients (up to a maximum of 6) in rising dose levels (Table 1). Dose 
escalation to the next higher Dose Level (DL) can only occur after the third patient in 
the DL has been followed for a minimum of 1 cycle after the first administration of 
study agent, and the current dose has been determined to have an acceptable safety 
profile according to the following rules summarized in Table 2. 


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Table 1 – Dose escalation scheme for Givinostat mono-therapy in Part A 
Givinostat daily dose  
Givinostat dose level 
(DL) 
DL used primarily to 
asses 
50 mg b.i.d. 
DL0 
Safety, PK, PD* 
100 mg b.i.d. 
DL1 
MTD, PK, PD 
150 mg b.i.d. 
DL2 
MTD, PK, PD 
200 mg b.i.d. 
DL3 
MTD, PK, PD 
150 mg t.i.d. 
DL4 
MTD, PK, PD 
200 mg t.i.d. 
DL5 
MTD, PK, PD 
* DL previously demonstrated as safe. 
The DL0 (i.e. 50 mg b.i.d.) has been previously shown to be well tolerated in studies 
(Section 6 “Effects in humans” of the current Investigator Brochure Dossier related to 
ITF2357). Therefore, it is preferred to assign patients to the highest available dose level 
(i.e. DL1, DL2, DL3, DL4 and DL 5) before assigning patients to DL0. 
Intermediate Dose Levels (IDLs) and, consequently, additionally DLs may be 
introduced to more accurately define the MTD. 
Note that if a pregnancy occurs, the patient will be replaced and another patient in that 
DL should be recruited. 
4.1.1.4 Dose escalation rules  
In Part A each patient will receive study drug at a specific DL. Once the first 3 patients 
of the first DL (i.e. DL1) have been treated for 1 cycle, tolerability data will be 
evaluated and a decision to escalate to the next dose will be made.  
Table 2 summarizes the dose escalation rules for Givinostat in Part A. 


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Table 2 - Dose escalation rules for Part A
Number of patients with 
DLT at a given dose level 
Action 
0 out of 3 
Enter 3 patients at the next dose level.
1 out of 3 
Enter at least 3 more patients at this dose level and 
•
if 0 of these 3 new patients experiences DLT, 
proceed to the next dose level; 
•
if  1 of this group suffer DLT (for a total of  2/6 
patients with a DLT), this dose exceeds the MTD 
and dose escalation is stopped. To further assess 
tolerability, 3 additional patients will be entered 
at the next lowest dose level if only 3 patients 
were treated previously at that dose. Upon 
determination of the MTD, the study proceeds 
directly to Part B. 
 2 
Dose escalation will be stopped. This dose exceeds the 
MTD. To further assess tolerability, 3 additional patients 
will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose and the study 
will proceed directly to Part B of the study.
At any time, if  2/3 or  2/6 patients at a given dose level develop a DLT, it is 
acceptable to de-escalate to an intermediate, not previously studied dose (see Table 1), 
if evaluation of toxicity at such a dose is desired, in lieu of proceeding directly to Part B
of the study. If this approach is taken, 3 patients should be enrolled at the intermediate 
dose, and the aforementioned rules should be used to determine enrolment at this dose. 
If the decision is made to proceed directly to the efficacy portion of the study (i.e. Part 
B), the efficacy part will start at the next lower dose below where  2/3 or  2/6 DLTs 
were observed (i.e. the MTD dose level).  
4.1.1.5 Definition of MTD
If 2 or more patients per dose level experience a DLT, dose escalation will terminate 
and the MTD is the next lower dose level if no more than one out of 6 patients had a 
DLT at that level. Once all patients enrolled in Part A have been treated for at least 1 
cycle, the study team will determine the MTD to be used in Part B based on the safety 
and tolerability profile of Givinostat observed as well as the PK and PD data, if 
applicable.  
No intra-patient dose escalation will be permitted prior to determining the MTD.  


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At that time, patients on treatment at lower dose levels may be allowed to escalate their 
Givinostat dose up to the MTD for the remainder part of the study (Part A) at the 
discretion of the Investigator and after the written authorization of Italfarmaco S.p.A.. 
Of note, patients initially dosed at lower dose levels that are allowed to escalate their 
Givinostat dose up to the MTD for the remainder part of the study (Part A), will follow 
the dose modification rules of Part B (see paragraph 4.3.3.2). Total daily dose may 
never exceed the MTD defined in Part A (i.e. 100 mg b.i.d.). 
4.1.2 Part B
Part B is a multicenter, open label, non-randomized, phase II, cohort expansion study to 
assess the preliminary clinical efficacy of Givinostat at the MTD in patients with 
JAK2V617F positive PV. 
Approximately twenty eight patients will be enrolled in Part B starting at the MTD 
defined in Part A (i.e. 100 mg b.i.d.), according to an optimized Simon’s 2-stage design 
[30]. 
The dose of Givinostat will be modified for protocol specified toxicities (see paragraph 
4.3.3.2). 
4.2 
Trial organization 
The conduct of this study will be committed to a Contract Research Organization 
(CRO). In any case, Italfarmaco S.p.A. remains responsible for the development, 
writing and finalization of the study protocol, the investigational medicinal product 
(IMP) production and the Pharmacovigilance activities. 
For all study activities, with the exception above mentioned, the designated CRO or 
their delegates (e.g. a Contact Manufacturing Organization (CMO) delegated for the 
IMP secondary packaging and management) can apply internal standard operating 
procedures (SOPs). 
Trial activities will be supervised by Italfarmaco S.p.A. through regular contacts with 
the staff of the designated CRO or their delegates and/or Investigators, as necessary. 
4.3 
Patient population  
The study will include patients of both genders with an established diagnosis of 
JAK2V617F Polycythemia Vera according to the revised WHO criteria, who have an 
active and/or not controlled disease.
In case of slow recruitment the Sponsor may decide to expand the population to patients 
with cMPN positive to JAK2V617F. 


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4.3.1 Inclusion criteria 
Patients must meet the following criteria to be eligible for study entry: 
1. Patients must be able to provide informed consent through the signature of an 
informed consent form; 
2. Patients must have an age 18 years; 
3. Patients must have a confirmed diagnosis of PV according to the revised WHO 
criteria; 
4. Patients must have JAK2V617F positive disease; 
5. Patients must have an active/not controlled disease defined as  
a) HCT  45% or HCT <45% in need of phlebotomy, and
b) PLT counts > 400 x109/L, and
c) WBC > 10 x109/L; 
6. Patients must have an Eastern Cooperative Oncology Group (ECOG) 
performance status [28]  1 in Part A, ECOG performance status  2 in Part B, 
within 7 days of initiating study drug; 
7. Female patient of childbearing potential has a negative serum or urine pregnancy 
test within 72 hours of the first dose of study therapy; please note that a 
borderline urine pregnancy test must be followed with a serum pregnancy test; 
8. Use of an effective means of contraception for women of childbearing potential 
and men with partners of childbearing potential;  
9. Adequate and acceptable organ function within 7 days of initiating study drug; 
10. Willingness and capability to comply with the requirements of the study. 
Note that if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months), 
eligibility for this part of the study may be expanded to all patients with cMPN. In 
this case, the inclusion criterion n. 5 will be modified as following only for Part A:
5. Patients must have an active/not controlled disease defined as: 
a) ET patients: PLT counts > 600 x109/L; 
b) MF patients: no response according to EUMNET criteria [29].
Note that an effective means of contraception for women of childbearing potential and 
men with partners of childbearing potential (i.e. inclusion criterion n. 5) is defined as 
following described based on different subject subgroups:   
A. Female subjects of childbearing potential: acceptable non-hormonal, contraceptive 
methods must be used from the 28 days before first dose of study drug through 3 
months after the last dose of study drug and include the following: 
•
True abstinence (absence of any sexual intercourse), when in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g. 
calendar, ovulation, symptothermal, postovulation methods) and withdrawal 
are not acceptable methods of contraception. 


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•
Double barrier contraception such as diaphragm or a barrier method of 
contraception in conjunction with spermicidal jelly such as for example 
cervical cap with spermicide jelly and the male partner must use a condom 
with spermicide. 
•
Intra-uterine device (non-hormone-releasing) in place for at least 90 days 
previously and the male partner must use a condom with spermicide. 
•
Tubal ligation at least 6 months previously and 1 additional acceptable 
contraception method. 
•
Vasectomy of the male partner (with a negative sperm post-vasectomy 
semen analysis) at least 6 months previously and 1 additional acceptable 
contraception method. 
B. Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria: 
•
Postmenopausal: Female subjects, less than 60 years of age, who have been 
amenorrheic for at least 2 years and have a serum FSH level within the 
laboratory’s reference range for postmenopausal females. Female subject 
who are 60 years of age or older who are amenorrheic for greater than 2 
years will be assume to be postmenopausal. 
•
Documented hysterectomy or bilateral oophorectomy or both all other 
female subjects (including subjects with tubal ligations and subjects that do 
not have a documented hysterectomy) will be considered to be of 
childbearing potential. 
C. Male Subjects, acceptable contraceptive methods must be used from Screening Visit 
through 3 months after the last dose of study drug, and include the following: 
•
True abstinence (absence of any sexual intercourse), when in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
•
Condom with spermicide and the female partner must use an acceptable 
method of contraception, such as an oral, transdermal, injectable or 
implanted steroid-based contraceptive, or a diaphragm or a barrier method of 
contraception in conjunction with spermicidal jelly such as for example 
cervical cap with spermicide jelly. 
•
Vasectomy (with a negative sperm post-vasectomy semen analysis) at least 6 
months previously and 1 additional acceptable contraception method.  
•
Male subjects must not donate sperm from the Screening Visit through 3 months 
after the last dose of study drug. 
Note also that  
–
Male condom cannot be used with female condom due to risk of tearing. 
–
The use of birth-control methods does not apply if the female partner has a 
bilateral oophorectomy, hysterectomy, or is postmenopausal (as defined above). 


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4.3.2 Exclusion criteria 
Patients must NOT meet any of the following criteria to be eligible for study entry: 
1. Active bacterial or mycotic infection requiring antimicrobial treatment; 
2. Pregnancy or nursing;   
3. A clinically significant QTc prolongation at baseline (e.g. repeated demonstration of 
a QTc interval  450 msec); 
4. Use of concomitant medications known to prolong the QT/QTc interval;  
5. Clinically significant cardiovascular disease including:  
a) Uncontrolled hypertension
despite medical treatment, myocardial infarction, 
unstable angina within 6 months from study start; 
b) New York Heart Association (NYHA) Grade II or greater congestive heart 
failure;  
c) History of any cardiac arrhythmia requiring medication (irrespective of its 
severity);   
d) A history of additional risk factors for TdP (e.g. heart failure, hypokalemia, 
family history of Long QT Syndrome);  
6. Known positivity for HIV; 
7. Known active HBV and/or HCV infection; 
8. Platelet count < 100 x109/L within 14 days before enrolment (i.e. the receipt of the 
Patient ID); 
9. Absolute neutrophil count < 1.2 x109/L within 14 days before enrolment (i.e. the 
receipt of the Patient ID); 
10. Serum creatinine > 2 x ULN; 
11. Total serum bilirubin > 1.5 x ULN except in case of Gilbert’s disease; 
12. Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 3 x ULN; 
13. History of other diseases (including active tumours), metabolic dysfunctions, 
physical examination findings, or clinical laboratory findings giving reasonable 
suspicion of a disease or condition that contraindicates use of an investigational 
drug or that might affect interpretation of the results of the study or render the 
subject at high risk from treatment complications; 
14. Prior treatment with a JAK2 or HDAC inhibitor or participation in an interventional 
clinical trial for cMPN, including PV, ET or MF; 
15. Systemic treatment for cMPN other than aspirin/cardio aspirin;  
16. Hydroxyurea within 28 days before enrolment (i.e. the receipt of the Patient ID); 
17. Interferon alpha within 14 days before enrolment (i.e. the receipt of the Patient ID); 
18. Anagrelide within 7 days before enrolment (i.e. the receipt of the Patient ID) 
19. Any other investigational drug or device within 28 days before enrolment (i.e. the 
receipt of the Patient ID); 
20. Patient with known hypersensitivity to the components of study therapy. 


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Of note, a repeated demonstration of a QTc interval  450 msec (i.e. exclusion criterion 
n. 3) means that, if the first ECG evaluation demonstrates a prolonged QTc interval (i.e. 
a QTc interval  450 msec), two additional ECG evaluations over a brief period of time 
(i.e. 5 minutes between each recording) must be performed. The averaged value of these 
three ECG evaluations has to be used for the evaluation of the QTc interval requested 
by the exclusion criterion n. 3. In the CRF all the performed ECG evaluations have to 
be entered as well as the average value of multiple ECG evaluation, if necessary.  
Note that an any other investigational drug or device (i.e. exclusion criterion n. 19) 
includes any investigational drug or device not already mentioned and detailed in the 
exclusion criteria n. 14, 15, 16 17 and/or 18. 
4.3.3  Criteria for dose modifications, treatment interruption and 
treatment discontinuation   
For patients who do not tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to allow the patients to continue the treatment with 
the study drug.  
4.3.3.1 Dose modification criteria in Part A  
In the Cycle 1 of Part A dose modifications will not be allowed. Patients receiving 
subsequent cycles of treatment in Part A may have up to two dose modifications for 
drug related DLT’s (see paragraph 4.1.1.1 for the DLT definition). The first dose 
modification should be one dose level below the current dose, the second modification 
should be two dose levels below. Study drug may be resumed at lower dose level once 
the event resolves to at least grade 1 or baseline values. If toxicities meeting 
modification criteria occur after the second dose reduction, therapy must be 
discontinued. Figure 1 outlines the dose modifications scheme for all DLs of Givinostat 
monotherapy, with exception of DL0 (i.e. 50 b.i.d.) and DL1 (i.e. 100 mg b.i.d.) 
represented by Figures 2 and 3, respectively. Patients with unresolved toxicities lasting 
2 weeks or longer will not be permitted to continue on study.  
Patients experiencing Grade 3 or 4 unmanageable toxicity will require immediate dose 
interruption and notification to the Sponsor. Treatment for each new cycle will be 
delayed until dose limiting toxicities that are clearly not related to disease progression 
have resolved to at least Grade 1 or the patient’s baseline.  


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Figure 1 - Criteria for dose modifications  
DLT is a Dose Limiting Toxicity. DLx represents a Dose Level with the exception of DL0 (i.e. 50 mg 
b.i.d.) and DL1 (i.e. 100 mg b.i.d.), represented by Figures 2 and 3, respectively. DLx-1 represents the next 
lower Dose Level (first dose reduction). DLx-2 represents the next lower dose level after a first dose 
reduction (second dose reduction). Grade  1 represents the severity of AE. 
Figure 2 - Criteria for dose modifications for patients treated in DL0  
DLT is a Dose Limiting Toxicity. Grade  1 represents the severity of AE. 


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Figure 3 - Criteria for dose modifications for patients treated in DL1 
DLT is a Dose Limiting Toxicity. Grade  1 represents the severity of AE. 
4.3.3.2 Dose modification criteria in Part B   
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 
Givinostat. The guidelines described here below (i.e. see paragraph 3.3.3.2.1 and 
paragraph 3.3.3.2.2) need to be followed. The objective of the Givinostat dose 
adjustment rules described below is to optimize the response for each individual patient, 
avoiding specific drug-related toxicities. Therefore, dose reductions or interruptions will 
be mandatory for specific toxicities (see paragraph 3.3.3.2.1) and dose increases after an 
initial dose reduction will be allowed in the case of inadequate efficacy at the reduced 
dosage in absence of specific toxicities (see paragraph 3.3.3.2.2).  
The severity of the above mentioned events will be graded according to NCI Common 
Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010). 
Each dose modification has to be recorded on the CRF.     


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Of note, the dose modification criteria described in this paragraph (i.e. see paragraph 
3.3.3.2.1 and paragraph 3.3.3.2.2 for details) will be followed also by patients initially 
dosed at lower dose levels in Part A that, after the definition of MTD, are allowed to 
escalate their Givinostat dose to the MTD for the remainder part of the study (Part A) at 
the discretion of the Investigator and after written authorization of Italfarmaco S.p.A..  
4.3.3.2.1 Dose adjustments for safety reasons in Part B
In Part B, the initial dose of Givinostat will be the MTD defined in Part A (i.e. 100 mg 
b.i.d.).  
Based on evaluations performed as part of the visit procedures of the Day 28 of each 
Cycle up to the Cycle 5 (i.e. Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, Cycle 4 
Day 28, Cycle 5 Day 28) and/or in any necessary additional study visit, the Givinostat 
doses have to be decreased in case of the occurrence of at least one of the toxicities 
described in the Table 3.  
The objective of these guidelines is to consider the patient’s data, prior clinic-
haematological response and dose tolerability, in order to achieve an optimized dose for 
each individual patient, or a balancing between the tolerable dose and the clinico-
haematological response, that also take into account the natural course of the disease.  
Reductions in Givinostat total daily dose for patients that meet dose reduction criteria 
(see Table 3 for details) will be achieved by adjusting the morning and evening 
administered dose level, since the total daily dose is equally divided between the 
morning and evening administration.     


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Table 3 - Dose reduction rules in Part B
Observed values/data 
Action 
Grade 1 thrombocytopenia  
(i.e. PLTs count < local LLN but  75 x 109/L)
Total daily dose must be reduced of 50 mg/die: 
•
For patients that are receiving the daily dose of 
100 mg b.i.d., daily dose must be reduced to 75 
mg b.i.d.. 
•
For patients that are receiving a reduced daily 
dose of 75 mg b.i.d. or 50 mg b.i.d., daily dose 
must be evaluated based on the Investigator’s 
decision 
and 
after 
discussion 
with 
the 
Sponsor’s representative(s).
Grade 2 thrombocytopenia  
(i.e. PLTs count < 75 x 109/L but  50 x 109/L) 
or 
Grade 2 anemia 
(i.e. Hb value < 10 g/dL but  8 g/dL) 
or 
Grade  3 non-haematological toxicities with 
exception of: 
a) Grade 
3 
diarrhoea 
without 
adequate 
supportive care lasting  less than 3 days, and 
b) Grade 3 nausea or vomiting without adequate 
supportive care lasting less than 3 days. 
Total daily dose must be reduced of 50 or 100 
mg/die, based on the Investigator’s decision 
and after discussion with the Sponsor’s 
representative(s): 
•
For patients that are receiving the daily dose of 
100 mg b.i.d., daily dose should be reduced to 
75 mg b.i.d. or 50 mg b.i.d., based on the 
Investigator’s decision and after  discussion 
with the Sponsor’s representative(s).
•
For patients that are receiving a reduced daily 
dose of 75 mg b.i.d. or 50 mg b.i.d., daily dose 
must be evaluated based on the Investigator’s 
decision 
and 
after 
discussion 
with 
the 
Sponsor’s representative(s). 
Grade 3 thrombocytopenia  
(i.e. PLTs count < 50 x 109/L but  25 x 109/L)
or 
Grade 3 anemia 
(i.e. Hb value < 8 g/dL; transfusion indicated) 
or 
Grade 3 febrile neutropenia  
(i.e.  ANC < 1.0 x 109/L with a single temperature of 
> 38.3°C / 101° F, or a sustained temperature  38°C / 
100.4°F for more than one hour)
Immediate temporary discontinuation of the 
treatment with Givinostat. 
The treatment will be interrupted for at least 
one week. Anyway,  the treatment for each new 
cycle will be delayed until the observed 
toxicity that is clearly not related to disease 
progression, has resolved to at least Grade 1 or 
the patient’s baseline value.  
Daily dose has to be restarted at 75 mg b.i.d. or 
50 mg b.i.d., based on the Investigator’s 
decision and after  discussion with the 
Sponsor’s representative(s). 
Patients with unresolved toxicities lasting 4 
weeks or longer will not be permitted to 
continue on study.


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Table 3 - Dose reduction rules in Part B (continue)
LLN is the Lower Limit of Normality of the value reported in each evaluation performed at local 
laboratory of each investigational site.  
  
The severity of the above mentioned events will be graded according to NCI Common 
Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010). 
Patients with unresolved toxicities lasting 4 weeks or longer will not be permitted to 
continue on study. 
In order follow the evolution of the observed abnormalities up to its stabilization and/or 
normalization (i.e. event resolved to at least Grade 1 or baseline values) and also to 
provide sufficient data to make dose adjustment decisions, it is strictly recommended
to perform additional study visits at least on bi-weekly basis upon occurrence of the 
following toxicities:  
- 
Grade 1 thrombocytopenia (i.e. PLTs count < local LLN but  75 x 109/L); 
- 
Grade 1 anemia (i.e. Hb value < local LLN but  10 g/dL),  
- 
ANC < 2.0 x 109/L; 
- 
Grade 2 non-haematological toxicities; 
- 
Any SAE (if feasible).  
Observed values/data 
Action 
Grade 4 thrombocytopenia  
(i.e. PLTs count  25 x 109/L) 
or 
Grade 4 anemia 
(i.e. life-threatening consequences; urgent intervention 
indicated) 
or 
Grade 4 febrile neutropenia  
(i.e. life-threatening consequences; urgent intervention 
indicated) 
or 
Grade  3 unmanageable toxicity 
Immediate temporary discontinuation of 
the treatment with Givinostat. 
The treatment will be interrupted for at 
least one week. Anyway,  the treatment for 
each new cycle will be delayed until the 
observed toxicity that is clearly not related 
to disease progression, has resolved to at 
least Grade 1 or the patient’s baseline 
value.  
The continuation of the study - and the 
study drug dosage - should be evaluated 
based on the Investigator’s decision and 
Sponsor’s recommendation.  
Patients with unresolved toxicities lasting 4 
weeks or longer will not be permitted to 
continue on study. 


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In addition, additional study visits at least on weekly basis should be performed upon 
occurrence of the following toxicities: 
- 
Grade  2 thrombocytopenia (i.e. PLTs count < 75 x 109/L); 
- 
Grade  2 anemia (i.e. Hb value < 10 g/dL),  
- 
ANC  1.5 x 109/L; 
- 
Drug-related Grade  3 non-haematological toxicities; 
- 
Drug-related SAE (if feasible).  
Of note, the lowest dosage of Givinostat that can be dispensed to the patients in Part B
is 50 mg b.i.d., i.e. a dosage that has been previously shown to be well tolerated. Of 
note, patients will self-administer daily Givinostat capsules at home at morning and at 
the evening (i.e. after 12 hours) with fluids and between meals (i.e. to take the study 
drug at least 2 two hours after the last meal, or no less than 1 hour before the meal). 
4.3.3.2.2 Dose increase for inadequate efficacy in Part B
In Part B, the initial dose of Givinostat will be the MTD defined in Part A (i.e. 100 mg 
b.i.d.).  
Based on evaluations performed as part of the visit procedures of the Day 28 of each 
Cycle up to the Cycle 5 (i.e. Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, Cycle 4 
Day 28, Cycle 5 Day 28) and/or in any necessary additional study visit, the Givinostat 
doses have to be decreased in case of the occurrence specific toxicities (see paragraph 
4.3.3.2.1).  
After a dose reduction, dosing may be restarted and then increased following recovery 
of the observed toxicity(ies) to controlled levels. The objective for restarting and then 
escalating after a reduction for safety reasons is to find the highest safe dose regimen of 
Givinostat for each patient that is necessary to obtain a clinico-haematological response, 
with increase in dose not more than the MTD defined in Part A (i.e. 100 mg b.i.d.). 
After a dose reduction and in order to optimize the response for each individual patient 
avoiding specific drug-related toxicities, the Givinostat dosage may be increased for 
patients who meet all the following criteria, based on evaluations performed as part of 
the visit procedures of the Day 28 of each Cycle up to the Cycle 5 (i.e. Cycle 1 Day 28, 
Cycle 2 Day 28, Cycle 3 Day 28, Cycle 4 Day 28, Cycle 5 Day 28):  
1. Inadequate efficacy as demonstrated by one or more of the following points: 
a) HCT  45%, or HCT < 45% but at least 1 phlebotomy performed after the 
first 3 weeks of treatment, or HCT < 45% but at least three point higher than 
the HCT obtained at baseline (i.e. HCT at baseline (in %) plus at least a 
value of 3%), or 
b) WBCs count > 10 x 109/L, or
c) PLTs count > 400 x 109/L, and  


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2. PLTs count > local LLN, and
3. Hb value  12 g/dL, and
4. ANC  1.5 x 109/L.  
Table 4 summarizes the dose increase rules to be apply for Givinostat dosage at the end 
(i.e. Day 28) of each Cycle of Part B up to Cycle 5 (i.e. Cycle 1 Day 28, Cycle 2 Day 
28, Cycle 3 Day 28, Cycle 4 Day 28, Cycle 5 Day 28). The objective of these guidelines 
is to consider the patient’s data, prior clinico-haematological response and dose 
tolerability, in order to achieve an optimized dose for each individual patient, or a 
balancing between the tolerable dose and the clinico-haematological response, that also 
take into account the natural course of the disease.  
Table 4 - Dose increase for inadequate efficacy in Part B
Observed values/data 
Action 
1. Inadequate efficacy as demonstrated by one 
or more of the following points: 
a) HCT  45%, or HCT < 45% but at least 1 
phlebotomy performed after the first 3 
weeks of treatment, or HCT < 45% but at 
least three point higher than the HCT 
obtained at baseline (i.e. HCT at baseline 
(in %) plus at least a value of 3%), or 
b) WBCs count > 10 x 109/L, or
c) PLTs count > 400 x 109/L, and  
2. PLTs count > local LLN, and
3. Hb value  12 g/dL, and
4. ANC  1.5 x 109/L.  
Total daily dose may be increased of 50 
mg/die:
•
For patients that are receiving a reduced 
daily dose of 75 mg b.i.d.,  daily dose must 
be increased to 100 mg b.i.d.. 
•
For patients that are receiving a reduced 
daily dose of 50 mg b.i.d., daily dose must 
be increased to 75 mg b.i.d.. 
•
Only for patients of Part A that are 
receiving a reduced daily dose of 50 mg 
o.d., daily dose must be increased to 50 mg 
b.i.d..   
The total daily dose increase may be no greater than an increase of 50 mg/die, since 
the following dose increase rules will apply as detailed in the Table 4: 
- For patients that are receiving a reduced daily dose of 75 mg b.i.d., the dose increase 
criteria allow to receive a maximum dosage of 100 mg b.i.d.; 
- For patients that are receiving a reduced daily dose of 50 mg b.i.d., the dose increase 
criteria allow to receive a maximum dosage of 75 mg b.i.d.. 


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- Only for patients of Part A that are receiving a reduced daily dose of 50 mg o.d., the 
dose increase criteria allow to receive a maximum dosage of 50 mg b.i.d.. 
Therefore, total daily dose may never exceed the MTD defined in Part A (i.e. 100 mg 
b.i.d.). 
4.3.3.3
Treatment interruption and treatment discontinuation in Parts A and B  
In some circumstances, it may be necessary to temporarily interrupt treatment as a result 
of adverse experiences that may have an unclear relationship to study drug. Study drug 
may be withheld by the Investigator at any time if there is concern about patient safety 
and for all aspects of the conduct of the protocol, since the safety of the individual 
patient is paramount. Treating Investigator may employ any means necessary to ensure 
patient safety, particularly in medical circumstances not anticipated by this protocol.  
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 
Givinostat (see paragraph 4.3.3.1 and paragraph 4.3.3.2). The objective of the 
Givinostat dose adjustment rules described below is to optimize the response for each 
individual patient, avoiding specific drug-related toxicities.  
If the patient inadvertently misses a drug dose, no additional trial medication should be 
taken that day or in the next days in the effort to replace the material that has been 
missed.  
If vomiting occurs, no additional trial medication should be taken that day in an effort to 
replace the material that has been vomited. 
If the study drug is interrupted for any reason for more than 4 weeks continuously, 
dosing may be not be restarted.  
Patients have the right to withdraw from the study at any time for any reason. The 
Investigator has the right to withdraw patients from the study due to medical reasons 
according to his/her discretion.  
When patients discontinue study medication, the reason must be categorized in the case 
report form (CRF) as one of the following:  
1. study completed; 
2. adverse event(s); 
3. disease progression; 
4. protocol violation; 
5. patient withdrew Informed Consent Form; 
6. lost at follow-up (despite every effort made to contact the patient); 


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7. physician decision due to safety reasons; 
8. sponsor decision (see paragraph 8.7); 
9. lack of compliance; 
10. patient found not eligible; 
11. death; 
12. pregnancy. 
If a pregnancy occurs, the patient will be replaced and another patient in that DL should 
be recruited. 
If the patient discontinues the study because of an adverse event whether or not drug 
related, he/she must be followed until resolution or stabilization of the event, whichever 
occurs first. 
In case of lack of compliance or in case the patient is found not eligible, the patient 
discontinuation have to be discussed between Investigator and Sponsor.    
If the patient discontinues for any reason (including discontinuation for pregnancy), 
with drug related adverse event ongoing at study end, he/she must be followed until 
resolution or stabilization of the event or until it is reasonable to consider the event not 
drug related any more or until the start of a new treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications included in list of 
“Drugs with risk of Torsades de Pointes” (see Appendix C) the treatment with 
Givinostat is to be promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-
up visits until recovery. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance every effort should be made 
to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF.


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4.4 
Treatments 
4.4.1 Investigational Medicinal Product (IMP) 
Completed and updated data following described are reported in the Section 4 
“Physical, chemical and pharmaceutical properties and formulation” of the current 
Investigator Brochure Dossier related to ITF2357.  
Givinostat is a histone-deacetylases inhibitor.  
For the purpose of this document the name “Givinostat” is used to indicate the whole 
study drug name “Givinostat hydrochloride monohydrate” (also known as ITF2357, i.e. 
its Italfarmaco S.p.A. research code). Therefore, the dosages/concentrations of the study 
drug are expressed as Givinostat hydrochloride monohydrate.  
The product will be supplied as hard gelatine capsules for oral administration at the 
strength of 50 mg and/or 75 mg and/or 100 mg each. 
Each capsule contains a granulate (obtained by wet granulation) composed of ITF2357, 
sodium starch glycolate, hydroxypropyl methyl cellulose (HPMC), sodium lauryl 
sulphate, lactose, magnesium stearate and colloidal silica. 
  
4.4.1.1 Dosage and administration 
In Part A patients will be treated in DLs at the following starting daily doses of 
Givinostat:  
•
50 mg b.i.d.; 
•
100 mg b.i.d.; 
•
150 mg b.i.d.; 
•
200 mg b.i.d.; 
•
150 mg t.i.d.; 
•
200 mg t.i.d.. 
Intermediate Dose Levels (IDLs) and, consequently, additionally DLs may be used to 
establish the MTD (for more details, see paragraph 4.1.1.3). 
In Part B patients will be treated at the MTD of Givinostat established in Part A (i.e. 
100 mg b.i.d.).  
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 
Givinostat (see paragraph 4.3.3.1 and paragraph 4.3.3.2). The objective of the 
Givinostat dose adjustment rules described below is to optimize the response for each 
individual patient, avoiding specific drug-related toxicities.  


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Both in Part A and in Part B, patients will self-administer daily Givinostat capsules at 
home as instructed by the Investigator (see paragraph 4.4.7.2 and paragraph 4.4.7.4), 
except for the first drug administration (i.e. Day 1 of the Cycle 1). Patients will not take 
the morning dose of Givinostat on the day selected for their timed PK and PD 
assessments (see paragraph 4.5.3.2 and paragraph 4.5.3.3). Study drug will be 
administered in the clinic for these specific visits, in order to obtain pre- and/or post-
dose plasma levels of Givinostat. On all the other days corresponding to study visits, 
patients will take the morning dose of study drug prior to the visit. 
In Part A, the lowest dosage of Givinostat that can be dispensed to the patients is 50 mg 
o.d.. In this case, the patient should take the study drug each day at the morning with 
fluids and between meals (i.e. to take the study drug at least 2 two hours after the last 
meal, or no less than 1 hour before the meal). In all other possible dosage (i.e. 50 mg 
b.i.d, or 100 mg b.i.d., or 150 mg/die), patients will self-administer daily Givinostat 
capsules at home at morning and at the evening (i.e. after 12 hours) with fluids and 
between meals (i.e. to take the study drug at least 2 two hours after the last meal, or no 
less than 1 hour before the meal). 
In Part B, the lowest dosage of Givinostat that can be dispensed to the patients is 50 mg 
b.i.d., while the highest dosage of Givinostat that can be dispensed to the patients is 100 
mg b.i.d.. In all the possible dosage (i.e. 50 mg b.i.d., 75 mg b.i.d., 100 mg b.i.d.), 
patients will self-administer daily Givinostat capsules at home at morning and at the 
evening (i.e. after 12 hours) with fluids and between meals (i.e. to take the study drug at 
least 2 two hours after the last meal, or no less than 1 hour before the meal).  
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 
Givinostat. The guidelines described here above (i.e. see paragraph 4.3.3.2.1 and 
paragraph 4.3.3.2.2) need to be followed. The objective of the Givinostat dose 
adjustment rules are to optimize the response for each individual patient, avoiding 
specific drug-related toxicities. Therefore, dose reductions or interruptions will be 
mandated for specific toxicities (see paragraph 4.3.3.2.1) and dose increases after an 
initial dose reduction will be allowed in the case of inadequate efficacy at the reduced 
dosage. 
Each dose modification has to be recorded on the CRF.     
4.4.2 Treatment assignment 
No randomization procedures are required in this study.  
In Part A, patients will be assigned to the DL0 (i.e. 50 mg b.i.d.) when no treatment 
slots in higher dose levels are available. 


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4.4.3 Patient numbering and screening  
Each patient will be identified in the study by a patient code. 
During the screening period (i.e. after the informed consent form signature and before 
the recruitment confirmation by the Italfarmaco S.p.A. or its designee), the patient code 
will be named patient screening ID and will be a combination of his/her site ID, study 
part ID and patient screening number. 
Both the site ID and the study part ID (i.e. “A” or “B” for Part A or Part B, 
respectively) will be assigned by the Sponsor or its designee to the investigator site.  
Upon signing the informed consent form, the patient screening number will be assigned 
by the Investigator. At each site, the first patient will be assigned patient number “01”, 
and subsequent patients will be assigned consecutive numbers (e.g. the second patient 
will be assigned patient number “02”, the third patient will be assigned patient number 
“03”, etc. etc.).   
When a study site has a patient ready to enrol, prior to dosing the site will compile a 
request for registration Form and send it to Italfarmaco S.p.A. or its designee in order to 
obtain the patient ID. The request for registration contains the site ID, the study part ID, 
the assigned patient screening number, a checklist related to the inclusion/exclusion 
criteria to verify the eligibility of the patient and collect some other information (e.g. 
date of birth, date of informed consent obtained). If the patient is eligible, Italfarmaco 
S.p.A. or its designee will confirm the enrolment of the patient assigning the related 
dose level and the patient ID (i.e. the patient code after the enrolment confirmation) 
which will be a combination of patient screening ID and dose level ID. 
Once assigned, both the patient screening ID and the patient ID must not be reused for 
any other patient. 


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The following scheme will resume the  patient identification process: 
If the patient will fail to be enrolled for any reason, the reason will be entered in the 
study CRF within 2 days that the patient is not enrolled. 
According to ICH-GCP guidelines, the Investigator will maintain a patient identification 
list, which ensures a distinctive identification of the patients by their name to screening 
numbers, date of birth, sex and date of inclusion. 
4.4.4 Blinding  
No blinding procedures are applicable as the study is open label. 
4.4.5 Concomitant therapy 
Patients must NOT receive the following treatments during the study:
a) Other investigational drugs while on this study; 
b) Cytotoxic agents, interferons or other approved treatment for cMPN other than 
aspirin/cardio-aspirin; 
c) Any drug known to provoke TdP (see Appendix C). 


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                                 Study N.:       DSC/12/2357/45
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Other concomitant medications (e.g. symptomatic treatment of pruritus) and significant 
non-drug therapy (e.g. phlebotomy, blood transfusion) are permitted and must be 
recorded in the CRF.  
4.4.6 Treatment compliance 
The Investigator will record in the CRF the assigned dose of Givinostat and any dose 
reduction (if applicable) to allow the evaluation of compliance to treatment. 
At each visit, patients will bring back to the study site all drug bottles previously 
received (i.e. used, partially used and unused) and receive a new supply. The number of 
residual capsules in the dispensed bottles will be counted by the Investigator and 
reported in the CRF.  
Then the bottles used, partially used and unused will be collected and sent back to 
Italfarmaco S.p.A. or their designee periodically or at the end of the study. 
Compliance with Givinostat treatment will be calculated by Italfarmaco S.p.A. or its 
designee based on the drug accountability documented by the site staff and monitored 
by Italfarmaco S.p.A. or its designee (i.e. capsule counts). A patient will be considered 
sufficiently compliant with Givinostat treatment if he/she has taken at least 80% of the 
prescribed dose over the total duration of study drug dosing. 
4.4.7 Drug supply 
4.4.7.1 Packaging 
The packaging will consist of HDPE plastic bottles - closed with a PP screw cap, 
tamper evident - containing hard gelatine capsules of Givinostat. Each bottle  contains: 
- 30 capsules of 50 mg of Givinostat, or
- 30 capsules of 75 mg of Givinostat, or
- 15 capsules of 100 mg of Givinostat.  
Depending on the need of supply of each Centre (e.g. number of treated patients) a 
variable number of bottles will be packed in a carton box for shipping. 
At each visit, patients will receive a number of bottles sufficient to cover the period 
between two visits.  
4.4.7.2 Labelling 
The IMP will be appropriately labelled at Italfarmaco S.p.A. or their designee (e.g. 
external providers when requested by the local law, CMO). 
Label of the bottles will comply with the legal requirements of each country and will be 
printed in the local language.  


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The labels will show all the information requested according to the Annex 13 to the 
Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4) and the local drug law (if 
any) and the local regulatory requirements. Only the patient specific bottle will be 
labelled with a tear-off label.  
The label of the medicinal product includes in the local language at least the following 
data: 
•
Sponsor’s study code;  
•
EudraCT No.;  
•
Patient ID;  
•
Name, address and telephone number of the Sponsor or/and the CRO or their 
delegates (if applicable);  
•
Name of the Investigator;  
•
Name and strength of the medicinal product;  
•
Pharmaceutical dosage form;  
•
Route of administration; 
•
Quantity of dosage units; 
•
Visit in which the patient receive the study drug; 
•
Directions for use (reference may be made to a leaflet or other explanatory 
document intended for the trial patient or person administering the product);  
•
Batch number; 
•
Expiry date;  
•
Declaration of the intended purpose (e.g. for clinical trial use only);  
•
Storage conditions;  
•
The wording “Keep out of reach of children”. 
The patient ID and the visit in which the patient receive the study drug will be reported 
on every label by the Investigator. 
The Investigator will also provide the patient with written instructions on the number of 
capsules to be taken at each administration (i.e. dosage schedule). 
4.4.7.3 Storage 
The IMP will be appropriately stored at Italfarmaco S.p.A. or their designee (e.g. 
external providers when requested by the local law, CMO) until distribution to the 
investigational sites.  
The investigational site will store the IMP under the same conditions, as specified in the 
label, ensuring that it is not accessible to unauthorized persons till its dispensing to 
patients.  


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Detailed instructions for the IMP storage and management will be provided in a 
separate and specific IMP handling instruction manual. 
4.4.7.4 IMP dispensing  
All IMP supplies are to be used only for this protocol and not for any other purpose.  
Investigator will be responsible for the delivery of IMP to the patient according to the 
protocol and to instruct the patient to take the IMP as per protocol. 
Patients will be administered the IMP on an outpatient basis. 
At each visit, the Investigator will supply the patients with the appropriate number of 
bottles sufficient to cover the period between two visits.  
The Investigator will also provide the patient with written instructions on the number of 
capsules to be taken at each administration. 
4.4.7.5 IMP accountability 
The Investigator will maintain accurate records of the disposition of all IMP received, 
distributed to patients (including date and time) and accidentally destroyed. Drug 
accountability will be noted by the field monitor during site visits and at the completion 
of the study. At each visit, patients will bring back to the study site all drug bottles 
previously received (used, partially used and unused) and receive a new IMP supply.  
At the study close-out, and, as appropriate during the course of the study, the 
Investigator will return all used and unused study drug, packaging, drug labels, and the 
completed drug forms to Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica,  
Viale Fulvio Testi, 330, 20126 Milan (MI), Italy or its designee (e.g. CMO).  
Only in some particular cases, after the authorization of Italfarmaco S.p.A. (or after a 
signed agreement between the investigational site and Italfarmaco S.p.A.), these 
materials can be destroyed locally. 
4.5 
Study Procedures 
Patient must be followed at the study centre according to the visit schedule and 
assessments outlined in the flow-chart (Appendix A).  
Patient’s consent must be obtained prior to any study-specific procedures. 
Prior to start any study procedure, patients will be informed in details by the 
Investigator about the nature of the study, its purpose and procedures and about the 
possible risks and benefits resulting from study participation. Each patient will be given 
written information and the opportunity to ask questions. Patients who have voluntarily 
signed the written informed consent may start the following study procedures. 


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4.5.1 Laboratory evaluations and vital signs assessment  
The laboratory examinations (haematology, blood chemistry and urinalysis) will be 
performed in the local laboratory of each site. In addition, the vital signs assessment, the 
ECG assessment/evaluation and the QTc determination (according with Bazett’s 
correction formula, Appendix D) will be performed at each investigational site.  
All these results will be transcribed into the CRF and the original signed and dated 
laboratory print-out/tracings, including the ECG and source document, will be 
monitored and stored at the study site. Of note, if the first ECG evaluation demonstrates 
a prolonged QTc interval (i.e. a QTc interval  450 msec), two additional ECG 
evaluations over a brief period of time (i.e. 5 minutes between each recording) must be 
performed. The averaged value of these three ECG evaluations has to be used for the 
evaluation of the QTc interval of the related visit. In the CRF all the performed ECG 
evaluations have to be entered as well as the average value of multiple ECG evaluation, 
if necessary. 
The laboratory examinations, the vital signs assessment, the ECG evaluation including 
the QTc determination are listed below: 
1) Haematology 
 
 Red blood cells (RBC) count, haematocrit (HCT), haemoglobin (Hb), mean 
corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration (MCHC), white blood cells (WBC) 
count (full and differential), platelets (PLT) count.  
2) Blood chemistry 
ALT/SGPT, AST/SGOT, alkaline phosphatase (ALP), total bilirubin, lactic 
dehydrogenase (LDH), creatinine, blood urea nitrogen (BUN) or Urea (see 
Appendix F to convert Urea to BUN), glucose, sodium (Na), potassium (K), 
calcium (Ca), chloride (Cl), magnesium (Mg), albumin, eGFR determination 
(according with the Mayo Clinic Quadratic Equation). 
3) Urinalysis 
pH, specific gravity, protein, glucose. 
4) Vital signs 
Respiratory rate, pulse rate and sitting blood pressure will be measured after 5 
minutes of rest. 
5) ECG and QTc 
ECG assessment and evaluation, QTc determination (according with Bazett’s 
correction formula, Appendix D). Of note, if the first ECG evaluation 
demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), two 
additional ECG evaluations over a brief period of time (i.e. 5 minutes between 
each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval of the related 
visit. In the CRF all the performed ECG evaluations have to be entered as well 
as the average value of multiple ECG evaluation, if necessary. 


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4.5.2 Physical examination 
Information about the physical examination must be present in the source 
documentation at the study site. Significant findings that are present prior to the start of 
study drug must be included in the Medical History section of the CRF or Current 
Medical Conditions section of the CRF. Significant findings reported after the start of 
treatment with the study drug that meet the definition of an AE must be recorded in the 
Adverse Event section of the CRF. 
Study visit schedule and required evaluations and procedures to be performed at each 
study visit are described below and summarized in the flow-chart in Appendix A. 
Methods of assessment of safety and efficacy are described in the paragraph 4.6 and 
paragraph 4.7 of the present protocol. 
4.5.3 Spleen evaluation, PK and PD characterization, molecular 
examinations and bone marrow histological evaluation 
4.5.3.1 Spleen evaluation  
The spleen evaluation must be performed at the study centre according to the visit 
schedule outlined in the flow-chart (Appendix A). 
The spleen evaluation will be performed during the study according to institutional 
guidelines and site-specific clinical practice (i.e. MRI or CT scan). The same imaging 
technique and the same instrument to assess spleen dimension (i.e. MRI or CT scan) 
should be used on a patient throughout the study, if possible.  
If possible, the spleen dimension will be evaluated as longitudinal diameter (hereafter 
“A”), antero-posterior diameter (hereafter “B”), transversal diameter (hereafter “C”) and 
Splenic Volumetric Index (hereafter “SVI”): 
 
 
SVI = (A x B x C) / 27 
No spleen evaluation will be performed in splenectomised patients. 
4.5.3.2 PK characterization  
Approximately 5.0 mL of blood for pharmacokinetic assessment will be collected as 
following described:  
1) Day 1 of Cycle 1 of Parts A and B: before the first Givinostat dose (pre-dose) and 2, 
3 and 8 (before the second Givinostat dose) hours after the first drug administration 
(Appendix A).  
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 1 (pre-dose) 
of Cycle 1 of Parts A and B and after that the patient will take the first drug 


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administration (e.g. at 8.00 a.m.); then, the patient will perform the PK post-dose 
evaluations at 10.00 a.m. (hour 2), 11.00 a.m. (hour 3) and at 16.00 p.m. (hour 8). 
2) Day 28 of the Cycle 1 of Part A: before the first daily Givinostat dose (pre-dose) 
and 1, 2, 4 and 8 (before the second Givinostat dose) after the first daily drug 
administration (Appendix A).  
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 28 of Cycle 1 
(pre-dose) of Part A and after that the patient will take the first daily drug 
administration (e.g. at 8.00 a.m.); then, the patient will perform the PK post-dose 
evaluations at 9.00 a.m. (hour 1), 10.00 a.m. (hour 2), 12.00 p.m. (hour 4) and at 
16.00 p.m. (hour 8). 
3) Day 28 of the Cycles 2, 3, 4, 5, and 6 of Part A: before the first daily Givinostat 
dose (pre-dose) (Appendix A).  
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 28 of Cycle 2 
and beyond Cycles (i.e. Cycles 3, 4, 5 and 6) of Part A (pre-dose) and after that the 
patient will take the first daily drug administration (e.g. at 8.00 a.m.). 
4) Day 28 of Cycle 2 of Part B: before the first daily Givinostat dose (pre-dose) and 1, 
2, 4 and 8 (before the second Givinostat dose) hours after the first daily drug 
administration (Appendix A). 
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 28 of Cycle 2 
(pre-dose) of Part B and after that the patient will take the first daily drug 
administration (e.g. at 8.00 a.m.); then, the patient will perform the PK post-dose 
evaluations at 9.00 a.m. (hour 1), 10.00 a.m. (hour 2), 12.00 a.m. (hour 4) and at 
16.00 p.m. (hour 8). 
The PK samples should be drawn as closely to the predefined time as possible. 
The exact timing of PK sampling could be adjusted based on emerging clinical and 
preclinical data. 
For all time points an additional PK blood sample will be collected as back-up sample. 
This assessment is mandatory and will be performed by a central laboratory. The exact 
date and time of the PK blood draws will be recorded along with the date and time of 
the last dose of study drug preceding the blood draw. Additional information about the 
PK time points, instructions for sample preparation and shipment will be provided in the 
related study handling manual. 
After evaluation of preliminary results and data exploration, some additional analyses 
may be performed to identify and quantify other molecular parameters of interest in 
term of improving of the knowledge of cMPN and the activity of the drug in these 
disorders.  
4.5.3.3 PD characterization  
Approximately 4.0 mL of blood for pharmacodynamic markers will be collected before 
the first Givinostat dose (pre-dose) and 12 hours after the first Givinostat dose (post-
dose) at Day 1 of Cycle 1 both in Part A and in Part B for measurement of levels of 


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molecular markers, to evaluate the pharmacodynamic effect of Givinostat and to 
identify markers predictive of clinical benefit of Givinostat (Appendix A). In addition, 
pharmacodynamic evaluations will be performed also using an aliquot of the PK 
samples collected at time points described in the paragraph 4.5.3.2 [34]. The molecular 
markers to be measured may include mRNA levels of JAK2, STAT5A, BclXL, PIM1, 
NFE2, LMO2, cMyc as well as HDAC3, STAT4, MYBL1, MEGF9, GLRX, FAM49A. 
The final list of pharmacodynamic markers to be measured will depend on ongoing 
scientific developments as well as availability of assays and other business 
considerations.  
For all time points an additional PD blood sample will be collected as back-up sample. 
This assessment is mandatory and will be performed by a central laboratory. The exact 
date and time of the PD blood draws will be recorded along with the date and time of 
the last dose of study drug preceding the blood draw. Instructions for sample 
preparation and shipment will be provided in a separate and specific laboratory manual. 
After evaluation of preliminary results and data exploration, some additional analyses 
may be performed to identify and quantify other molecular parameters of interest in 
term of improving of the knowledge of cMPN and the activity of the drug in these 
disorders.  
4.5.3.4 JAK2V617F characterization  
JAK2V617F characterization (i.e. JAK2V617F allele burden evaluated by quantitative RT-
PCR) will be performed in a central laboratory (Appendix E). Detailed instructions for 
sample preparation and shipment will be provided in a separate and specific laboratory 
manual.  
For all time points a blood sample will be collected as back-up sample. 
After evaluation of preliminary results and data exploration, some additional analyses 
may be performed to identify and quantify other molecular parameters of interest in 
term of improving of the knowledge of cMPN and the activity of the drug in these 
disorders.  
4.5.3.5 Molecular examinations  
All molecular examinations (e.g. JAK2V617F allele burden evaluated by quantitative RT-
PCR, mRNA isolation, gene expression) will be performed in a central laboratory.  
Detailed instructions for sample preparation and shipment will be provided in a separate 
and specific laboratory manual.  
The results will be transcribed into the CRF by the central laboratory team or its 
designee and the original signed and dated laboratory print-out/tracings will be 
monitored and stored at the central laboratory.  
After evaluation of preliminary results and data exploration, some additional analyses 
may be performed to identify and quantify other molecular parameters of interest in 


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term of improving of the knowledge of cMPN and the activity of the drug in these 
disorders.  
4.5.3.6 Bone marrow histological evaluation 
A bone marrow histological evaluation will be performed to all patients recruited in 
Part B in order to assess the presence of age adjusted normocellularity and/or trilinear 
hyperplasia as requested by the “new” ELN response criteria (i.e. the revised ELN 
response criteria) [33] (see paragraph 4.8.7).  
This examination will be performed in the local laboratory of each site. The results of 
this test will be transcribed into the CRF and the original signed and dated laboratory 
print-out/tracings, including the assessment of the presence of age adjusted 
normocellularity and/or trilinear hyperplasia, will be monitored and stored at the study 
site. 
Please note that, in case the patient performs the bone marrow histological evaluation as 
requested by the “new” ELN criteria (i.e. the revised ELN response criteria) [33] (see 
paragraph 4.8.7) – i.e. bone marrow evolution including the assessment of the presence 
of age adjusted normocellularity and/or trilinear hyperplasia - 1 month before the study 
start (i.e. the signature of the Informed Consent Form), this examination has not to be 
repeated for this study in order to limit the discomfort for the patient. In any case, the 
results of this test will be transcribed into the CRF and the original signed and dated 
laboratory print-out/tracings, including the assessment of the presence of age adjusted 
normocellularity and/or trilinear hyperplasia, will be monitored and stored at the study 
site. 
In case the patient drops-out the study during the first 3 Cycles (i.e. before the Day 28 
of Cycle 3), this evaluation has not to be performed at End of Study visit. 
Finally, in case the patient refuses to provide this written consent to perform the bone 
marrow evaluation, this patient can be anyway recruited in Part B. However, this 
patient will not be counted to assess the related exploratory endpoints (i.e. overall 
response rate of Givinostat at the MTD after 6 cycles according to the revised ELN 
response criteria [33], and the evaluation of the effect of Givinostat on each single 
response parameter according to the revised ELN response criteria [33]).   
4.5.4  Visit schedule 
Patient must be followed at the study centre according to the visit schedule and 
assessments outlined in the flow-chart (Appendix A).  
The investigative team at the study site will be responsible for all treatment 
administrations and evaluations throughout the study period.  


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4.5.4.1 Part A 
4.5.4.1.1 Pre-treatment evaluations (up to 4 weeks: -28 to Day -1) 
The following procedures will be performed at the pre-treatment visit of Cycle 1 of  
Part A as reported below: 
•
Informed consent signing; 
•
Demographic data (race, sex and date of birth); 
•
Adverse event recording; 
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable); 
•
Medical history;  
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
height, weight, body temperature and ECOG performance status;  
•
Pregnancy test (if indicated);  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula);  
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL 
Questionnaire; 
•
Request of enrolment and receipt of patient ID. 
Appendix A (in particular, paragraph 10.1.1.1) summarize timing information. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance 
status [28]  1 within 7 days of initiating study drug.


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The pregnancy test (if indicated) has to be performed within 72 hours before the 
first Givinostat dose. The test can be performed by urine or serum pregnancy test. In 
case of a borderline-positive urine pregnancy test, this must be confirmed with a serum 
pregnancy test and the result recorded in the CRF.If the first ECG evaluation 
demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), two additional 
ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) 
must be performed. The averaged value of these three ECG evaluations has to be used 
for the evaluation of the QTc interval requested by the exclusion criterion n. 3. In the 
CRF all the performed ECG evaluations have to be entered as well as the average value 
of multiple ECG evaluation, if necessary.
Patients with splenomegaly will perform the spleen evaluation as per site-specific 
clinical practice. Therefore, patients with splenomegaly before the treatment start will 
be followed according to institutional guidelines (i.e. MRI or CT scan). The same 
imaging technique and the same instrument should be used on a patient throughout the 
study, if possible. No spleen evaluation will be performed in splenectomised patients. 
Pre-treatment evaluations will be performed at one or more clinic visit to determine 
eligibility for the study. Pre-treatment evaluations must be performed up to 4 weeks 
before the treatment start within ± 7 days. 
If all eligibility criteria are met at the pre-treatment visit, the treatment with Givinostat 
can start.  
After the check that all eligibility criteria are met by the patient and in any case before 
the treatment start, all patients with an uncontrolled HCT (i.e. HCT  45%) have to 
perform at least one phlebotomy to normalize (if possible) the HCT value (i.e. HCT 
<45%).  
In case of patients phlebotomy-dependent, all efforts have to be afforded by 
Investigators to record all phlebotomies witch recruited patients experienced at 
least 6 months before the treatment start.  
4.5.4.1.2 Cycle 1 
Appendix A (in particular, paragraph 10.1.1.1) summarize timing information. 
Patients can take drug at home, except for the first drug administration.
If the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval. In the CRF all the 
performed ECG evaluations have to be entered as well as the average value of multiple 
ECG evaluation, if necessary. 


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Day 1 
The following procedures must be performed exactly at Day 1 of Cycle 1 of Part A as 
reported below:  
1) Pre-dose evaluations: 
The following procedures will be performed before the first Givinostat dose as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug 
therapies (e.g. phlebotomies, transfusions) 
recording (if applicable);
•
Physical examination, weight, body temperature and ECOG performance 
status;
•
Vital signs (blood pressure, pulse rate, respiratory rate);  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see 
Appendix F to convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, 
albumin, eGFR determination (according with the Mayo Clinic 
Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula);  
•
PD sample collection; 
•
PK sample collection and preparation, in order to allow to perform both 
the PK and PD evaluations starting from the same sample [34].  
2) Post-dose evaluations: 
The following procedures will be performed after the first Givinostat dose as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug 
therapies (e.g. phlebotomies, transfusions) 
recording (if applicable);
•
Vital signs (blood pressure, pulse rate, respiratory rate) 4 hours after the 
first Givinostat dose;  
•
ECG, QTc determination (according with Bazett’s correction formula) 3 
hours after the first Givinostat dose; 
•
PD sample collection 12 hours after the first Givinostat dose; 


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•
PK sample collection (2, 3 and 8 hours post-dose) and preparation, in 
order to allow to perform both the PK and PD evaluations starting from 
the same sample [34]; 
•
First Givinostat dose and accountability. 
Day 2 
The following procedures will be performed exactly at Day 2 of Cycle 1 of Part A as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Used/unused/partially used Givinostat supply return, Givinostat administration 
and Givinostat accountability.
Days 3 and 4 
The following procedures will be performed exactly at Days 3 and 4 of Cycle 1 of Part 
A as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Used/unused/partially used Givinostat supply return, Givinostat administration 
and Givinostat accountability. 
Days 8, 15 and 22 
The following procedures will be performed at Days 8, 15 and 22 of Cycle 1 of Part A
(within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 78 of 142 
Confidential
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Used/unused/partially used Givinostat supply return, Givinostat administration 
and Givinostat accountability. 
Day 10 
The following procedures will be performed at Day 10 of Cycle 1 of Part A (within ± 3 
days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Used/unused/partially used Givinostat supply return, Givinostat administration 
and Givinostat accountability. 
Days 28 
The following procedures will be performed at Day 28 of Cycle 1 of Part A (within ± 3 
days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 79 of 142 
Confidential
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
PK sample collection (pre-dose and 1, 2, 4 and 8 hours post-dose) and 
preparation, in order to allow to perform both the PK and PD evaluations 
starting from the same sample [34]; 
•
Used/unused/partially used Givinostat supply return, Givinostat administration 
and Givinostat accountability. 
End of Study 
In case of the patient drops-out of the study, the following procedures will be performed 
7 days after last drug intake (within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Assessment of disease-related symptoms using the MPN-SAF QOL 
Questionnaire; 
•
Used/unused/partially 
used 
Givinostat 
supply 
return 
and 
Givinostat 
accountability. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 80 of 142 
Confidential
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until 
it is reasonable to consider the event not drug related any more or until the start of a 
new treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications included in list of 
“Drugs with risk of Torsades de Pointes” (see Appendix C) the treatment with 
Givinostat is to be promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-
up visits until recovery. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance every effort should be made 
to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
At study close-out, and as appropriate during the course of the study, the Investigator 
will return all used and unused study drug, packaging, drug labels, and the completed 
drug forms to Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica, Viale Fulvio 
Testi, 330, 20126 Milan (MI), Italy, or their designee.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a 
signed agreement between the investigational site and Italfarmaco S.p.A.), these 
materials can be destroyed locally. 
4.5.4.1.3 Cycles 2, 3, 4, 5 and 6 
Appendix A (in particular, paragraph 10.1.1.2) summarize timing information. 
Patients with splenomegaly will perform the spleen evaluation as per site-specific 
clinical practice. Therefore, patients with splenomegaly before the treatment start will 
be followed according to institutional guidelines (i.e. MRI or CT scan). The same 
imaging technique and the same instrument should be used on a patient throughout the 
study, if possible. No spleen evaluation will be performed in splenectomised patients. 
The spleen evaluation must be performed at the study centre according to the visit 
schedule outlined in the flow-chart (Appendix A). 
If the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 81 of 142 
Confidential
evaluations has to be used for the evaluation of the QTc interval. In the CRF all the 
performed ECG evaluations have to be entered as well as the average value of multiple 
ECG evaluation, if necessary. 
Day 1 
The following procedures will be performed at Day 1 of Cycles 2, 3, 4, 5 and 6 of Part 
A (within ± 3 days) as reported below: 
•
First Givinostat dose of the related cycle and accountability. 
Day 28 of Cycles 2, 4 and 5 
The following procedures will be performed at Day 28 of Cycles 2, 4 and 5 of Part A
(within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
PK sample collection (pre-dose) and preparation, in order to allow to perform 
both the PK and PD evaluations starting from the same sample [34]; 
•
Used/unused/partially used Givinostat supply return, Givinostat administration 
and Givinostat accountability. 
Day 28 of Cycles 3 and 6 
The following procedures will be performed at Day 28 of Cycles 3 and 6 of Part A
(within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 82 of 142 
Confidential
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
PK sample collection (pre-dose) and preparation, in order to allow to perform 
both the PK and PD evaluations starting from the same sample [34]; 
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL 
Questionnaire; 
•
Givinostat administration (only for cycle 3); 
•
Used/unused/partially 
used 
Givinostat 
supply 
return 
and 
Givinostat 
accountability. 
All phlebotomies performed in the first 3 weeks of treatment will be not counted to 
assess the clinico-haematological response according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1);. 
End of Study 
The following procedures will be performed at the end of study visit (in case of 
completed study) or 7 days after last drug intake (in case of the patient drops-out of 
the study) (within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 83 of 142 
Confidential
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL 
Questionnaire; 
•
Used/unused/partially used Givinostat supply return and accountability. 
In case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can 
be counted for the End of Study visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations 
requested to be done at the Day 28 of Cycle 6) and she/he is eligible to continue the 
study drug treatment in the long-term study (i.e. Study DSC/11/2357/44), the evaluation 
performed at the Cycle 6 Day 28 visit of this study can be also counted for the pre-
treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluation is present between the two studies (e.g. haematological and biochemical 
evaluations). No additional Givinostat study (i.e. Study DSC/12/2357/45)-specific 
assumption has to be done at the completion of the Day 28 of Cycle 6. Indeed, in 
case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6 of this study), she/he is eligible to continue the study drug 
treatment in the long-term study (i.e. Study DSC/11/2357/44) and she/he receive the 
written authorization of the treatment from the Sponsor of their designee (i.e. a patient’s 
confirmation form that includes the patient ID to use into the Study DSC/11/2357/44), 
the patient will continue the study drug treatment into the Study DSC/11/2357/44, 
receiving the study (i.e. Study DSC/11/2357/44)-specific drug to be taken. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 84 of 142 
Confidential
it is reasonable to consider the event not drug related any more or until the start of a 
new treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications included in list of 
“Drugs with risk of Torsades de Pointes” (see Appendix C) the treatment with 
Givinostat is to be promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-
up visits until recovery. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance every effort should be made 
to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
At study close-out, and as appropriate during the course of the study, the Investigator 
will return all used and unused study drug, packaging, drug labels, and the completed 
drug forms to Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica, Viale Fulvio 
Testi, 330, 20126 Milan (MI), Italy, or their designee.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a 
signed agreement between the investigational site and Italfarmaco S.p.A.), these 
materials can be destroyed locally. 
4.5.4.2 Part B 
Appendix A (in particular, paragraph 10.1.2) summarize timing information. 
Patients should be told to arrive after an overnight fast of at least 8 hours at all 
study visits that request a blood test. However, the study visits should still be 
conducted even if the patient does not adhere to fasting requirements and this will not 
be considered a protocol violation. In these cases, this information (i.e. not fasting 
condition) has to be noted by the Investigator in the medical chart and reported in CRF, 
in order to avoid any misunderstanding of the collected data (e.g. glucose value is 
influenced by fasting/ not fasting conditions).    
If the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval. In the CRF all the 
performed ECG evaluations have to be entered as well as the average value of multiple 
ECG evaluation, if necessary. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 85 of 142 
Confidential
The spleen evaluation will be performed during the study according to institutional 
guidelines and site-specific clinical practice (i.e. MRI or CT scan). The same imaging 
technique and the same instrument should be used on a patient throughout the study, if 
possible. No spleen evaluation will be performed in splenectomised patients. 
Patients can take drug at home, except for the first drug administration. 
4.5.4.2.1 Pre-treatment evaluations (up to 4 weeks: -28 to Day -1) 
The following procedures will be performed at the pre-treatment visit of Part B as 
reported below: 
•
Informed consent signing; 
•
Demographic data (race, sex and date of birth); 
•
Adverse event recording; 
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable); 
•
Medical history;  
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
height, weight, body temperature and ECOG performance status;  
•
Pregnancy test (if indicated);  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL 
Questionnaire [24, 32]; 
•
Bone marrow histological evaluation, in patients who have consented to this 
optional exploratory research, who haven’t this assessment in the month before 
the 1 month before the study start (i.e the signature of the Informed Consent 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 86 of 142 
Confidential
Form, and that have not any medical contraindication to bone marrow sampling 
as judged by the Investigator); 
•
Request of enrolment and receipt of patient ID. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance 
status [28]  2 within 7 days of initiating study drug.
The pregnancy test (if indicated) has to be performed within 72 hours before the 
first Givinostat dose. The test can be performed by urine or serum pregnancy test. In 
case of a borderline-positive urine pregnancy test, this must be confirmed with a serum 
pregnancy test and the result recorded in the CRF.Pre-treatment evaluations will be 
performed at one or more clinic visit to determine eligibility for the study. Pre-treatment 
evaluations must be performed up to 4 weeks before the treatment start within ± 7 days.  
Please note that, in case the patient performs the bone marrow histological evaluation as 
requested by the “new” ELN criteria (i.e. the revised ELN response criteria) [33] (see 
paragraph 4.8.7) – i.e. bone marrow evolution including the assessment of the presence 
of age adjusted normocellularity and/or trilinear hyperplasia - 1 month before the study 
start (i.e the signature of the Informed Consent Form), this examination has not to be 
repeated for this study in order to limit the discomfort for the patient. In any case, the 
results of this test will be transcribed into the CRF and the original signed and dated 
laboratory print-out/tracings, including the assessment of the presence of age adjusted 
normocellularity and/or trilinear hyperplasia, will be monitored and stored at the study 
site. 
In case the patient refuses to provide this written consent to perform the bone marrow 
evaluation, this patient can be anyway recruited in Part B. However, this patient will 
not be counted to assess the related exploratory endpoints (i.e. overall response rate of 
Givinostat at the MTD after 6 cycles according to the revised ELN response criteria 
[33], and the evaluation of the effect of Givinostat on each single response parameter 
according to the revised ELN response criteria [33]).   
If all eligibility criteria are met at the pre-treatment visit, the treatment with Givinostat 
can start. 
After the check that all eligibility criteria are met by the patient and in any case before 
the treatment start, all patients with an uncontrolled HCT (i.e. HCT  45%) have to 
perform phlebotomy(ies) to normalize the HCT value (i.e. HCT <45%).  
In case of patients who are phlebotomy-dependent, all efforts have to be made by 
Investigators to record all phlebotomies witch recruited patients experienced at 
least 6 months before the treatment start.  


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 87 of 142 
Confidential
4.5.4.2.2 Day 1 of Cycle 1 
The following procedures must be performed exactly at Day 1 of Cycle 1 of Part B as 
reported below:  
1) Pre-dose evaluations: 
The following procedures will be performed before the first Givinostat dose as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug 
therapies (e.g. phlebotomies, transfusions) 
recording (if applicable);
•
PD sample collection; 
•
PK sample collection and preparation, in order to allow to perform both 
the PK and PD evaluations starting from the same sample [34] (if 
requested). 
2) Post-dose evaluations: 
The following procedures will be performed after the first Givinostat dose as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug 
therapies (e.g. phlebotomies, transfusions) 
recording (if applicable);
•
PD sample collection 12 hours after the first Givinostat dose; 
•
PK sample collection (2, 3 and 8 hours post-dose) and preparation, in 
order to allow to perform both the PK and PD evaluations starting from 
the same sample [34] (if requested); 
•
First Givinostat dose and accountability. 
4.5.4.2.3 Day 28 of Cycles 1, 2, 4 and 5 
The following procedures will be performed at Day 28 of Cycles 1, 2, 4 and 5 of Part B
(within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 88 of 142 
Confidential
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte; 
•
Used/unused/partially used Givinostat supply return, Givinostat administration 
and Givinostat accountability; 
•
Only at Cycle 2: PK sample collection (pre-dose and 1, 2, 4 and 8 hours post-
dose) and preparation, in order to allow to perform both the PK and PD 
evaluations starting from the same sample [34] (if requested). 
4.5.4.2.4 Day 28 of Cycles 3 and 6 
The following procedures will be performed at Day 28 of Cycles 3 and 6 of Part B
(within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte; 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 89 of 142 
Confidential
•
Assessment of disease-related symptoms using the MPN-SAF QOL 
Questionnaire [24, 32]; 
•
Bone marrow histological evaluation (only for cycle 6) in patients who have 
consented to this optional exploratory research and that have not any medical 
contraindication to bone marrow sampling as judged by the Investigator; 
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Therapeutic response evaluation according to the “new” ELN criteria (i.e. 
revised ELN response criteria) [33] (see paragraph 4.8.7) (only for cycle 6); 
•
Only for Cycle 3: Givinostat administration; 
•
Used/unused/partially 
used 
Givinostat 
supply 
return 
and 
Givinostat 
accountability. 
All phlebotomies performed in the first 3 weeks of treatment will be not counted to 
assess the therapeutic response. 
4.5.4.2.5 End of study 
The following procedures will be performed at the end of study visit (in case of 
completed study) or 7 days after last drug intake (in case of the patient drops-out of 
the study) (within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), 
weight, body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 


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Collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL 
Questionnaire [24, 32]; 
•
Bone marrow histological evaluation, in patients who have consented to this 
optional exploratory research, and that have not any medical contraindication to 
bone marrow sampling as judged by the Investigator;
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Therapeutic response evaluation according to the “new” ELN criteria (i.e. 
revised ELN response criteria) [33] (see paragraph 4.8.7); 
•
Used/unused/partially 
used 
Givinostat 
supply 
return 
and 
Givinostat 
accountability. 
In case the patient drops-out the study during the first 3 Cycles (i.e. before the Day 28 
of Cycle 3), the bone marrow histological evaluation has not to be performed at End of 
Study visit. 
In case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can 
be counted for the End of Study visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations 
requested to be done at the Day 28 of Cycle 6) and she/he is eligible to continue the 
study drug treatment in the long-term study (i.e. Study DSC/11/2357/44), the evaluation 
performed at the Cycle 6 Day 28 visit of this study can be also counted for the pre-
treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluation is present between the two studies (e.g. haematological and biochemical 
evaluations). No additional Givinostat study (i.e. Study DSC/12/2357/45)-specific 
assumption has to be done at the completion of the Day 28 of Cycle 6. Indeed, in 
case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6 of this study), she/he is eligible to continue the study drug 
treatment in the long-term study (i.e. Study DSC/11/2357/44) and she/he receive the 
written authorization of the treatment from the Sponsor of their designee (i.e. a patient’s 
confirmation form that includes the patient ID to use into the Study DSC/11/2357/44), 
the patient will continue the study drug treatment into the Study DSC/11/2357/44, 
receiving the study (i.e. Study DSC/11/2357/44)-specific drug to be taken. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until 
it is reasonable to consider the event not drug related any more or until the start of a 
new treatment, whichever occurs first.  


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If the patient needs to take one of the concomitant medications included in list of 
“Drugs with risk of Torsades de Pointes” (see Appendix C) the treatment with 
Givinostat is to be promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-
up visits until recovery. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance every effort should be made 
to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
At study close-out, and as appropriate during the course of the study, the Investigator 
will return all used and unused study drug, packaging, drug labels, and the completed 
drug forms to Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica, Viale Fulvio 
Testi, 330, 20126 Milan (MI), Italy or their designee.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a 
signed agreement between the investigational site and Italfarmaco S.p.A.), these 
materials can be destroyed locally. 
4.5.4.3 Information to be collected on screening failures 
Patients who sign an informed consent form but who do not start study treatment for 
any reason will be considered a screen failure. The reason for screen failure and each 
patient’s demographic information will be entered in the CRF within 2 days.  
4.6 
Efficacy assessments 
Appendix A and paragraph 4.5.4 summarize timing information. 
4.6.1 Criteria for assessing clinico-haematological improvement 
Disease response will be evaluated according to the following clinico-haematological 
ELN criteria [21] (see paragraph 4.6.1) after 3 and 6 cycles (i.e. at weeks 12 and 24, 
respectively) of treatment with Givinostat both in Part A (exploratory endpoints) and in 
Part B (primary and secondary endpoints, respectively).  


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•
Complete response:  
1. HCT<45% without phlebotomy, and
2. Platelets  400 x109/L, and
3. WBC 10 x109/L, and
4. Normal spleen size, and
5. No disease-related systemic symptoms (i.e. pruritus, headache, microvascular 
disturbances). 
•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1. HCT <45% without phlebotomy, or  
2. Response in 3 or more of the other criteria. 
•
No response: any response that does not satisfy partial response.
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months) 
and the eligibility for this part of the study may be expanded to all patients with cMPN, 
disease response for this part of the study will be evaluated according to the clinico-
haematological ELN and EUMNET criteria [29] after 3 and 6 cycles of treatment with 
Givinostat, in ET and MF patients, respectively. 
For ET (from the clinico-hematological ELN response criteria): 
•
Complete response:  
1. Platelets  400 x109/L, and
2. No 
disease 
related 
systemic 
symptoms 
(i.e. 
pruritus, 
headache, 
microvascular disturbances), and
3. Normal spleen size, and
4. WBC 10 x109/L. 
•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1. Platelet count < 600 x 109/L, or 
2. Platelet count decrease > 50% from baseline. 
•
No response: any response that does not satisfy partial response.
Both for PV and ET patients, all phlebotomies performed in the first 3 weeks of 
treatment will not be counted to assess the clinico-haematological response. 


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For MF (from EUMNET response criteria)  
•
Complete response: complete response in anemia, splenomegaly, constitutional 
symptoms, platelet and leukocyte count.
1. Complete response in anaemia: Haemoglobin  12 g/dL for transfusion-
independent patients or  11 g/dL for transfusion-dependent patients 
(applicable only for patients with baseline haemoglobin level of < 10 g/dL); 
2. Complete response in splenomegaly: Spleen not palpable; 
3. Complete response in constitutional symptoms: Absence of constitutional 
symptoms (fever, drenching night sweats, or  10% weight loss); 
4. Complete response in platelet count: Platelet count 150-400 x109/L; 
5. Complete response in leukocyte count: Leukocyte count 4-10 x109/L. 
•
Major response: Any response in both anaemia and splenomegaly without 
progression in constitutional symptoms or complete response in anaemia 
without progression in splenomegaly or partial response in anaemia in a baseline 
transfusion-dependent patient combined with response in constitutional 
symptoms without progression in splenomegaly or any response in 
splenomegaly combined with response in constitutional symptoms without 
progression in anaemia.
1. Partial response in splenomegaly: Either  50% decrease in spleen size if 
baseline  10 cm from left costal margin (LCM) or  30% decrease if 
baseline > 10 cm from LCM. 
2. Partial response in platelet count: A  50% decrease in platelet count if 
baseline > 800 x109/L or platelet count increase by   50% x 109/L if 
baseline < 100 x109/L. 
3. Partial response in leukocyte count: A  50% decrease in leukocyte count of 
baseline >  20 x109/L or leukocyte count increase by  1 x109/L if baseline < 
4 x109/L 
4. Progression in anaemia: A hemoglobin decrease of  2 g/dL  or  a 50% 
increase in transfusion requirement or becoming transfusion dependent 
5. Progression in splenomegaly: A  50% increase in spleen size if baseline 
10 cm from LCM or a  30% increase if baseline > 10 cm from LCM. 
6. Progression in constitutional symptoms: Appearance of constitutional 
symptoms. 
•
Moderate response: Complete response in anaemia with progression in 
splenomegaly or partial response in anaemia without progression in  
splenomegaly or any response in splenomegaly without progression in   anaemia 
and constitutional symptoms.  


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•
Minor response: Any leukocyte- or platelet-based response without progression 
in anaemia, splenomegaly, or constitutional symptoms.
•
No response: Any response that does not qualify at least as minor response. 
In all cases (PV, ET and MF patients), the disease-related systemic symptoms will be 
evaluated directly by patients according to MPN-SAF QOL questionnaire [24, 32]. 
In all cases, the response status of the patient may be reviewed by a panel of 
independent Investigators, if necessary. 
4.6.2 Criteria for determination of MTD 
Once all patients enrolled in Part A have been treated for at least 1 cycle, the study team 
(see paragraph 4.1.1.2) will determine the MTD to be used in Part B based on the safety 
and tolerability profile of Givinostat observed as well as the PK and PD data, if 
applicable.  
4.6.3 Criteria for characterization of PK 
Plasma concentrations from Parts A and B will be evaluated by dose and time point for 
all patients and time points with at least one PK assessment.  
4.6.4 The Efficacy Population 
The analysis sets are defined in the paragraph 6.2.1.  
Patients with a disease-related global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that 
time should be reported in CRF as disease progression clinically assessed. Every effort 
should be made to document the objective progression even after discontinuation of 
treatment. 
The response status of the patient may be reviewed by a panel of independent 
investigators, if necessary. 
4.7 
Safety assessments 
Safety and tolerability will be evaluated by monitoring haematology and blood 
chemistry, urinalysis (only in the first cycle of Part A), by measurement of physical 


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examination, vital signs, weight, body temperature, ECOG performance status, ECG 
assessment and evaluation, QTc determination and adverse events recording at 
scheduled times as described above. Appendix A and paragraph 4.5.4 summarize timing 
information. 
All significant findings already present during the screening visit before drug 
administration will be reported in the appropriate section of CRF (Medical History 
section or Current Medical Conditions section). Significant findings occurring after 
patient enrolment, identified as Adverse Event (AE), will be recorded in Adverse Event 
section of CRF. 
The following criteria will use to assess the safety and tolerability both in Part A
(primary endpoint) and after 3 and 6 cycles (primary and secondary endpoints, 
respectively) in Part B: 
•
Number of patients experiencing adverse events.  
•
Type, incidence, and severity of treatment-related adverse events, graded 
according to Common Terminology Criteria for Adverse Events (CTCAE v. 
4.03, 14th June 2010).  
4.7.1 Laboratory evaluations  
The following laboratory examinations (haematology, blood chemistry and urinalysis) 
will be performed at each investigational unit by a local  laboratory co-operating with 
the Investigator following its own procedures:  
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full 
and differential), PLT count;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, 
creatinine, BUN or Urea (as per site-specific clinical practice; see Appendix F to 
convert Urea to BUN) , glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation); 
•
Urinalysis: pH, specific gravity, protein, glucose. 
The required amount of blood and urine will be collected at each visit as scheduled 
above. Appendix A and paragraph 4.5.4 summarize timing information. 
All results of laboratory examinations will be entered into the appropriate CRF sections. 
The original laboratory print-outs will be filed in the patient file at the study site. 
Of note, if the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc 
interval  450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 
minutes between each recording) must be performed. The averaged value of these three 
ECG evaluations has to be used for the evaluation of the QTc interval of the related 
visit. In the CRF all the performed ECG evaluations have to be entered as well as the 
average value of multiple ECG evaluation, if necessary. 


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4.7.2 Clinical safety assessments 
Clinical safety assessments will include a thorough physical examination, vital signs 
assessment (respiratory rate, pulse rate and sitting blood pressure will be measured after 
5 minutes of rest), weight, body temperature, ECOG performance status, ECG 
assessment and evaluation, QTc determination (according with Bazett’s correction 
formula, Appendix D).  
Appendix A and paragraph 4.5.4 summarize timing information. 
All results of the above mentioned clinical safety assessments will be entered into the 
appropriate CRF sections. The original print-outs related to these evaluations, including 
the ECG and QTc recording, will be filed in the patient file at the study site.  
Of note, if the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc 
interval  450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 
minutes between each recording) must be performed. The averaged value of these three 
ECG evaluations has to be used for the evaluation of the QTc interval of the related 
visit. In the CRF all the performed ECG evaluations have to be entered as well as the 
average value of multiple ECG evaluation, if necessary. 
4.7.3  Adverse events 
All AEs either observed by the Investigator, or reported by the patient spontaneously or 
in a response to a direct question must be evaluated by the Investigator and will be 
recorded on the AE section of the CRF.As reported also in the paragraph 4.3.3, if the 
patient discontinues for any reason (including discontinuation for pregnancy), with drug 
related adverse event ongoing at study end, he/she must be followed until resolution or 
stabilization of the event or until it is reasonable to consider the event not drug related 
any more or until the start of a new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-
up visits until recovery. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance every effort should be made 
to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
For AEs definitions, coding and reporting procedures see paragraph 5. 


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4.8 Exploratory parameters 
4.8.1 Evaluation of the effects of Givinostat on each single parameter of 
the clinico-haematological ELN response criteria 
Each single parameter of the clinico-haematological ELN response criteria [21] (see 
paragraph 4.6.1) will be used to evaluate the effect of Givinostat in PV patients. 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months) 
and the eligibility for this part of the study may be expanded to all patients with cMPN, 
in this part of the study each single parameter of the ELN and EUMNET criteria will be 
used to evaluate the effect of Givinostat in ET and MF patients, respectively. 
4.8.2 Evaluation of the effects of Givinostat on PD markers 
To evaluate the effects of Givinostat on PD markers will be used mRNA analysis.  
After evaluation of preliminary results and data exploration, some additional analyses 
may be performed to identify and quantify other molecular parameters of interest in 
term of improving of the knowledge of cMPN and the activity of the drug in these 
disorders.   
4.8.3 Spleen size assessment
The spleen evaluation must be performed at the study centre according to the visit 
schedule outlined in the flow-chart (Appendix A). 
To evaluate the effects of Givinostat on spleen size will be used MRI or CT scan.  
The spleen evaluation will be performed during the study according to institutional 
guidelines and site-specific clinical practice (i.e. MRI or CT scan). For this reason, it is 
strictly recommended to the sites to provide the Sponsor or their designee with the local 
normal spleen values of the imaging performed for each patient according institutional 
guidelines and site-specific clinical practice (i.e. MRI or CT scan). 
The same imaging technique and the same instrument to assess spleen dimension (i.e. 
MRI or CT scan) should be used on a patient throughout the study, if possible.  
If possible, the spleen dimension will be evaluated as longitudinal diameter (hereafter 
“A”), antero-posterior diameter (hereafter “B”), transversal diameter (hereafter “C”) and 
Splenic Volumetric Index (hereafter “SVI”): 
 
 
SVI = (A x B x C) / 27 


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4.8.4 Improvement of constitutional symptoms  
To evaluate the improvement of disease-related constitutional symptoms, the 
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) questionnaire 
(about 20 items) will be used in Parts A and B,  in order to assess the most important 
clinical symptoms among patients with MPNs [24].  
In addition, starting from MPN-SAF questionnaire, in Part B also the MPN-SAF Total 
Symptom Score [32] will be assessed as requested by the “new” ELN criteria (i.e. 
revised ELN response criteria) [32].  
4.8.5 Reduction of the JAK2V617F allele burden
To evaluate the reduction of the JAK2V617F allele burden will be used the qRT-PCR. 
This molecular examination will be performed in a central laboratory (Appendix E).  
After evaluation of preliminary results and data exploration, some additional analyses 
may be performed to identify and quantify other molecular parameters of interest in 
term of improving of the knowledge of cMPN and the activity of the drug in these 
disorders. 
4.8.6 Reduction of the symptomatic treatment of pruritus in term of 
dosage and/or days of treatment 
To evaluate the reduction of the symptomatic treatment of pruritus, the dosage and/or 
the days of treatment of each concomitant medication taken by the patient to treat this 
symptom will be used. This assessment will be performed using the data entered by 
Investigators in the specific section of the CRF. 
4.8.7 Evaluation of preliminary efficacy according to the revised ELN criteria
Disease response will be evaluated also according to the following “new” ELN criteria 
(i.e. the revised ELN response criteria) after 6 cycles of treatment with Givinostat in 
Part B [33]. 


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•
Complete remission:  
1. Durable resolution of disease-related signs including palpable hepato-
splenomegaly improvement, and large symptoms improvement, and
2. Durable peripheral blood count remission, defined as HCT < 45% without 
phlebotomies, and PLT count  400 x109/L, and WBC count < 10 x109/L, 
and
3. No progressive disease, and absence of any hemorrhagic or thrombotic event, 
and
4. Bone marrow histological remission defined as the presence of age-adjusted 
normo-cellularity, and disappearance of tri-linear hyperplasia, and absence of 
grade > 1 reticulin fibrosis. 
•
Partial remission:  
1. Durable resolution of disease-related signs including palpable hepato-
splenomegaly, and large symptoms improvement, and
2. Durable peripheral blood count remission, defined as HCT < 45% without 
phlebotomies, and PLT count  400 x109/L, and WBC count < 10 x109/L, 
and
3. No progressive disease, and absence of any hemorrhagic or thrombotic event, 
and
4. No bone marrow histological remission defined as persistence of tri-linear 
hyperplasia. 
•
No response: any response that does not satisfy  partial remission.
•
Progressive Disease: transformation into post-PV myelofibrosis, myelodysplastic 
syndrome or acute leukemia (according to the IWG-MRT criteria for the 
diagnosis of post-PV myelofibrosis and according to WHO criteria for the 
diagnosis of myelodysplastic syndrome and acute leukemia).
Please note that according to the “new” ELN criteria (i.e. revised ELN response 
criteria) [33]: 
1) Molecular response is not required for assignment as Complete Remission or 
Partial Remission. Molecular response evaluation requires analysis in peripheral 
blood granulocytes. Complete response is defined as eradication of a pre-
existing abnormality. Partial response applies only to patients with at least 20% 
mutant allele burden at baseline. Partial response is defined as   50% decrease 
in allele burden. 
2) “Durable” is defined as lasting at least 12 weeks. 
3) “Large symptom improvement” is defined as  10 points of decrease in MPN-
SAF Total Symptom Score [32]. 


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4.8.8 Evaluation of the effects of Givinostat on each single parameter of 
the revised ELN response criteria 
Each single parameter of the “new” ELN criteria (i.e. revised ELN response criteria) 
[33] (see paragraph 4.8.7) will be used to evaluate the effect of Givinostat in PV 
patients in Part B. 
4.9 
Definition of end of the study 
The end of the study (last patient last visit) will occur after all patients in whole study 
(Part B) have completed their last assessment as per protocol. Note that the analysis of 
the biological samples could be performed after the end of study due to scientific (i.e. 
after evaluation of preliminary results and data exploration, some additional analyses 
may be performed to identify and quantify other molecular parameters of interest in 
term of improving of the knowledge of cMPN and the activity of the drug in these 
disorders) or technical reason. 
In any case, after the completion of the analysis all data will be formally reported in a 
Clinical Study Report and/or in a specific technical report.     
5. 
ADVERSE EVENTS 
The Investigator is responsible for the detection and documentation of AEs as defined in 
this protocol. AE data will be obtained at all study visits, based on information 
spontaneously provided by the patient and/or through questioning. Additionally, 
patients will be advised that they can contact the Investigator at any time to report or 
discuss AEs. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until 
it is reasonable to consider the event not drug related any more or until the start of a 
new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-
up visits until recovery. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance every effort should be made 
to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 


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5.1 
 Definitions 
5.1.1 Adverse Event (AE) 
An Adverse Event is “any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment” (ICH E2A). 
AEs include: 
•
Onset of any clinical sign or symptom; 
•
Worsening (change in nature, severity or frequency) of conditions present at the 
start of the trial; 
•
Patient deterioration due to the primary illness; 
•
Intercurrent illnesses; 
•
Drug interactions; 
•
Events related or possibly related to concomitant medications; 
•
Abnormal laboratory values, as well as significant shifts from baseline within the 
range of normal, which the investigator considers to be clinically significant. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
5.1.2 Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established: “all noxious and 
unintended responses to a medicinal product related to any dose should be considered 
Adverse Drug Reaction”. 
The phrase "responses to a medicinal products" means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 
Regarding marketed medicinal products, a well-accepted definition of an adverse drug 
reaction in the post-marketing setting is found in WHO Technical Report 498 [1972] 
and reads as follows: ”a response to a drug which is noxious and unintended and which 
occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease 
or for modification of physiological function.” 
The old term "side effect" has been used in various ways in the past, usually to describe 
negative (unfavourable) effects, but also positive (favourable) effects. It is 
recommended that this term no longer be used and particularly should not be regarded 
as synonymous with adverse event or adverse reaction. 


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5.1.3 Unexpected Adverse Drug Reaction  
An Unexpected Adverse Drug Reaction is “an Adverse Drug Reaction, the nature or 
severity of which is not consistent with the applicable product information (e.g. 
Investigator’s Brochure for an unapproved investigational medicinal product or 
summary of product characteristics, SPC, for marketed products)”. 
All adverse events judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is 
evidence or argument to suggest a causal relationship. 
5.1.4 Serious Adverse Event (SAE) 
A Serious Adverse Event (experience) or reaction is “any untoward medical occurrence 
that at any dose: 
•
results is fatal (results in the outcome death); 
•
is life-threatening*; 
•
required in-patient hospitalisation or prolongation of existing hospitalisation; 
•
results in persistent or significant disability/incapacity; 
•
is a congenital anomaly/birth defect; 
•
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above; 
•
consists in the transmission of an infective agent through the IMP.” 
*The term life-threatening refers to an event in which the patient is at risk of  death at 
the time of the event; it does not refer to an event which hypothetically may cause 
death if it is more severe. 
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious in other situations. Important adverse events/ reactions that are not immediately 
life-threatening or do not result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above, should also be considered serious. 
The pre-planned hospitalization or adverse reaction expected as part of the trial 
treatment (e.g. standard expected side effect of chemotherapy) should not considered as 
SAE. 
A Suspected Unexpected  Serious Adverse Reaction (SUSAR) is referred to an adverse 
drug reaction which comply with both the definitions of “serious” and “unexpected”. 


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5.2 
AE Reporting 
The Investigators or their designees are requested to collect and asses any spontaneous 
AE reported by the patient and to question the patient about AEs and undercurrent 
illnesses at each visit during the treatment period and any follow-up visit performed to 
monitor any drug-related AE that is still ongoing beyond the last scheduled visit until 
recovery. The questioning of patients regarding AEs is generalized such as “How have 
you been feeling since your last visit?” Any AE occurring after a patient has signed the 
Informed Consent form and up to the follow-up study visit, whether volunteered by the 
patient, discovered during general questioning by the Investigators or detected through 
physical examination, laboratory test or other means, will be recorded on the specific 
section of the CRF. Each AE will be described by:  
- 
the seriousness; 
- 
the duration (start and end dates); 
- 
the severity; 
- 
the relationship with the IMP; 
- 
the action taken.  
The severity of AE should be assessed and graded according to the most recently 
published NCI Common Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010).  
The relationship with the IMP should be assessed as: 
- 
related to IMP; 
- 
not related to IMP; 
- 
unknown.  
The assessment of the relationship of an adverse event with the administration of IMP is 
a clinical decision based on all available information at the time of the completion of the 
CRF. 
An assessment of “Not related” would include the existence of a clear alternative 
explanation, or non-plausibility. 
An assessment of “Related” indicates that there is a reasonable suspicion that the 
adverse event is associated with the use of the IMP. 
An assessment “Unknown” indicates there is not a reasonable suspicion that the adverse 
event is associated with the use of the IMP and at the same time there is not the 
existence of a clear alternative explanation or non-plausibility. In this case, Investigator 
has to collect all possible information in order to assess the relationship with the IMP, 
particularly in case of Serious Adverse Events. 
Factors to be considered in assessing the relationship of the adverse event to study drug 
include: 
- 
The temporal sequence from IMP administration; 
- 
The recovery on discontinuation and recurrence on reintroduction; 
- 
The concomitant diseases; 


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- 
The evolution of the treated disease; 
- 
The concomitant medication; 
- 
The pharmacology and pharmacokinetics of the IMP; 
- 
The presence of an alternative explanation. 
5.2.1 Abnormal laboratory findings and other objective measurements 
Abnormal laboratory findings and other objective measurements should not be routinely 
captured and reported as AEs as they will be collected and analysed separately in the 
CRF. However, abnormal laboratory findings and other objective measurements that 
meet the criteria for an SAE, result in discontinuation of the IMP or require medical 
intervention, or are judged by the Investigator to be clinically significant changes from 
baselines values should be captured and reported on the AE pages of the CRF. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until 
it is reasonable to consider the event not drug related any more or until the start of a 
new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-
up visits until recovery. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance every effort should be made 
to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
When reporting an abnormal laboratory finding on the AE pages of the CRF, a clinical 
diagnosis should be recorded in addition to the abnormal value itself, if this is available 
(for example “anaemia” in addition to “haemoglobin = 10.5 g/dl”). 
5.2.2  Baseline medical conditions 
Medical conditions present at the screening visit, that do not worsen in severity or 
frequency during the study are defined as baseline medical conditions and are not AEs.  
These medical conditions should be adequately documented on the appropriate page of 
the CRF, i.e. the medical history page. However, medical conditions present at the 
initial study visit that worsen in severity or frequency during the study should be 
recorded and reported as AEs. 


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5.3 
SAE Reporting  
Any SAE, including death from any cause that occurs after a patient has signed the 
Informed Consent and up to any follow-up visit performed to monitor any drug-related 
AE that is still ongoing beyond the last scheduled visit until recovery (regardless of 
relationship to study drug) must be reported by the Investigators to Italfarmaco S.p.A. 
within 24 hours of learning of its occurrence. 
Related SAEs MUST be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. Anyway, no active 
subject monitoring by the Investigators is required. 
The Investigators are required to complete the SAE Form, according with the 
procedures described in the study manual and within 24 hours of learning of its 
occurrence. Sufficient details must be provided to allow for a complete medical 
assessment of the AE and independent determination of possible causality. The 
Investigators are obliged to pursue and provide additional information as requested by 
Italfarmaco S.p.A. or their designee(s). 
The Investigator must notify the SAE to the Drug Safety Unit (hereinafter “DSU”) of 
Italfarmaco S.p.A. by sending the SAE Form, according with the procedures indicated 
in the study manual and within 24 hours of learning of its occurrence.  
The details of the DSU are specified here below: 
Italfarmaco S.p.A. 
Drug Safety UnitVia dei Lavoratori, 54  
20092 Cinisello Balsamo (MI), Italy  
Phone: 
 
Fax:  
 
Fax (back-up): 
Mobile: 
 
e-mail:  
 
The same procedure must be applied to the SAE follow-up information. 
All serious and unexpected AE that are associated with the use of the study drug 
(SUSARs) will be notified by Italfarmaco S.p.A. DSU to the competent authority within 
the required time and following procedures required by applicable laws. It is imperative 
that Italfarmaco S.p.A. be informed as soon as possible, so that reporting can be done 
within the required time frame.  
The SAEs will also be recorded in the dedicated AE section of the CRF. 
PPD
PPD
PPD
PPD
PPD


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5.3.1 Over-dosage  and other situations putting the patient at risk of 
adverse reaction 
In general, a drug overdose in a clinical trial is defined as the accidental or intentional 
use of a drug or medicine in an amount exceeding the protocol defined dose(s). In this 
study, if an AE is associated with (“results from”) the overdose of Givinostat, the AE is 
reported as a SAE, even if no other criteria for seriousness are met. 
If a dose of Givinostat meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as 
a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.”Any instance of overdose (suspected or 
confirmed, with and without an AE) must be reported to the sponsor within 24 hours 
and, only in case of AEs, it must be fully documented as a SAE. Details of any signs or 
symptoms and their management should be recorded in the SAE Form including details 
of any antidote(s) or systematic treatment administered. Any signs or symptoms of 
over-dosage will be treated symptomatically.  
Any other situations putting the patient at risk of adverse reaction, such as misuse and 
abuse, medication errors, suspect of transmission of infective agents must be reported to 
the sponsor within 24 hours and must be fully documented as a SAE. 
5.3.2 Pregnancy   
Female patients who have a positive pregnancy test during the pre-treatment evaluations 
assessment are not eligible for study participation. If a patient becomes pregnant while 
on study, the treatment shall be immediately stopped. The investigator is required to 
report the pregnancy to Italfarmaco S.p.A. DSU within 24 hours of learning of its 
occurrence via telephone and/or fax and/or mail (only in case the mail will be 
automatically generated by the e-CRF). If initially reported via telephone, this must be 
followed-up with a written report via fax and/or mail (only in case the mail will be 
automatically generated by the e-CRF) within 24 hours of the telephone report.  
Patients should be instructed to notify the investigator if, after completion of the study, 
it is determined that they became pregnant during the treatment phase or through 3 
months after the last dose of study drug. 
Whenever possible, a pregnancy with an onset within the above defined time frame 
should be followed until termination, any premature termination should be reported, and 
the status of the mother and child should be reported to the sponsor after delivery. 
If the Investigator is made aware that the partner of a male patient who is participating 
to the study become pregnant, he/she is required to report the pregnancy to Italfarmaco 
S.p.A. DSU within 24 hours via telephone and/or fax and/or mail (only in case the mail 
will be automatically generated by the e-CRF). If initially reported via telephone, this 


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must be followed-up with a written report via fax and/or mail (only in case the mail will 
be automatically generated by the e-CRF) within 24 hours of the telephone report.  
Whenever possible, such pregnancy should be followed until termination, any 
premature termination should be reported, and the status of the mother and child should 
be reported to the sponsor after delivery.
6. 
STATISTICAL METHODS 
6.1 
Experimental design 
Two-part, multicenter, open label, non-randomized, phase Ib/II study. 
6.2 
Statistical methods to be employed 
Methods here represent the outline of the intended methods.  
A Statistical Analysis Plan (SAP) will be produced before the database lock and will 
contain full details of all planned summaries, listings and analyses. 
A standard 3+3 design adopting a modified Fibonacci escalation schema will be used  in 
Part A [25, 26, 27].  
Sample size for Part B was discussed for the primary end point defined as the Overall 
Response Rate after 3 cycles. Simon’s 2-stage design will be employed in Part B [30] 
with the aim of testing the “null hypothesis” that RR  0.50 versus the “alternative” that 
RR  0.75. Response rate will be assessed as defined in paragraph 6.2.5.2. Overall up to 
28 patients will need to be recruited, 12 patients being enrolled in Stage-1. PV patients 
enrolled at the MTD in Part A may be counted towards Stage 1. Under the “null 
hypothesis” (if RR = 0.50), the expected total sample size is of 18.2 patients, the 
probability of early termination at the end of Stage-1 is 0.613 and the probability of 
rejecting the “null hypothesis” is 0.081 (the target for the type-I error being 0.100). 
Under the “alternative hypothesis” (if RR = 0.75), the probability of rejecting the “null 
hypothesis” in favour of the “alternative” is 0.902 (the type-II error being 0.098). After 
testing the treatment on 12 patients in Stage-1, if 6 or fewer patients respond to the 
treatment the trial will be terminated rejecting the “alternative” that RR  0.75. 
Otherwise, the trial goes on to Stage-2 enrolling further 16 patients to a total of 28 
patients. If at the end of Stage-2, a total of 17 or fewer patients respond to the treatment 
the “alternative hypothesis” that RR  0.75 will be rejected; alternatively, if 18 or more 
patients respond, the “null hypothesis” that RR  0.50 will be rejected. Estimations are 
obtained from proprietary software (based on SAS ® 9.2) according to the algorithm 
proposed by R. Simon [30]. 
Summary statistics will be calculated for all variables. For each continuous variable, the 
mean, standard deviation, median, minimum value and maximum value will be 
computed. For each discrete variable the number of patients in each category with non-
missing values in relation to all patients with non-missing values of that variable will be 
provided. Results will be displayed within each cohort and overall, where applicable.  


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Statistical calculations will be carried-out by resorting to SAS version 9.2 (or later). 
Both continuous and categorical data will be summarized and tabulated in 2-way tables 
(variable-by-visit). The main purpose of this phase Ib/II study consists in providing 
accurate estimates of clinically relevant variables and measures. From the statistical 
viewpoint this translates in estimating confidence intervals (CIs) with adequate 
precision where precision represents the degree of uncertainty. 
The two tailed 95% CIs of the sample estimates will be computed using parametric 
approaches if deemed appropriate. Otherwise the StatXact-4 software will be used in 
order to compute Exact/Nonparametric 95% CIs.      
Sub-groups analyses will be performed mainly for exploratory purposes. Since these 
analyses will be used to promote hypothesis rather than confirm them, no adjustments 
for type I error inflation due to multiplicity of the tests will be considered. Moreover 
post-hoc and data-driven analyses will be carefully considered and ranked according to 
their biological plausibility. 
6.2.1 Analysis Sets 
The following analysis sets will be defined:  
- Safety analysis set (SAF): The Safety analysis set will include all recruited patients 
who receive at least one dose of study medication. All safety analyses will be 
conducted on this population. 
- Intent-to-treat analysis set (ITT): The Intent-to-treat analysis set will include all 
recruited patients who receive at least one dose of study medication and from whom 
at least one post-baseline efficacy measurement is obtained. All efficacy analyses 
will be conducted on this population and will be based on the effective/actual
DL/daily doses of Givinostat at which each patient has been treated. 
- Per Protocol analysis set (PP): In order to assess the robustness of the efficacy 
analysis, the analysis of the efficacy end-point could be repeated in the Per Protocol 
(PP) analysis set. The Per-protocol analysis set will include all ITT  patients who 
receive at least 14 daily doses without interruptions, and without any major 
deviation from the protocol procedures.  
- MTD analysis set: The MTD analysis set will include all patients who experienced  
DLTs in Cycle 1 of Part A, or who received at least 90% of the doses of study 
medication in Cycle 1 of Part A. The data regarding the Cycle 1 of Part A will be 
used to determine MTD from this analysis set.  
- PK Analysis set: will consist of all SAF patients who with at least 1 PK assessment. 
This analysis set will be used for PK analysis. 
The number and percentage of the patients included in the analysis populations will be 
reported in a table showing the reason of exclusion for all patients enrolled into study. A 
listing of reasons of exclusion from analysis population will be provided.  


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6.2.2 Background and demographic characteristics 
Demographic data and other baseline characteristics, including medical history, will be 
analyzed based on safety population. Summary statistics will be provided for all 
collected variables. For continuous variables, the following statistics will be calculated: 
mean, standard deviation, median, minimum and maximum values. For discrete 
variables, the following statistics will be presented: number of patients with non missing 
values in each category in relation to all patients with non missing values of the 
respective variable.  
Medical history will be listed by patient based on safety population. 
6.2.3 IMP 
The duration (days) of exposure of Givinostat will be calculated for each patient, and 
will be summarized descriptively including the mean, standard deviation, median, 
minimum and maximum. 
In addition, the daily dosage (mg) of Givinostat will be summarized for each patient, 
and will be summarized descriptively including the mean, standard deviation, median, 
minimum and maximum. 
Reason for treatment discontinuation and number of patients treated beyond protocol-
specified discontinuation criteria will also be summarized. Analysis will be based on 
safety population. 
6.2.4 Prior and Concomitant medications and prior and concomitant 
significant non-drug therapies 
Prior medications and significant non-drug therapies (e.g. phlebotomies, transfusions) to 
treat PV will include regimens discontinued up to 24 weeks prior to enrolment. The 
information captured will include drug name, start and stop dates, best response to 
therapy (where applicable) and reason for discontinuations.  
Prior medications and prior significant non-drug therapies are defined as those starting 
and ending prior to the first administration of investigational study drug. Concomitant 
medications and concomitant significant non-drug therapies are defined as those started 
at or after first administration of study drug and include those started prior to the first 
administration of investigational study drug but continued during the study.  
Prior and concomitant medications will be classified according to active drug substance 
using the WHO-DRL drug dictionary (using the most updated version). Frequency 
tabulations will be presented for prior and concomitant medication by primary 
therapeutic subgroup (3rd level ATC code), and generic name. Frequency tabulations 
will be also presented for significant non-drug therapies. 
All analyses will be based on safety population.  


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6.2.5 Primary Efficacy and Safety evaluation 
6.2.5.1 Part A
The following primary safety parameters will be evaluated in Part A based on SAF: 
•
Number of patients experiencing adverse events. 
•
Type, incidence, and severity of treatment-related adverse events, graded 
according to Common Terminology Criteria for Adverse Events (CTCAE v. 
4.03, 14th June 2010). 
AEs will be coded using MedDRA dictionary (using the most updated version). 
Adverse events (AEs) will be reported on a per subject basis. If a patient has more than 
one AE for a treatment that coded to the same preferred term (PT), the patient will be 
counted only once for that preferred term. Similarly, if a patient has more than one AE 
for a treatment within a system organ class (SOC) category, the patient will be counted 
only once in that system organ class category. A patient with multiple CTCAE grades 
for an AE will be summarized under the maximum CTCAE grade recorded for the 
event.  
Any Adverse Events which started at or after the first administration of study treatment 
will be considered a treatment Emergent Adverse Event (TEAE). If the start date is 
missing for an AE, the AE will be considered to be treatment emergent. 
An overview of AEs including the number of subjects with at least one AE, at least one 
TEAE, at least one drug-related TEAE, at least one serious TEAE, any SAE, any AE 
leading to death, any TEAE leading to death, any TEAE leading to drug discontinuation 
discontinuation, at least one grade  3 TEAE, will be presented. The following AE 
frequency tables will be also provided:  
•
incidence of TEAEs by primary SOC and PT; 
•
incidence of drug-related TEAEs by primary SOC and PT; 
•
incidence of TEAEs by maximum severity, primary SOC and PT; 
•
incidence of TEAEs by strongest relationship,  maximum severity, primary SOC 
and PT; 
•
incidence of TESAEs by primary SOC and PT; 
•
incidence of TEAEs leading to study drug discontinuation by primary SOC and 
PT; 
•
incidence of TEAEs leading to dose modification by primary SOC and PT. 
In addition, the following primary parameter will be evaluated in Part A based on MTD 
analysis set population: 
•
MTD of Givinostat. 


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6.2.5.2 Part B
The following primary efficacy parameters will be evaluated in Part B after 3 cycles of 
treatment (i.e. at the end of Cycle 3) based on ITT and PP: 
•
For PV and ET (if any): Complete response (CR) and partial response (PR) rate 
according to clinico-haematological ELN response criteria [21] (see paragraph 
4.6.1); 
•
For MF (if any): Complete response (CR), major response, moderate response 
and minor response rate according to the EUMNET response criteria (see 
paragraph 4.6.1).
Note that only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 
months, the eligibility for this part of the study may be expanded to all patients with 
cMPN.  
The clinico-haematological ELN response criteria [21] (see paragraph 4.6.1) and 
EUMNET response criteria will be used to assess the preliminary efficacy of Givinostat 
(primary endpoint) after 3 cycles of treatment in Part B for PV/ET and MF patients, 
respectively (see paragraph 4.6.1 for more details). 
Frequency and percentage of patients in each response category (complete response 
(CR), partial response (PR), no response (NR) for PV and ET; Complete response (CR), 
major response, moderate response and minor response rate for MF) will be presented at 
each time point. In order to evaluate the response rate, subjects who discontinued 
prematurely the study for any reason (AE, consent withdrawal, lost to follow up) will be 
defined as ‘Non Responder’. Other missing data will not be replaced, if not otherwise 
specified. 
In addition, the following primary safety parameters will be evaluated in Part B after 3 
cycles of treatment (i.e. at the end of Cycles 3, or including data related to Cycles 1, 2 
and 3) based on SAF: 
•
Number of patients experiencing adverse events. 
•
Type, incidence, and severity of treatment-related adverse events, graded 
according to Common Terminology Criteria for Adverse Events (CTCAE v. 
4.03, 14th June 2010). 
AEs will be coded using MedDRA dictionary (using the most updated version). 
Adverse events (AEs) will be reported on a per subject basis. If a patient has more than 
one AE for a treatment that coded to the same preferred term (PT), the patient will be 
counted only once for that preferred term. Similarly, if a patient has more than one AE 
for a treatment within a system organ class (SOC) category, the patient will be counted 
only once in that system organ class category. A patient with multiple CTCAE grades 
for an AE will be summarized under the maximum CTCAE grade recorded for the 
event.  
Any Adverse Events which started at or after the first administration of study treatment 
will be considered a treatment Emergent Adverse Event (TEAE). If the start date is 
missing for an AE, the AE will be considered to be treatment emergent.  


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TEAE included in this analysis are defined  as those starting prior to the date of  the first 
administration of  Cycle 4 and include those started prior  but continued during the 
subsequent cycle. 
An overview of AEs including the number of subjects with at least one AE, at least one 
TEAE, at least one drug-related TEAE, at least one serious TEAE, any SAE, any AE 
leading to death, any TEAE leading to death, any TEAE leading to drug discontinuation 
discontinuation, at least one grade  3 TEAE, will be presented. The following AE 
frequency tables will be also provided:  
•
incidence of TEAEs by primary SOC and PT; 
•
incidence of drug-related TEAEs by primary SOC and PT; 
•
incidence of TEAEs by maximum severity, primary SOC and PT; 
•
incidence of TEAEs by strongest relationship, maximum severity, primary SOC 
and PT; 
•
incidence of TESAEs by primary SOC and PT; 
•
incidence of TEAEs leading to study drug discontinuation by primary SOC and 
PT; 
•
incidence of TEAEs leading to dose modification by primary SOC and PT. 
6.2.6 Secondary Efficacy and Safety evaluation 
6.2.6.1 Part A
The following secondary efficacy parameters will be evaluated in Part A after 3 and 6 
cycles of treatment (i.e. at the end of Cycles 3 and 6, respectively) based on ITT and 
PP: 
•
Preliminary efficacy of Givinostat (secondary endpoint) for PV/ET and MF 
patients, respectively (see paragraph 4.6.1 for more details): 
-
For PV and ET (if any): Complete response (CR) and partial response (PR) 
rate according to the clinico-haematological ELN response criteria [21] (see 
paragraph 4.6.1); 
-
For MF (if any): Complete response (CR), major response, moderate 
response and minor response rate according to the EUMNET response 
criteria (see paragraph 4.6.1).
Note that only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 
months, the eligibility for this part of the study may be expanded to all patients with 
cMPN.  
Frequency and percentage of patients in each response category (complete response 
(CR), partial response (PR), no response (NR) for PV and ET; Complete response (CR), 
major response, moderate response and minor response rate for MF) will be presented at 
each time point. In order to evaluate the response rate, subjects who discontinued 
prematurely the study for any reason (AE, consent withdrawal, lost to follow up) will be 


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defined as ‘Non Responder’. Other missing data will not be replaced, if not otherwise 
specified. 
The following secondary parameter will be evaluated in Part A based on PK analysis 
set: 
–
Individual Givinostat concentrations tabulated by dose cohort along with 
descriptive statistics.  
The PK analysis will be conducted on the PK population.  
Plasma concentrations from Part A will be listed and tabulated by dose and time point 
for all patients and time points with at least 1 PK assessment.  
Descriptive statistics for all PK parameters for Part A will be calculated. These tables 
will include number of observations, mean, standard deviation, median, minimum and 
maximum and additionally the geometric mean and coefficient of variation (not for time 
to maximum plasma concentration). 
6.2.6.2 Part B
The following secondary efficacy parameter will be evaluated in Part B after 6 cycles 
of treatment (i.e. at the end of Cycle 6) based on ITT and PP: 
•
Preliminary effectiveness of Givinostat (secondary endpoint) after 6 cycles of 
treatment in Part B for PV/ET and MF patients, respectively (see paragraph 
4.6.1 for more details): 
-
For PV and ET (if any): Complete response (CR) and partial response (PR) 
rate according to the clinico-haematological ELN response criteria [21] (see 
paragraph 4.6.1); 
-
For MF (if any): Complete response (CR), major response, moderate 
response and minor response rate according to the EUMNET response 
criteria (see paragraph 4.6.1).
Note that only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled 
in 3 months), the eligibility for this part of the study may be expanded to all 
patients with cMPN.  
Frequency and percentage of patients in each response category (complete 
response (CR), partial response (PR), no response (NR) for PV and ET; 
Complete response (CR), major response, moderate response and minor 
response rate for MF) will be presented at each time point. In order to evaluate 
the response rate, subjects who discontinued prematurely the study for any 
reason (AE, consent withdrawal, lost to follow up) will be defined as ‘Non 
Responder’. Other missing data will not be replaced, if not otherwise specified. 


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The following secondary safety parameter will be evaluated in Part B after 6 cycles of 
treatment (i.e. at the end of Cycles 6, or including data related to Cycles 4, 5 and 6) 
based on safety population: 
•
Number of patients experiencing adverse events. 
•
Type, incidence, and severity of treatment-related adverse events, graded 
according to Common Terminology Criteria for Adverse Events (CTCAE v. 
4.03, 14th June 2010). 
AEs will be coded using MedDRA dictionary (using the most updated version). 
Adverse events (AEs) will be reported on a per subject basis. If a patient has more than 
one AE for a treatment that coded to the same preferred term (PT), the patient will be 
counted only once for that preferred term. Similarly, if a patient has more than one AE 
for a treatment within a system organ class (SOC) category, the patient will be counted 
only once in that system organ class category. A patient with multiple CTCAE grades 
for an AE will be summarized under the maximum CTCAE grade recorded for the 
event.  
Any Adverse Events which started at or after the first administration of study treatment 
will be considered a treatment Emergent Adverse Event (TEAE). If the start date is 
missing for an AE, the AE will be considered to be treatment emergent. 
TEAE included in this analysis are defined  as those starting after the  date of  the first 
administration of  Cycle 4. 
An overview of AEs including the number of subjects with at least one AE, at least one 
TEAE, at least one drug-related TEAE, at least one serious TEAE, any SAE, any AE 
leading to death, any TEAE leading to death, any TEAE leading to drug 
discontinuation, at least one grade  3 TEAE, will be presented. The following AE 
frequency tables will be also provided:  
•
incidence of TEAEs by primary SOC and PT; 
•
incidence of drug-related TEAEs by primary SOC and PT; 
•
incidence of TEAEs by maximum severity, primary SOC and PT; 
•
incidence of TEAEs by strongest relationship,  maximum severity, primary SOC 
and PT; 
•
incidence of TESAEs by primary SOC and PT; 
•
incidence of TEAEs leading to study drug discontinuation by primary SOC and 
PT; 
•
incidence of TEAEs leading to dose modification by primary SOC and PT. 
The following secondary parameters will be evaluated in Part B based on PK analysis 
set: 
•
Individual Givinostat concentrations tabulated with descriptive statistics: plasma 
concentrations from Part B will be listed and tabulated by time point for all 
patients and time points with at least 1 PK assessment; descriptive statistics for 
all PK parameters for Part B will also be calculated; these tables will include 


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number of observations, mean, standard deviation, median, minimum and 
maximum and additionally the geometric mean and coefficient of variation (not 
for time to maximum plasma concentration). 
6.2.7 Exploratory evaluations 
6.2.7.1 Parts A and B 
The following exploratory parameters will be evaluated using ad-hoc descriptive 
analysis in Parts A and B based on ITT and PP: 
•
The effect of Givinostat on each single response parameter according to the 
clinico-haematological ELN (for PV and ET) [21] (see paragraph 4.6.1) and 
EUMNET response criteria (for MF); note that only in case the enrolment in 
Part A is slow (i.e. < 5 patients enrolled in 3 months, the eligibility for this 
part of the study may be expanded to all patients with cMPN.  
•
Effects of Givinostat on PD markers. 
•
Effects of Givinostat on spleen size in patients with confirmed splenomegaly at 
baseline. 
•
Improvement of constitutional symptoms evaluated according to MPN-SAF 
QOL questionnaire [24, 32]. 
•
Reduction of the JAK2V617F allele burden, tested by quantitative RT-PCR. 
•
Reduction of the symptomatic treatment of pruritus in term of dosage and/or 
days of treatment. 
The following exploratory parameters will be evaluated using ad-hoc descriptive 
analysis in Part B based on ITT and PP: 
•
The preliminary efficacy of Givinostat after 6  cycles of treatment according to 
the “new” ELN criteria (i.e. revised ELN response criteria) [33] (see paragraph 
4.8.7). 
•
The effect of Givinostat on single parameters of the “new” ELN criteria (i.e. 
revised ELN response criteria) [33] (see paragraph 4.8.7). 
Explorative endpoints will be summarized by descriptive methods. Default summary 
statistics and changes from baseline (where applicable) to each time point for all 
parameters will be produced. 
   
6.2.8 Other Safety evaluation 
All patients who receive at least one dose will be included in the safety evaluation. 
Safety data including laboratory evaluations, physical exams. ECG monitoring and vital 
signs assessments will be summarized at each time point. Descriptive statistics 


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(arithmetic mean, standard deviation, median, minimum and maximum) will be 
calculated for quantitative safety data as well as for the difference from baseline, if 
applicable. Frequency counts will be compiled for classification of qualitative safety 
data. In addition, a shift table describing out of normal range shifts (low/normal/high 
values) will be provided for clinical laboratory results. A normal-abnormal shift table 
will also be presented for physical exam and ECG results. 
6.2.9 Interim analyses 
Italfarmaco S.p.A. will perform a preliminary analysis of data after the completion of 
the first cycle of treatment from all patients recruited in Part A, in order to assess the 
MTD to be used for Part B.  
Moreover, a preliminary analysis will be performed on the 12 patients of the first stage 
of Part B: if six or fewer responses will be observed during the first stage then the study 
will be stopped; if seven or more  responses will be observed in the first stage of Part B, 
further 16 patients will be enrolled in the second stage of Part B. In this case, a final 
statistical analysis will be performed considering all patients enrolled in the two study 
phases. 
In addition, Italfarmaco S.p.A. can perform a preliminary analysis of data in case of 
necessary safety and efficacy updates (e.g. to update regulatory documents and/or the 
drug safety profile, to revise the development program).  
6.3 
Sample size and power considerations 
A standard 3+3 design adopting a modified Fibonacci escalation schema will be used  in 
Part A [25, 26, 27].  
Sample size for Part B was discussed for the primary end point defined as the Overall 
Response Rate after 3 cycles. Simon’s 2-stage design will be employed in Part B [30] 
with the aim of testing the “null hypothesis” that RR  0.50 versus the “alternative” that 
RR  0.75. Response rate will be assessed as defined in paragraph 6.2.5.2. Overall up to 
28 patients will need to be recruited, 12 patients being enrolled in Stage-1. PV patients 
enrolled at the MTD in Part A may be counted towards Stage 1. Under the “null 
hypothesis” (if RR = 0.50), the expected total sample size is of 18.2 patients, the 
probability of early termination at the end of Stage-1 is 0.613 and the probability of 
rejecting the “null hypothesis” is 0.081 (the target for the type-I error being 0.100). 
Under the “alternative hypothesis” (if RR = 0.75), the probability of rejecting the “null 
hypothesis” in favour of the “alternative” is 0.902 (the type-II error being 0.098). After 
testing the treatment on 12 patients in Stage-1, if 6 or fewer patients respond to the 
treatment the trial will be terminated rejecting the “alternative” that RR  0.75. 
Otherwise, the trial goes on to Stage-2 enrolling further 16 patients to a total of 28 
patients. If at the end of Stage-2, a total of 17 or fewer patients respond to the treatment 
the “alternative hypothesis” that RR  0.75 will be rejected; alternatively, if 18 or more 
patients respond, the “null hypothesis” that RR  0.50 will be rejected. Estimations are 


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obtained from proprietary software (based on SAS ® 9.2) according to the algorithm 
proposed by R. Simon [30]. 
7. 
ETHICS AND GOOD CLINICAL PRACTICE  
The investigator will ensure that this study is conducted in full conformity with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to 
the individual.  
The study must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” ICH Tripartite Guideline or with local law if it affords greater protection to 
the subject.  
For studies conducted in the EU/EEA countries, the investigator will ensure compliance 
with the EU Clinical Trial Directive [2001/20/EC] and according to country regulation. 
For studies conducted in the USA or under US IND, the investigator will additionally 
ensure adherence to the basic principles of “GCP” as outlined in the current version of 
21 CFR, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, part 
50, “Protection of Human Subjects”, and part 56, “Institutional Review Boards”. 
This study will also be carried out in accordance with Italfarmaco S.p.A.’s SOPs. 
The investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of GCP that it 
conforms to. 
7.1 
Institutional Review Board/Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and 
other information to patients, must be reviewed by a properly constituted Institutional 
Review Board/Ethics Committee (IRB/EC). A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/EC must be given to 
Italfarmaco S.p.A. before study initiation. The name and occupation of the chairman 
and the members of the IRB/EC must be supplied to Italfarmaco S.p.A.. Any 
amendments to the protocol, other than administrative ones, must be approved by this 
committee. 
7.2 Informed consent 
Prior to the beginning of the study, the investigator must have the ECs/IRB written 
approval/favourable opinion of the written Informed Consent and any other written 
information to be provided to patients or legally authorized representative. The 
approved patient information letter/Informed Consent must be filed in the study files 
(TMF and IF). 
Written informed consent must be obtained before any study specific procedure takes 
place.   


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The investigator must explain to each patient (or legally authorized representative) the 
nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail. Each patient (or 
legally authorized representative) must be informed that participation in the study is 
voluntary, that the patient may withdraw from the study at any time for any reason and 
that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, 
written in non-technical language. The patient (or legally authorized representative) 
should read and consider the statement before signing and dating it, and should be given 
a copy of the signed document. If written consent is not possible, oral consent can be 
obtained if witnessed by a signed statement from one or more persons not involved in 
the study, mentioning why the patient was unable to sign the form.  
8. 
ADMINISTRATIVE PROCEDURES 
8.1 
Changes to the protocol 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by Italfarmaco S.p.A.. 
Amendments can be classified as substantial when impact one of the following criteria:  
Ȭ
The safety or physical or mental integrity of the patient; 
Ȭ
The scientific value of the study; 
Ȭ
The conduct or management of the study; 
Ȭ
The quality or safety of any IMP used in the study.
Substantial amendments require the authorization to the Competent Authority and the 
positive opinion of the relevant Ethic Committee (EC) before implementation. 
In case of urgent safety measures to protect patient against any immediate hazard these 
measures can be taken without prior authorization from the Competent Authority or 
favourable opinion of the EC. In this case the Competent Authority and EC will be 
informed as soon as possible using the fasted means of communication followed by a 
written report. 
Amendments classified as non-substantial require only notification to the ECs involved. 
A progress report must be submitted to the EC at required intervals and not less than 
annually. 
At the completion or termination of the study, the study center must submit a close-out 
letter to the EC and Italfarmaco S.p.A.. 
8.2 
Monitoring procedures 
The study will be monitored by a CRO according to GCP guidelines.  


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A site visit will be held prior to initiation of patient enrolment. The protocol, CRFs, 
study drug supplies and relevant procedures will be explained to the Investigator’s and 
his/her staff in detail at the site visit. During the study, the study monitor will visit the 
site regularly, to check the completeness of patient records, the accuracy of entries on 
the CRFs, the adherence to the protocol and to GCP, the progress of enrolment, and also 
to ensure that study medication is being stored, dispensed and accounted for according 
to specifications. The investigator and key trial personnel must be available to assist the 
monitor during these visits. 
The investigator must give the monitor access to relevant hospital or clinical records, to 
confirm their consistency with the CRF entries. No information in these records about 
the identity of the patients will leave the study centre. Monitoring standard procedures 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs and the recording of primary 
efficacy and safety variables. The investigator is responsible for completing the CRFs 
expeditiously to capture all the relevant information, while the monitor is responsible 
for reviewing them and clarifying any data queries.  
8.3 
Recording of data and retention of documents 
Data on patients collected on CRFs during the trial will be documented in an 
anonymous fashion and the patient will only be identified by the patient number and by 
his/her date of birth. All the information required by the protocol should be provided 
and any omissions require explanation. All CRFs must be completed expeditiously after 
the patient’s visit. 
The CRO will provide the study site with electronic CRF and the guidelines for the CRF 
compilation for each patient.  
The investigator must maintain source documents for each patient in the study. All 
information on CRFs must be traceable to these source documents, which are generally 
maintained in the patient's file. The source documents should contain all demographic 
and medical information, including laboratory data, electrocardiograms, etc. 
Essential documents of the study must be retained by the investigator for as long as 
needed to comply with national and international regulations (in Italy at least 7 years).  
8.4 
Auditing procedures 
Italfarmaco S.p.A. reserves the right to conduct auditing activities at any/all 
participating centres and contracted a CRO or their delegates in order to verify 
compliance with Italfarmaco S.p.A. internal SOPs, CRO and/or their delegates SOPs, 
the principles of GCP and all applicable laws. A Regulatory Authority may also wish to 
conduct an inspection (during the study or even after its completion). If an inspection is 
requested by a Regulatory Authority, the Investigator must inform Italfarmaco S.p.A. 
immediately that this request has been made. 


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8.5 
Handling of study medication 
All study medication will be supplied to the pharmacy of the Centre by Italfarmaco 
S.p.A. or its designee. Drug supplies must be kept in an appropriate, secure area and 
stored in accordance with the conditions specified on the drug labels. The investigator 
must maintain an accurate record of the shipment and dispensing of the IMP in the drug 
accountability form.  An accurate record of the date and amount of study drug dispensed 
to each patient must be available for inspection at any time. Copies of the drug 
accountability form will be provided to Italfarmaco S.p.A. by the investigator. 
All drug supplies are to be used only for this protocol and not for any other 
purpose. The investigator must not destroy any partly-used or unused drug supply 
without authorization from Italfarmaco S.p.A.. At the conclusion of the study, and, as 
appropriate during the course of the study, the investigator will return all used and 
unused drug containers to Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica,  
Viale Fulvio Testi, 330, 20126 Milan (MI), Italy or their designee (e.g. CMO), and a 
copy of the completed IMP accountability form to the Italfarmaco S.p.A. monitor.  
8.6 
 Ownership of data, disclosure and confidentiality 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the sponsor, patients should not be identified by their names, but by an 
identification code. The investigator should keep an enrolment log showing codes, 
names and addresses. 
By signing the protocol, the Investigator agrees to keep all information provided by 
Italfarmaco S.p.A. in strict confidence and to request similar confidentiality from 
his/her staff and the IRB/ECs. Study documents provided by Italfarmaco S.p.A. 
(protocols, investigators' brochures, CRFs and other material) will be stored 
appropriately to ensure their confidentiality. The information provided by Italfarmaco 
S.p.A. to the Investigator may not be disclosed to others without direct written 
authorization from Italfarmaco S.p.A., except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial.  
Italfarmaco S.p.A assures that the key design items of the Protocol will be published in 
a publicly accessible database such as “Clinicaltrials.gov”. Moreover, upon completion 
of the Study and finalization of the Study report, the Results of these study will be 
submitted for publication or posted in a publicly accessible data base.  
By signing the protocol, the investigators and their co-workers accept to submit any 
intended communication (abstract, paper or oral presentation) to Italfarmaco S.p.A. 
reasonably in advance (at least 30 working days for an abstract or oral presentation and 
60 working days for a manuscript). This is to allow Italfarmaco S.p.A. to review the 
communications for accuracy and confidentiality, to provide any relevant 
supplementary information and to allow establishment of co-authorship and in no way 


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has to be intended as a restriction of the sponsor to the investigators’ right to publish the 
results of the study. In case Italfarmaco S.p.A. identifies specific need/opportunity to 
patent any of the study findings, the Investigator will allow a six month time-window 
between his submission to Italfarmaco S.p.A. and the intended publication and actual 
submission/communication to third parties, in order to allow Italfarmaco S.p.A. to 
undertake appropriate patenting steps.  
8.7 
Study discontinuation 
Italfarmaco S.p.A. has the right to terminate this study at any time. Reasons for 
terminating the study may include the following:
•
unsatisfactory patient enrolment;  
•
inaccurate or incomplete quality or quantity of data recording;
•
incidence or severity of adverse drug reactions in this or other studies with 
Givinostat indicating a potential health hazard to patients;
•
poor adherence to protocol and regulatory requirements;
•
plans to modify or discontinue the development of the study drug.


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9. 
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monotherapy, 
Poster 
at 
ASH 
2011, 
Session 
Name: 
634.Myeloproliferative Syndromes, Publication N.: 1748, Submission ID: 
40637, ClinicalTrial.gov Identifier: NCT00928707. 
24. Scherber et al., The Myeloproliferative Neoplasm Symptom Assessment Form 
(MPN-SAF): International Prospective Validation and Reliability Trial in 402 
patients, Blood, 2011 July 14; 118(2): 401-408. 
25. Le Tourneau C, Lee JJ, Siu LL, Dose Escalation Methods in Phase I Cancer 
Clinical Trials, JNCI, 2009 May 20; 101(10): 708–720. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 124 of 142 
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26. Rubinstein LV and Simon RM, Phase I clinical trial design, In Budman, 
Calvert, Rowinsky, (eds.), Handbook of Anticancer Drug Development, 
Elsevier, Amsterdam, 297-308, 2003.  
27. Omura GA, Modified Fibonacci Search, J. Clin. Oncol., 2003 August 15; 
21(16): 3177 – 3177. 
28. Oken M.M., Creech R.H., Tormey DC et al., Toxicity and response Criteria of 
the eastern cooperative oncology group, Am. J. Clin. Oncol. 1982; 5: 649-655. 
29. Barosi G, Bordessoule D, Briere J et al., Response criteria for myelofibrosis with 
myeloid metaplasia: results of an initiative of the European Myelofibrosis 
Network (EUMNET), Blood 2005; 106: 2849-53. 
30. Simon R., Optimal two-stage designs for phase II clinical trials, Controlled 
Clinical Trials, 1989; 10: 1-10. 
31. Lippert E., Girodon F., Hammond E., et al.: Concordance of assays designed for 
the quantification of JAK2V617F: a multicenter study, Haematologica 2008; 94: 8-
45. 
32. Emanuel R.M., Dueck A.C., Geyer H.L. et al.: Myeloproliferative neoplasm 
(MPN) symptom assessment form total symptom score: prospective international 
assessment of an abbreviated symptom burden scoring system among patients 
with MPNs, JCO November 20, 2012; 30 (33): 4098-4103. 
33. Barosi G., Mesa R., Finazzi G. et al.: Revised response criteria for polycythemia 
vera and essential thrombocythemia: a ELN and IWG-MRT consensus project, 
Blood, 2013 June 6; 121(23): 4778-81. 
34. Daniel J. De Angelo D. J.,1 Mesa R. A., Fiskus W., Tefferi A. et al.: Phase II 
trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary 
myelofibrosis, post–essential thrombocythaemia, and post–polycythaemia vera 
myelofibrosis, British Journal of Haematology, 2013 August;162(3):326-35.  


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
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10. 
APPENDICES 
Appendix A: Flow-chart  
Appendix B:  ECOG performance status table 
Appendix C:  Drugs at risk of causing TdP 
Appendix D:  Bazett’s correction formula 
Appendix E: JAK2V617F genotyping and quantification in granulocytes 
Appendix F: Conversion Formula (from Urea to BUN) 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
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10.1 Appendix A: Flow-chart 
10.1.1 Flow-chart of Part A 
10.1.1.1 Flow-chart of Cycle 1
Cycle Description 
Screening 
Cycle 1 
Cycle Day 
-28 to 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 
28 
EOS11
Treatment phase 
Pre-dose 
Pre-
dose 
Post-
dose 
TREATMENT 
Window 
± 7 days 
Not applicable 
± 3 days 
Visit at the 
investigational site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent Form 
signature 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
(drugs) 
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug therapies (e.g. 
phlebotomies, 
transfusions) 
X
X
X
X
X
X
X
X
X
X
X
X
Medical history 
X
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
vital signs (blood pressure, 
pulse rate, respiratory 
rate), height, weight, body 
temperature and ECOG 
performance status1
X
 
 
X
 
 
X
X
X
X
X
Physical examination, 
weight, body temperature 
and ECOG performance 
status 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood 
pressure, pulse rate, 
respiratory rate)  
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood 
pressure, pulse rate, 
respiratory rate) 4 hours 
after the first Givinostat 
dose
 
X 
 
 
 
 
 
 
 
 
 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
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Cycle Description 
Screening 
Cycle 1 
Cycle Day 
-28 to 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 
28 
EOS11
Treatment phase 
Pre-dose 
Pre-
dose 
Post-
dose 
TREATMENT 
Window 
± 7 days 
Not applicable 
± 3 days 
Visit at the 
investigational site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (if 
indicated) 2
X
 
 
 
 
 
 
 
 
 
 
 
Blood chemistry3
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
ECG, QTc determination 
(according with Bazett’s 
correction formula)  3 
hours after the first 
Givinostat dose12
 
X 
 
 
 
 
 
 
 
 
 
ECG, QTc determination 
(according with Bazett’s 
correction formula)12
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Urinalysis4
X 
 
 
 
 
 
 
 
 
 
X 
X 
Haematology5
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
PD sample collection*
 
X 
 
 
 
 
 
 
 
 
 
 
PD sample collection 12 
hours after the first 
Givinostat dose  *
 
 
X 
 
 
 
 
 
 
 
 
 

ǡ



͸ǡ*

X 
X 







X 

Spleen evaluation (by 
MRI or CT scan)7
X 
 
 
 
 
 
 
 
 
 
 
X 
Therapeutic response 
evaluation 8
 
 
 
 
 
 
 
 
 
 
 
X 
Collection of a blood 
sample for the quantitative 
RT-PCR evaluation of 
JAK2V617F mutational 
status on peripheral blood 
(PB) granulocyte* 
X 
 
 
 
 
 
 
 
 
 
 
 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 128 of 142 
Confidential
Cycle Description 
Screening 
Cycle 1 
Cycle Day 
-28 to 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 
28 
EOS11
Treatment phase 
Pre-dose 
Pre-
dose 
Post-
dose 
TREATMENT 
Window 
± 7 days 
Not applicable 
± 3 days 
Visit at the 
investigational site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of disease-
related symptoms using 
the MPN-SAF QOL 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
X 
Request of enrolment and 
receipt of patient ID 
X 
 
 
 
 
 
 
 
 
 
 
 
First Givinostat dose and 
accountability 
 
 
X 
 
 
 
 
 
 
 
 
 
Givinostat administration 
and accountability9
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Used/unused/partially 
used Givinostat supply 
return from patient(s) and 
Givinostat accountability10
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1   Height will be measured at the pre-treatment evaluations only.  
 Patients must have an ECOG  1  within 7 days of initiating study drug. 
2 Pregnancy test has to be performed within 72 hours before the first Givinostat dose. The test can be 
performed by urine or serum pregnancy test. In case of a  borderline-positive urine pregnancy test, this 
must be confirmed with a serum pregnancy test.
3 Blood Chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or Urea 
(according with the site-specific clinical practice), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation). 
4 Urinalysis: pH, specific gravity, protein, glucose. 
5 Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and differential), PLT 
count. 
6 PK sample collection: as following summarize: 
- Day 1: pre-dose and 2, 3 and 8 hours post-dose; 
- Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose. 
Patients will not take the morning dose of Givinostat on the day selected for their timed PK  
assessments. Study drug will be administered in the clinic for these specific visits, in order to obtain 
pre- and/or post-dose plasma levels of Givinostat.  On all the other days corresponding to study visits, 
patients will take the morning dose of study drug prior to the visit. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 129 of 142 
Confidential
7 Spleen evaluation as per site-specific clinical practise: Patients with splenomegaly will be followed 
according to institutional guidelines (i.e. MRI or CT scan). The same imaging technique and the same 
instrument should be used on a patient throughout the study, if possible. No spleen evaluation will be 
performed in splenectomised patients. 
8 Therapeutic response evaluation: for PV and ET (if any), according with the clinico-haematological 
ELN response criteria [21] (see paragraph 4.6.1); for MF (if any), according with EUMNET response 
criteria. 
9 Givinostat administration: patients can take drug at home, except for the first drug administration. 
10 IMP: at study close-out, and as appropriate during the course of the study, the Investigator will 
return all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126, Milan (MI), 
Italy or their designee (e.g. CMO).  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed agreement 
between the investigational site and Italfarmaco S.p.A.), these materials can be destroyed locally. 
11 EOS: In case of the patient drops-out of the study, the end of Study (EOS) visit will be performed 7 
days after last drug intake. 
Note that, as reported in the paragraph 4.3.3, if the patient discontinues for any reason (including 
discontinuation for pregnancy), with drug related adverse event ongoing at study end, he/she must be 
followed until resolution or stabilization of the event or until it is reasonable to consider the event not 
drug related any more or until the start of a new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” should be 
indicated as the primary reason whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any patient 
permanently discontinuing study treatment. Should any drug-related AE still be ongoing beyond the last 
scheduled visit, this must be followed at subsequent follow-up visits until recovery. If a patient does not 
return for a scheduled visit, every effort should be made to contact the patient. In any circumstance 
every effort should be made to complete and report the observations as thoroughly as possible. All 
relevant information related to the reason for treatment discontinuation including contributory factors 
must be included on the CRF. 
12 ECG: If the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), 
two additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) 
must be performed. The averaged value of these three ECG evaluations has to be used for the evaluation 
of the QTc interval. In the CRF all the performed ECG evaluations have to be entered as well as the 
average value of multiple ECG evaluation, if necessary. 
* For all time points a blood sample will be collected as back-up sample. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 130 of 142 
Confidential
10.1.1.2 Flow-chart of Cycle 2 and beyond
Day 1 of 
each cycle
Day 28 of 
cycles 2, 4 
and 5 
Day 28 of 
cycles 3 and 6 
End of study visit 
(in case of completed 
study)
or 7 days after last drug 
intake (in case of the 
patient drops-out of the 
study)8
Treatment phase 
TREATMENT 
Window 
 
± 3 days 
Visit at the investigational site 
X
X
X
Adverse event recording  
 
X
X
X
Concomitant medications (drugs) 
 
X
X
X
Non-drug therapies (e.g. phlebotomies, 
transfusions) 
 
X
X
X
Physical examination, vital signs (blood 
pressure, pulse rate, respiratory rate),  
weight, body temperature and ECOG 
performance status 
 
X 
X 
X 
Blood chemistry1
 
X 
X 
X 
ECG, QTc determination (according with 
Bazett’s correction formula)9
 
X 
X 
X 
Haematology2
 
X 
X 
X 
PK sample collection and preparation, in 
order to allow to perform both the PK and 
PD evaluations starting from the same 
sample 3, *
 
X 
X 
 
Spleen evaluation (by MRI or CT scan)4
 
 
X 
X 
Therapeutic response evaluation5
 
 
X 
X 
Collection of a blood sample for the 
quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral 
blood (PB) granulocyte *
 
 
X 
X 
Assessment of disease-related symptoms 
using the MPN-SAF QOL Questionnaire 
 
 
X 
X 
Givinostat administration6
X 
X 
X10 
 
First Givinostat dose of the related cycle 
and accountability 
X 
 
 
 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 131 of 142 
Confidential
Day 1 of 
each cycle 
Day 28 of 
cycles 2, 4 
and 5 
Day 28 of 
cycles 3 and 6 
End of study visit 
(in case of completed 
study) 
or 7 days after last drug 
intake (in case of the 
patient drops-out of the 
study)8 
Treatment phase 
TREATMENT 
Window 
 
± 3 days 
Visit at the investigational site 
X
X
X
Used/unused/partially used Givinostat 
supply return from patient(s) and 
accountability7
 
X 
X 
X 
1 Blood Chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or Urea 
(according with the site-specific clinical practice), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation). 
2 Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and differential), PLT 
count.  
3 PK sample collection: pre-dose. Patients will not take the morning dose of Givinostat on the day 
selected for their timed PK  assessments. Study drug will be administered in the clinic for these specific 
visits, in order to obtain pre- and/or post-dose plasma levels of Givinostat.  On all the other days 
corresponding to study visits, patients will take the morning dose of study drug prior to the visit. 
4 Spleen evaluation as per site-specific clinical practise: Patients with splenomegaly will be followed 
according to institutional guidelines (i.e. MRI or CT scan). The same imaging technique and the same 
instrument should be used on a patient throughout the study, if possible. No spleen evaluation will be 
performed in splenectomised patients. 
5 Therapeutic response evaluation: for PV and ET (if any), according with the clinico-haematological 
ELN criteria [21] (see paragraph 4.6.1); for MF (if any), according with EUMNET response criteria. 
6 Givinostat administration: patients can take drug at home. 
7 IMP: at study close-out, and as appropriate during the course of the study, the Investigator will 
return all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126, Milan (MI), 
Italy or their designee (e.g. CMO). Only in some particular cases, after the authorization of  Italfarmaco 
S.p.A. (or after a signed agreement between the investigational site and Italfarmaco S.p.A.), these 
materials can be destroyed locally. 
8 EOS: as reported in the paragraph 4.3.3, if the patient discontinues for any reason (including 
discontinuation for pregnancy), with drug related adverse event ongoing at study end, he/she must be 
followed until resolution or stabilization of the event or until it is reasonable to consider the event not 
drug related any more or until the start of a new treatment, whichever occurs first.   
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” should be 
indicated as the primary reason whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any patient 
permanently discontinuing study treatment. Should any drug-related AE still be ongoing beyond the last 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 132 of 142 
Confidential
scheduled visit, this must be followed at subsequent follow-up visits until recovery. If a patient does not 
return for a scheduled visit, every effort should be made to contact the patient. In any circumstance 
every effort should be made to complete and report the observations as thoroughly as possible. All 
relevant information related to the reason for treatment discontinuation including contributory factors 
must be included on the CRF. 
Of note, in case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can be 
counted for the End of Study visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6) and she/he is eligible to continue the study drug treatment in the long-
term study (i.e. Study DSC/11/2357/44), the evaluation performed at the Cycle 6 Day 28 visit of this 
study can be also counted for the pre-treatment evaluations of the Study DSC/11/2357/44, provided that 
no difference in the evaluation is present between the two studies (e.g. haematological and biochemical 
evaluations). No additional Givinostat study (i.e. Study DSC/12/2357/45)-specific assumption has 
to be done at the completion of the Day 28 of Cycle 6. Indeed, in case the patient completes the study 
(i.e. performs all the evaluations requested to be done at the Day 28 of Cycle 6 of this study), she/he is 
eligible to continue the study drug treatment in the long-term study (i.e. Study DSC/11/2357/44) and 
she/he receive the written authorization of the treatment from the Sponsor of their designee (i.e. a 
patient’s confirmation form that includes the patient ID to use into the Study DSC/11/2357/44), the 
patient will continue the study drug treatment into the Study DSC/11/2357/44, receiving the study (i.e. 
Study DSC/11/2357/44)-specific drug to be taken. 
9 ECG: If the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), 
two additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) 
must be performed. The averaged value of these three ECG evaluations has to be used for the evaluation 
of the QTc interval. In the CRF all the performed ECG evaluations have to be entered as well as the 
average value of multiple ECG evaluation, if necessary. 
10 Givinostat administration: Only for cycle 3. 
* For all time points a blood sample will be collected as back-up sample. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 133 of 142 
Confidential
10.1.2 Flow-chart of Part B 
Pre-treatment 
evaluations*** 
(up to 4 weeks:  
-28 to Day -1) 
Day 1 of the first 
Cycle***
Day 28 of 
Cycles 1, 2, 
4 and 5***
Day 28 
of  
Cycles 3 
and 6***
End of study visit  
(in case of completed 
study)  
or 7 days after last drug 
intake (in case of the 
patient drops-out of the 
study)11, ***
Treatment phase 
Pre-dose 
Pre-dose 
Post-dose 
TREATMENT 
Windows 
± 7 days 
Not applicable 
± 3 days 
Visit at the investigational site 
X 
X 
X 
X
X
X
Informed Consent Form 
signature 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Adverse event recording  
X
X 
X 
X
X
X
Concomitant medications 
(drugs) 
X
X 
X 
X
X
X
Non-drug therapies (e.g. 
phlebotomies, transfusions) 
X
X 
X 
X
X
X
Medical history 
X
 
 
 
 
 
Physical examination, vital 
signs (blood pressure, pulse 
rate, respiratory rate), height, 
weight, body temperature and 
ECOG performance status1
X
 
 
X 
X 
X 
Pregnancy test (if indicated) 2
X
 
 
 
 
 
Blood chemistry3
X
 
 
X 
X 
X 
ECG, QTc determination 
(according with Bazett’s 
correction formula)12
X
 
 
X 
X 
X 
Urinalysis4
X 
 
 
 
 
 
Haematology5
X
 
 
X 
X 
X 
PD sample collection before the 
first Givinostat dose *
 
X 
 
 
 
 
PD sample collection 12 hours 
after the first Givinostat dose *  
 
 
X 
 
 
 
PK sample collection6, *
and preparation, in order to 
allow to perform both the PK 
and PD evaluations starting 
from the same sample (if 
requested)
 
X 
X 
X 
 
 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 134 of 142 
Confidential
Pre-treatment 
evaluations  
(up to 4 weeks:  
-28 to  
Day -1)***
Day 1 of the first 
Cycle***
Day 28 of 
Cycles 1, 2, 
4 and 5 
Day 28 
of  
Cycles 3 
and 6 
End of study visit  
(in case of completed 
study)  
or 7 days after last drug 
intake (in case of the 
patient drops-out of the 
study)11
Treatment phase 
Pre-dose 
Pre-dose 
Post-dose 
TREATMENT 
Windows 
± 7 days 
Not applicable 
± 3 days 
Visit at the investigational site 
X 
X 
X 
X
X
X
Spleen evaluation (by MRI or 
CT scan)7
X 
 
 
 
X 
X 
Collection of blood sample for 
quantitative RT-PCR evaluation 
of JAK2V617F mutational status 
on peripheral blood (PB) 
granulocyte *
X 
 
 
X 
X 
X 
Assessment of disease-related 
symptoms using the MPN-SAF 
QOL Questionnaire [24, 32] 
X 
 
 
 
X 
X 
Bone marrow histological 
evaluation in order to assess the 
presence of age adjusted 
normocellularity and/or trilinear 
hyperplasiaA
X 
 
 
 
XB 
XC
Therapeutic response 
evaluation8
 
 
 
 
X 
X 
Request of enrolment and 
receipt of patient ID 
X 
 
 
 
 
 
Givinostat administration9
 
 
 
X 
X** 
 
First Givinostat dose and 
accountability 
 
 
X 
 
 
 
Used/unused/partially used 
Givinostat supply return from 
patient(s) and accountability10
 
 
 
X 
X 
X 
1   Height will be measured at the pre-treatment evaluations only.  
Patients must have an ECOG  2, within 7 days of initiating study drug. 
2 Pregnancy test has to be performed within 72 hours before the first Givinostat dose. The test can be 
performed by urine or serum pregnancy test. In case of a positive or borderline-positive urine pregnancy 
test, this must be confirmed with a serum pregnancy test.
3 Blood Chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or Urea 
(according with the site-specific clinical practice), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR 
determination (according with the Mayo Clinic Quadratic Equation). 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27
Clinical Study Protocol 
Version 3.0 – 29th July 2015 
SOP 2 final version12.09 
 
Page 135 of 142 
Confidential
4 Urinalysis: pH, specific gravity, protein, glucose. 
5 Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and differential), PLT 
count. 
6 PK sample collection: as following summarize: 
- Day 1 of Cycle 1: pre-dose and 2, 3 and 8 hours post-dose; 
- Day 28 only of Cycle 2: pre-dose and 1, 2, 4 and 8 hours post-dose. 
Patients will not take the morning dose of Givinostat on the day selected for their timed PK  
assessments. Study drug will be administered in the clinic for these specific visits, in order to obtain 
pre- and/or post-dose plasma levels of Givinostat.  On all the other days corresponding to study visits, 
patients will take the morning dose of study drug prior to the visit. 
7 Spleen evaluation as per site-specific clinical practise: The spleen evaluation will be performed during 
the study according to institutional guidelines and site-specific clinical practice (i.e. MRI or CT scan). 
The same imaging technique and the same instrument should be used on a patient throughout the study, 
if possible. No spleen evaluation will be performed in splenectomised patients.
8 Therapeutic response evaluation: both according with the clinico-haematological ELN criteria [21] (see 
paragraph 4.6.1) (both at cycle 3 and at cycle 6) and according with the “new” ELN criteria (i.e. 
revised ELN response criteria) [33] (see paragraph 4.8.7) (only at cycle 6).  
9 Givinostat administration: patients can take drug at home, except for the first drug administration. 
10 IMP: at study close-out, and as appropriate during the course of the study, the Investigator will 
return all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126 Milan (MI), 
Italy or their designee (e.g. CMO).  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed agreement 
between the investigational site and Italfarmaco S.p.A.), these materials can be destroyed locally. 
11 EOS: as reported in the paragraph 4.3.3, if the patient discontinues for any reason (including 
discontinuation for pregnancy), with drug related adverse event ongoing at study end, he/she must be 
followed until resolution or stabilization of the event or until it is reasonable to consider the event not 
drug related any more or until the start of a new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” should be 
indicated as the primary reason whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any patient 
permanently discontinuing study treatment. Should any drug-related AE still be ongoing beyond the last 
scheduled visit, this must be followed at subsequent follow-up visits until recovery. If a patient does not 
return for a scheduled visit, every effort should be made to contact the patient. In any circumstance 
every effort should be made to complete and report the observations as thoroughly as possible. All 
relevant information related to the reason for treatment discontinuation including contributory factors 
must be included on the CRF. 
Of note, in case the patient completes the study (i.e. performs all the evaluations requested to be done at 
the Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can be counted for the End 
of Study visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6) and she/he is eligible to continue the study drug treatment in the long-
term study (i.e. Study DSC/11/2357/44), the evaluation performed at the Cycle 6 Day 28 visit of this 
study can be also counted for the pre-treatment evaluations of the Study DSC/11/2357/44, provided that 
no difference in the evaluation is present between the two studies (e.g. haematological and biochemical 


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                                 Study N.:       DSC/12/2357/45
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evaluations). No additional Givinostat study (i.e. Study DSC/12/2357/45)-specific assumption has 
to be done at the completion of the Day 28 of Cycle 6. Indeed, in case the patient completes the study 
(i.e. performs all the evaluations requested to be done at the Day 28 of Cycle 6 of this study), she/he is 
eligible to continue the study drug treatment in the long-term study (i.e. Study DSC/11/2357/44) and 
she/he receive the written authorization of the treatment from the Sponsor of their designee (i.e. a 
patient’s confirmation form that includes the patient ID to use into the Study DSC/11/2357/44), the 
patient will continue the study drug treatment into the Study DSC/11/2357/44, receiving the study (i.e. 
Study DSC/11/2357/44)-specific drug to be taken. 
12 ECG: If the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), 
two additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) 
must be performed. The averaged value of these three ECG evaluations has to be used for the evaluation 
of the QTc interval. In the CRF all the performed ECG evaluations have to be entered as well as the 
average value of multiple ECG evaluation, if necessary. 
* For all time points a blood sample will be collected as back-up sample. 
**  Only for cycle 3. 
*** Patients should be told to arrive after an overnight fast of at least 8 hours at all study visits that 
request a blood test.  However, the study visits should still be conducted even if the patient does not 
adhere to fasting requirements and this will not be considered a protocol violation. In these cases, this 
information (i.e. not fasting condition) has to be noted by the Investigator in the medical chart and 
reported in CRF, in order to avoid any misunderstanding of the collected data (e.g. glucose value is 
influenced by fasting/not fasting conditions).   
A Please note that, in case the patient performs the bone marrow histological evaluation as requested by 
the “new” ELN criteria (i.e. the revised ELN response criteria) [33] (see paragraph 4.8.7) – i.e. bone 
marrow evolution including the assessment of the presence of age adjusted normocellularity and/or 
trilinear hyperplasia - 1 month before the study start (i.e the signature of the Informed Consent Form), 
this examination has not to be repeated for this study in order to limit the discomfort for the patient. In 
any case, the results of this test will be transcribed into the CRF and the original signed and dated 
laboratory print-out/tracings, including the assessment of the presence of age adjusted normocellularity 
and/or trilinear hyperplasia, will be monitored and stored at the study site.  
Finally, in case the patient refuses to provide this written consent to perform the bone marrow 
evaluation, this patient can be anyway recruited in Part B. However, this patient will not be counted to 
assess the related exploratory endpoints (i.e. overall response rate of Givinostat at the MTD after 6 
cycles according to the revised ELN response criteria [33], and the evaluation of the effect of Givinostat 
on each single response parameter according to the revised ELN response criteria [33]).   
B Only for cycle 6.
C In case the patient drops-out the study during the first 3 Cycles (i.e. before the Day 28 of Cycle 3) , this 
evaluation has not to be performed at End of Study visit.


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10.2 Appendix B: ECOG Performance Status* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol (1982). 


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10.3 Appendix C: Drugs at risk of causing TdP 
Drugs that are generally accepted by the Scientific Advisory Board of the AZCERT to 
have a risk of causing Torsades de Pointes. 
Generic Name
List 
Amiodarone  
Anti-arrhythmic / abnormal heart rhythm
Amiodarone 
Anti-arrhythmic / abnormal heart rhythm 
Arsenic trioxide 
Anti-cancer / Leukemia 
Astemizole 
Antihistamine / Allergic rhinitis 
Azithromycin
Antibiotic / bacterial infection 
Bepridil 
Anti-anginal / heart pain 
Chloroquine
Anti-malarial / malaria infection 
Chlorpromazine 
Anti-psychotic/ Anti-emetic / schizophrenia/ nausea
Cisapride
GI stimulant / heartburn 
Citalopram
Anti-depressant / depression 
Clarithromycin
Antibiotic / bacterial infection 
Disopyramide 
Anti-arrhythmic / abnormal heart rhythm 
Dofetilide 
Anti-arrhythmic / abnormal heart rhythm 
Domperidone
Anti-nausea / nausea 
Droperidol 
Sedative;Anti-nausea / anesthesia adjunct, nausea 
Erythromycin 
Antibiotic;GI stimulant / bacterial infection; increase GI motility 
Erythromycin 
Antibiotic;GI stimulant / bacterial infection; increase GI motility 
Flecainide
Anti-arrhythmic / abnormal heart rhythm 
Halofantrine 
Anti-malarial / malaria infection 
Haloperidol 
Anti-psychotic / schizophrenia, agitation 
Ibutilide
Anti-arrhythmic / abnormal heart rhythm 
Levomethadyl
Opiate agonist / pain control, narcotic dependence 
Mesoridazine
Anti-psychotic / schizophrenia 
Methadone
Opiate agonist / pain control, narcotic dependence 
Methadone
Opiate agonist / pain control, narcotic dependence 
Moxifloxacin 
Antibiotic / bacterial infection 
Pentamidine 
Anti-infective / pneumocystis pneumonia 
Pentamidine 
Anti-infective / pneumocystis pneumonia 
Pimozide
Anti-psychotic / Tourette's tics 
Probucol
Antilipemic / Hypercholesterolemia 
Procainamide 
Anti-arrhythmic / abnormal heart rhythm 
Procainamide 
Anti-arrhythmic / abnormal heart rhythm 


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Quinidine
Anti-arrhythmic / abnormal heart rhythm 
Quinidine
Anti-arrhythmic / abnormal heart rhythm 
Sotalol 
Anti-arrhythmic / abnormal heart rhythm 
Sparfloxacin 
Antibiotic / bacterial infection 
Terfenadine
Antihistamine / Allergic rhinitis 
Thioridazine
Anti-psychotic / schizophrenia 
Vandetanib
Anti-cancer / Thyroid cancer 
Source: www.azcert.org/medical-pros/drug-lists/pubMed-drug-list.cfm
Revised: 17/05/2012 
Arizona Center for Education and Research on Therapeutics (AZCERT) 
The Critical Path Institute
Tucson, Arizona and Rockville, Maryland 


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10.4 Appendix D: Bazett’s correction formula 
BAZETT’S CORRECTION FORMULA 
QTc= QT/ RR0.5 
RR = interval from the onset of one QRS complex to the onset of the next QRS 
complex, measured in seconds.  


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10.5 Appendix E: JAK2V617F genotyping and quantification in 
granulocytes
JAK2V617F genotyping and quantification will be performed in Part A at the screening, 
at Day 28 of Cycle 3, at Day 28 of Cycle 6 and at the end of study, and in Part B at the 
screening, at Day 28 of each Cycle (i.e. Day 28 of the Cycles 1, 2, 3, 4, 5 and 6) and at 
the end of study. A sample of peripheral blood in EDTA (20 mL) will be obtained, and 
either granulocyte are separated in the same institution up to the freezing of a 
granulocyte pellet, or the blood sample is sent the same day with an O/N courier to the 
Central Laboratory. Granulocytes are prepared from peripheral blood (PB) samples 
using density-gradient centrifugation and residual erythrocyte lyses; granulocytes are 
frozen as a pellet. Frozen pellets from different patients can be sent in blocks to the 
Central Laboratory in dry ice. DNA is extracted using solid-phase extraction. The 
presence and the mutation, and the allelic burden, are evaluated in triplicate in each 
sample, using a quantitative real-time PCR (RT-PCR) technique and standard curve 
with plasmids available the Central Laboratory [31]. 


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10.6 Appendix F: Conversion formula (from Urea to BUN) 
CONVERSION FORMULA (FROM UREA TO BUN) 
BUN (mg/dL) = [Urea (mg/dL)] / 2.14 


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                                 Study N.:       DSC/12/2357/45
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Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
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STUDY N.: DSC/12/2357/45 
EUDRACT N.:  2013-000860-27 
A two-part study to assess the safety and preliminary efficacy of 
Givinostat in patients with JAK2V617F positive Polycythemia Vera
Document type: 
Amendment 2 
Development Phase: 
Phase Ib/II 
Document status: 
Version 1.0 
Release: 29th July 2015 
Sponsor:
ITALFARMACO S.p.A. 
Via dei Lavoratori, 54
20092 Cinisello Balsamo (MI), Italy
Tel.: 
  
Fax: 
Property of Italfarmaco 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Italfarmaco   
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                                 Study N.:       DSC/12/2357/45
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AMENDMENT 2 RATIONALE 
The clinical study protocol DSC/12/2357/45 version 2.0 (including Amendment 1, version 1.0, 
23rd July 2013) has been amended for the following reasons: 
•
To update the safety sections according to the current notification of SAE Form (i.e. by 
eCRF), Adverse Events definition  and the details of the Drug Safety Unit. 
•
To amend some wording in the preclinical rationale (paragraph 1.3) based on the most 
updated information. 
•
To update the approved drugs for the treatment of Polycythemia Vera and Myelofibrosis, 
based on the current data. 
•
To add the neuromuscular disorders in the indications explored with Givinostat. 
•
To clarify that is necessary that the long-term study (Study N.: DSC/11/2357/44) has 
already received all necessary approvals in that specific country and site, and that the 
study was initiated in that particular site, in order to allow patients achieving clinical 
benefit to continue treatment with Givinostat (at the same dose and schedule) after 
completion of the study DSC/12/2357/45. 
•
To update the sections related to Part B, based on the definition of the MTD of 
Givinostat as chronic treatment in Polycythemia Vera patients, now available.  
Of note, on July 2015 the tolerability data related to the patients enrolled in Part A – i.e. 
the six patients treated at the Dose Level 1 (i.e. 100 mg b.i.d., hereinafter “DL1”) and 3 
patients treated at the Intermediate Dose Level (i.e. 150 mg/die, also defined “DL6”) - 
have been considered in order to define the MTD of Givinostat as chronic treatment in 
Polycythemia Vera patients.  
Even if only one DLT was observed in the 6 patients treated at DL1 during the first cycle 
of treatment (i.e. a  “grade  3 non-haematological toxicity” (dyspepsia), judged “drug-
related” by the Investigator) and the escalation at higher Dose Levels could be possible, 
the study team agreed unanimously to consider the DL1 (i.e. 100 mg b.i.d.) as MTD of 
Givinostat to be used in Part B as chronic treatment in PV patients, considering the 
following points: 
-
Givinostat is a chronic treatment for PV patients in the current schedule; 
-
The observed PLTs decrease; 


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                                 Study N.:       DSC/12/2357/45
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-
The knowledge of the safety profile of HDACi and, in particular, of Givinostat (i.e. 
thrombocythopenia is a side-effect); 
-
It could be preferable/ethical to avoid to expose 3 patients to the higher dosage (i.e. 
150 mg b.i.d., DL2) that, as above reported, will be reasonably untollerated by the 
patients. 
Therefore, the dosage to use in Part B as established in Part A by the study team, i.e. 100 
mg b.i.d., is the MTD of Givinostat defined taking into account the chronic schedule of 
the study drug as prescribed in this current study.   
•
To update the dose modification rules to be applied in Part B and in Part A for patients 
who may be allowed to escalate their Givinostat dose up to the MTD for the remainder of 
the study (Part A) at the discretion of the Investigator and Sponsor. 
The dose modifications rules to be applied in Part B have been updated based on the data 
related to the patients enrolled in Part A of this study and to the results obtained in 
previous studies with Givinostat on chronic myeloproliferative neoplasms. The objective 
of the updated Givinostat dose adjustments rules are to optimize the response for each 
individual patient, avoiding specific drug-related toxicities. Therefore, dose reductions or 
interruptions are mandated for specific toxicities and dose increases after an initial dose 
reduction are allowed in case of inadequate efficacy at the reduced dosage in absence of 
specific toxicities.  
Of note, the same dose modification criteria may be followed also by patients initially 
dosed at lower dose levels in Part A that, after the definition of MTD, are allowed to 
escalate their Givinostat dose at MTD for the remainder part of the study (Part A) at the 
discretion of the Investigator and Sponsor.    
•
To add the Contract Manufacturing Organization as possible delegate for the 
management of the study drug (e.g. secondary packaging, distribution to the sites). 
•
To clarify the meaning of “any other investigational drug or device” (i.e. exclusion 
criterion n. 19).  
•
To add the strength of 75 mg. 
•
To add some clarifications in the instructions related to the study administration and 
dispensing. 
•
To add pharmacodynamic evaluations that will be performed using an aliquot of the PK 
samples. 


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                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
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•
To specify the calculation of eGFR (i.e. a derived biochemical parameter) according with 
the Mayo Clinic Quadratic Equation, as agreed with the German Regulatory Authority. 
•
To clarify that it is allowed the evaluation of Urea (in spite of BUN) according with the 
the site-specific clinical practice. 
•
To add the recommendation to perform two additional ECG evaluations over a brief 
period (i.e. 5 minutes between each recording), if the first ECG evaluation demonstrates a 
prolonged QTc interval (i.e. a QTc interval  450 msec). 
•
To clarify that no spleen evaluation will be performed in splenectomised patients, while 
the spleen evaluation is requested in all other patients in Part B, since the presence of 
splenomegaly is one of the parameter to evaluate as per primary objectives of Part B (i.e. 
according to the ELN response criteria). 
•
To specify that in Part B it is recommended that patients should be told to arrive after an 
overnight fast of at least 8 hours at all study visits that request a blood test. 
•
To add the collection of a blood sample for the quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral blood (PB) granulocyte at the following visits 
of Part B: Day 28 of Cycles 1, 2, 4 and 5. 
•
To clarify that, in case the patient completes the study (i.e. performs all the evaluations 
requested to be done at the Day 28 of Cycle 6), the evaluation performed at the Cycle 6 
Day 28 visit can be also counted for the End of Study visit. 
•
To specify that, in case the patient completes the study (i.e. performs all the evaluations 
requested to be done at the Day 28 of Cycle 6) and she/he is eligible to continue the study 
drug treatment in the long-term study (i.e. Study DSC/11/2357/44), the evaluation 
performed at the Cycle 6 Day 28 visit of this study can be also counted for the pre-
treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluation is present between the two studies (e.g. haematological and biochemical 
evaluations).  
•
To clarify that all efficacy analyses will be conducted on this population and will be 
based on the effective DL/daily doses of Givinostat at which each patient has been 
treated. 


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                                 Study N.:       DSC/12/2357/45
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Version 1.0  – 29th  July 2015 
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Further to what is reported above, with the present amendment some typographic mistakes 
existing in the clinical study protocol version 2.0 (including Amendment 1, version 1.0, 23rd July 
2013) have been put right. In addition, with the present amendment some sentences existing in 
the clinical study protocol version 2.0 (including Amendment 1, version 1.0, 23rd July 2013) 
have been clarified in order to better detail the right procedures to be followed. 
AMENDMENT 2 SUMMARY OF CHANGES 
Substantive additions to the protocol are denoted in bold. Substantive deletions are in 
strikethrough. 
EMERGENCY SAFETY PROCEDURES 
Any SAE (see chapter “Adverse Events” for definition and details), that occurs after a patient has 
signed the Informed Consent Form and up to the follow-up visit (regardless of relationship to 
study drug) must be reported by the Investigators to Italfarmaco S.p.A. within 24 hours of 
learning of its occurrence. 
Related SAEs MUST be collected and reported even if the study has been closed.  
The Investigator must notify the SAE to the Italfarmaco S.p.A. Drug Safety Unit (hereinafter 
“DSU”) of Italfarmaco S.p.A. by sendingfaxing the SAE fForm, according with the 
procedures described in the study manual and within 24 hours of learning of its occurrence. 
The details of the DSU are specified below:a SAE, at the number specified below; then, the 
Investigator must confirm any SAE notifications by mailing to the mail address or phoning to the 
phone number specified below: 
 
 
 
Italfarmaco S.p.A.  
  
Drug Safety Unit  
Italfarmaco S.p.A.  
Via dei Lavoratori, 54  
20092 Cinisello Balsamo (MI), Italy  
Phone:  
 
Fax:   
 
Fax (back-up): 
mMobile:  
 
e-mail:  
 
mobile  
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                                 Study N.:       DSC/12/2357/45
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GLOSSARY OF ABBREVIATIONS 
… 
 
CRF 
Case Report Form 
CRO 
CMO 
Contract Research Organization 
Contact Manufacturing Organization 
CT 
Computerized Tomography 
CTCAE 
DSU 
Common Terminology Criteria for AE 
Drug Safety Unit 
… 
STUDY SYNOPSIS 
STUDY TITLE 
A two-part study to assess the safety and preliminary efficacy of 
Givinostat in patients with JAK2V617F positive Polycythemia Vera. 
STUDY NUMBER  
DSC/12/2357/45 
EUDRACT No. 
2013-000860-27 
STUDY TYPE 
International  
CLINICAL PHASE 
Ib/II 
DISEASE 
Patients with JAK2 positive chronic myeloproliferative neoplasms 
(cMPN), particularly Polycythemia Vera (PV). 
STUDY RATIONALE 
In recent years several reports have documented that histone 
deacetylases (HDACs) inhibitors induce neoplastic cells to undergo 
growth arrest, differentiation and/or apoptotic cell death.  
Among these agents, Givinostat (ITF2357) has most recently 
demonstrated effects on haematological parameters as well as 
constitutional parameters in patients with PV.  
Preliminary signs of clinical activity in patients with JAK2 mutant 
cMPN, have been observed in two studies with Givinostat (Studies N. 
DSC/07/2357/28 and DSC/08/2357/38). In these studies, the maximum 
administered dose of Givinostat was 150 mg per day which was 
generally well tolerated. Assuming a linear relationship between dose 
and efficacy, greater clinical efficacy can be expected with increased 


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                                 Study N.:       DSC/12/2357/45
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doses of Givinostat. 
Since the MTD of Givinostat has not been defined previously, the first 
aim of the current study is, therefore, to determine the maximum 
tolerated dose of Givinostat in patients with PV. This study will 
investigate the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) activity of Givinostat monotherapy. As such, 
the study will characterize Dose Limiting Toxicities (DLTs) and 
Maximum Tolerated Dose (MTD) of Givinostat.  
The second aim of this study is to characterize the clinical efficacy of 
Givinostat at the MTD. 
PRIMARY OBJECTIVES Part A 
•
To characterize the safety, tolerability and MTD of Givinostat 
in patients with PV.  
Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD 
after 3 cycles according to the clinico-haematological European 
LeukemiaNet (ELN) response criteria. 
•
To determine the safety and tolerability of Givinostat at the 
MTD after 3 cycles. 
SECONDARY 
OBJECTIVES 
Part A 
•
To evaluate the preliminary efficacy of Givinostat after 3 and 6  
cycles of treatment according to the clinico-haematological 
ELN response criteria. 
•
To characterize PK. 
Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD 
after 6 cycles according to the clinico-haematological ELN 
response criteria. 
•
To determine the safety and tolerability of Givinostat at the 
MTD after 6 cycles. 
•
To characterize PK. 
EXPLORATORY 
OBJECTIVES 
Parts A and B  
•
To evaluate the effect of Givinostat on single parameters of the 
clinico-haematological ELN response criteria. 
•
To evaluate the effects of Givinostat on PD markers. 
•
To evaluate the effects of Givinostat on spleen size (by MRI or 
CT scan) in patients with confirmed splenomegaly at baseline. 


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•
To evaluate the effects of Givinostat on disease-related quality 
of life. 
•
To evaluate the effect of Givinostat on JAK2V617F allele burden. 
•
To evaluate the reduction of the symptomatic treatment of 
pruritus. 
Part B  
•
To evaluate the preliminary efficacy of Givinostat after 6  
cycles of treatment according to the “new” ELN response 
criteria (i.e. the revised ELN response criteria). 
•
To evaluate the effect of Givinostat on single parameters of the 
the “new” ELN response criteria (i.e. the revised ELN response 
criteria). 
PRIMARY ENDPOINTS 
Part A 
•
Safety and tolerability evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse 
events, graded according to Common Terminology Criteria 
for Adverse Events (CTCAE v. 4.03, 14th June 2010). 
•
Determination of the MTD of Givinostat based on cycle 1 
DLT’s. 
Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial 
Response (PR) - of Givinostat at the MTD after 3 cycles; the 
response will be evaluated according to the clinico-
haematological ELN response criteria. 
•
Safety and tolerability of Givinostat at the MTD  after 3 cycles
evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse 
events, graded according to CTCAE v. 4.03. 
SECONDARY 
ENDPOINTS 
Part A 
•
Overall response rate - i.e. Complete Response (CR) and Partial 
Response (PR) - of Givinostat at the MTD after 3 and 6 cycles; 
the response will be evaluated according to the clinico-
haematological ELN response criteria. 


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•
Individual Givinostat concentrations tabulated by dose cohort 
along with descriptive statistics. 
Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial 
Response (PR) - of Givinostat at the MTD after 6 cycles; the 
response will be evaluated according to the clinico-
haematological ELN response criteria. 
•
Safety and tolerability of Givinostat at the MTD after 6 cycles
evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse 
events, graded according to CTCAE v. 4.03. 
•
Individual Givinostat concentrations tabulated with descriptive 
statistics. 
EXPLORATORY 
ENDPOINTS 
Part A and Part B  
•
To evaluate the effect of Givinostat on each single response 
parameter according to the clinico-haematological ELN 
response criteria. 
•
To evaluate the effects of Givinostat on PD markers by mRNA 
analysis. 
•
To evaluate the effects of Givinostat on spleen size (by MRI or 
CT scan) in patients with confirmed splenomegaly at baseline. 
•
Improvement of constitutional symptoms evaluated according 
to MPN-SAF QOL questionnaire. 
•
Reduction of the JAK2V617F allele burden, tested by quantitative 
RT-PCR. 
•
Reduction of the symptomatic treatment of pruritus in term of 
dosage and/or days of treatment. 
Part B  
•
Overall response rate - i.e. Complete Remission and Partial 
Remission - of Givinostat at the MTD after 6 cycles; the 
response will be evaluated according to the “new” ELN 
response criteria (i.e. the revised ELN response criteria). 
•
To evaluate the effect of Givinostat on each single response 
parameter according to the “new” ELN response criteria (i.e. 
the revised ELN response criteria). 


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STUDY DESIGN 
Two-part, multicenter, open label, non-randomized, phase Ib/II study. 
NUMBER OF PATIENTS About 52 evaluable patients, approximately 24 in Part A and 28 in Part 
B. 
TEST PRODUCT, DOSE 
AND MODE OF 
ADMINISTRATION 
Givinostat is a histone-deacetylases inhibitor.  
The product will be supplied as hard gelatine capsules for oral 
administration at the strength of 50 mg and/or 75 mg and/or 100 mg 
each.  
In Part A patients will treated in Dose Levels (DLs) at the following 
daily doses of Givinostat:  
•
50 mg b.i.d.;,
•
100 mg b.i.d.; 
•
150 mg b.i.d.;,
•
200 mg b.i.d.; 
•
150 mg t.i.d.;
•
200 mg t.i.d.. 
Intermediate Dose Levels (IDLs) and, consequently, additionally DLs 
may be used to establish the MTD. 
In Part B patients will be treated at the MTD established in Part A. 
TREATMENT PLAN 
This is a two-part, multicenter, open label, non-randomized, phase Ib/II 
study to assess the safety and tolerability, MTD and preliminary 
efficacy of Givinostat in patients with JAK2V617F positive PV. Part A is 
the dose finding part while Part B is assessing the preliminary efficacy. 
Patients will be enrolled either in Part A or Part B and transition from 
one part to the other is not allowed. 
Eligible patients for this study will have a confirmed diagnosis of PV 
according to the revised WHO criteria and the JAK2V617 positivity. 
Only if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 
months), eligibility for this part of the study may be expanded to all 
patients with cMPN.  
Study therapy will be administered in 28 day cycles (4 weeks of 
treatment). 
Disease response will be evaluated according to the ELN criteria after 
3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with 
Givinostat for both parts of the study. All phlebotomies performed in 
the first 3 weeks of treatment will not be counted to assess the clinico-
haematological response. 


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The study will last up to a maximum of 24 weeks of treatment. 
However, after completion of the trial, all patients achieving clinical 
benefit will be allowed to continue treatment with Givinostat (at the 
same dose and schedule) in a long-term study (Study N.: 
DSC/11/2357/44), provided that the long-term study has already 
received all necessary approvals in that specific country and site, 
and the study has been already initiated in that particular site. 
Safety will be monitored at each visit throughout the entire duration of 
the study. Treatment will be administered on an outpatient basis and 
patients will be followed regularly with physical and laboratory tests, 
as specified in the protocol; in case of hospitalization, the treatment 
will be continued or interrupted according to the Investigators’ 
decision. 
Part A
Part A is the dose escalation part of this study, evaluating the safety 
and tolerability and MTD of Givinostat in patients with JAK2V617F
positive PV. 
Approximately 24 patients will be enrolled in this part of the study. 
In Part A, Dose Limiting Toxicity (DLT) is defined as the following 
drug-related toxicity: 
•
Grade 4 haematological toxicities, or 
•
Grade 3 febrile neutropenia, or 
•
Grade  3 non-haematological toxicities with exception of:
a) Grade 3 diarrhoea without adequate supportive care lasting  
less than 3 days, and 
b) Grade 3 nausea or vomiting without adequate supportive 
care lasting  less than 3 days, or 
•
Any drug-related SAE, or 
•
Any toxicity that is clearly not related to disease progression or 
intercurrent illness requiring interruption of dosing for more 
than 3 days during the first cycle. 
The severity of the above mentioned events will be graded according to 
CTCAE v. 4.03.  
Dose escalation will be conducted according to a standard 3+3 design, 
adopting a modified Fibonacci escalation schema. Patients will be 
enrolled in cohorts of 3 new patients (up to a maximum of 6) in rising 
dose levels.  


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Givinostat 
daily dose  
Givinostat dose 
level (DL) 
DL used primarily to asses 
50 mg b.i.d. 
DL0 
Safety, PK, PD* 
100 mg b.i.d. 
DL1 
MTD, PK, PD 
150 mg b.i.d. 
DL2 
MTD, PK, PD 
200 mg b.i.d. 
DL3 
MTD, PK, PD 
150 mg t.i.d. 
DL4 
MTD, PK, PD 
200 mg t.i.d. 
DL5 
MTD, PK, PD 
* DL previously demonstrated as safe. 
The DL0 (i.e. 50 mg b.i.d.) has been previously shown to be well 
tolerated in several disorders and also in cMPN patients (Study N. 
DSC/07/2357/28 and Study N. DSC/08/2357/38). Therefore, it is 
preferred to assign patients to the highest available dose level (i.e. 
DL1, DL2, DL3, DL4 and DL5) before assigning patients to DL0. 
Intermediate Dose Levels (IDLs) and, consequently, additionally DLs 
may be introduced to more accurately define the MTD. 
In Part A each patient will receive study drug at a specific DL. Once 
the first 3 patients of the first DL (i.e. DL1) have been treated for 1 
cycle, tolerability data will be evaluated and a decision to escalate to 
the next dose will be made. 


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N. of patients 
with DLT at a 
given DL 
Action 
0 out of 3 
Enter 3 patients at the next dose level.
1 out of 3 
Enter at least 3 more patients at this dose level 
and 
•
if 0 of these 3 new patients experiences 
DLT, proceed to the next dose level; 
•
if  1 of this group suffer DLT (for a total 
of  2/6 patients with a DLT), this dose 
exceeds the MTD and dose escalation is 
stopped. To further assess tolerability, 3 
additional patients will be entered at the 
next lowest dose level if only 3 patients 
were treated previously at that dose. Upon 
determination of the MTD, the study 
proceeds directly to Part B. 
 2 
Dose escalation will be stopped. This dose 
exceeds the MTD. To further assess tolerability, 3 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose and the study will proceed 
directly to Part B of the study.
At any time, if  2/3 or  2/6 patients at a given dose level develop a 
DLT, it is acceptable to de-escalate to an intermediate, not previously 
studied dose, if evaluation of toxicity at such a dose is desired, in lieu 
of proceeding directly to Part B of the study. If this approach is taken, 
3 patients should be enrolled at the intermediate dose, and the 
aforementioned rules should be used to determine enrolment at this 
dose. If the decision is made to proceed directly to the efficacy portion 
of the study (i.e. Part B), the efficacy part will start at the next lower 
dose below where  2/3 or  2/6 DLTs were observed (i.e. the MTD 
dose level). 
If 2 or more patients per dose level experience a DLT, dose escalation 
will terminate and the MTD is the next lower dose level if no more 
than one out of 6 patients had a DLT at that level. Once all patients 


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enrolled in Part A have been treated for at least 1 cycle, the study team 
will determine the MTD to be used in Part B based on the safety and 
tolerability profile of Givinostat observed as well as the PK and PD 
data, if applicable.  
No intra-patient dose escalation will be permitted prior to determining 
the MTD. At that time, continuing patients on treatment at lower dose 
levels may be allowed to escalate their Givinostat dose up to the MTD 
the remainder of the study (Part AB) at the discretion of the 
Investigator and Sponsor after the written authorization of 
Italfarmaco S.p.A.. Of note, patients initially dosed at lower dose 
levels that are allowed to escalate their Givinostat dose up to the 
MTD for the remainder part of the study (Part A), will follow the 
dose modification rules of Part B.  
Only PV patients from Part A assigned to the dose selected for Part B
(MTD) may be counted towards the efficacy assessment in Part B.  
Part B
Part B is a multicenter, open label, non-randomized, phase II, cohort 
expansion study to assess the preliminary clinical efficacy of 
Givinostat at the MTD in patients with JAK2V617F positive PV. 
Approximately twenty eight patients will be enrolled in Part B at the 
MTD defined in Part A, according to an optimized Simon’s 2-stage 
design. 
The dose of Givinostat will be modified for protocol specified 
toxicities. Patients experiencing severe toxicity will have their 
treatment interrupted until recovery of the toxicity and then restarted at 
a reduced dose level. After the second occurrence of dose limiting 
toxicity patients will be permanently withdrawn from the study. 
INCLUSION CRITERIA 
1. Patients must be able to provide informed consent and be willing to 
sign an informed consent form; 
2. Patients must have an age 18 years; 
3. Patients must have a confirmed diagnosis of PV according to the 
revised WHO criteria; 
4. Patients must have JAK2V617F positive disease; 
5. Patients must have an active/not controlled disease defined as  
a) HCT  45% or HCT <45% in need of phlebotomy, and 
b) PLT counts > 400 x109/L, and 


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c) WBC > 10 x109/L; 
6. Patients must have an Eastern Cooperative Oncology Group 
(ECOG) performance status  1 in Part A, ECOG performance 
status  2 in Part B within 7 days of initiating study drug; 
7. Female patient of childbearing potential has a negative serum or 
urine pregnancy test within 72 hours of the first dose of study 
therapy; please note that a borderline urine pregnancy test must be 
followed with a serum pregnancy test; 
8. Use of an effective means of contraception for women of 
childbearing potential and men with partners of childbearing 
potential;  
9. Adequate and acceptable organ function within 7 days of initiating 
study drug; 
10. Willingness and capability to comply with the requirements of the 
study. 
Note that if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 
3 months), eligibility for this part of the study may be expanded to all 
patients with cMPN. In this case, the inclusion criteriaon n. 5 will be 
modified as following only for Part A: 
5. Patients must have an active/not controlled disease defined as: 
a) ET patients: PLT counts > 600 x109/L; 
b) MF patients: no response according to EUMNET criteria. 
Note that an effective means of contraception for women of 
childbearing potential and men with partners of childbearing potential 
(i.e. inclusion criteriaon n. 5) is defined as following described based 
on different subject subgroups:   
A. Female subjects of childbearing potential: acceptable non-
hormonal, contraceptive methods must be used from the 28 days 
before first dose of study drug through 3 months after the last dose 
of study drug and include the following: 
•
True abstinence (absence of any sexual intercourse), when 
in line with the preferred and usual lifestyle of the subject. 
Periodic 
abstinence 
(e.g., 
calendar, 
ovulation, 
symptothermal, postovulation methods) and withdrawal are 
not acceptable methods of contraception. 
•
Double barrier contraception such as diaphragm or a barrier 


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method of contraception in conjunction with spermicidal 
jelly such as for example cervical cap with spermicide jelly 
and the male partner must use a condom with spermicide. 
•
Intra-uterine device (non-hormone-releasing) in place for at 
least 90 days previously and the male partner must use a 
condom with spermicide. 
•
Tubal ligation at least 6 months previously and 1 additional 
acceptable contraception method. 
•
Vasectomy of the male partner (with a negative sperm post-
vasectomy semen analysis) at least 6 months previously and 
1 additional acceptable contraception method. 
B. Female subjects of non-childbearing potential must meet at least 1 
of the following criteria: 
•
Postmenopausal: Female subjects, less than 60 years of age, 
who have been amenorrheic for at least 2 years and have a 
serum FSH level within the laboratory’s reference range for 
postmenopausal females. Female subject who are 60 years 
of age or older who are amenorrheic for greater than 2 years 
will be assume to be postmenopausal. 
•
Documented hysterectomy or bilateral oophorectomy or 
both aAll other female subjects (including subjects with 
tubal ligations and subjects that do not have a documented 
hysterectomy) will be considered to be of childbearing 
potential. 
C. Male Subjects, acceptable contraceptive methods must be used 
from Screening Visit through 3 months after the last dose of study 
drug, and include the following: 
•
True abstinence (absence of any sexual intercourse), when 
in line with the preferred and usual lifestyle of the subject. 
Periodic 
abstinence 
(e.g. 
calendar, 
ovulation, 
symptothermal, postovulation methods) and withdrawal are 
not acceptable methods of contraception. 
•
Condom with spermicide and the female partner must use 
an acceptable method of contraception, such as an oral, 
transdermal, 
injectable 
or 
implanted 
steroid-based 
contraceptive, or a diaphragm or a barrier method of 
contraception in conjunction with spermicidal jelly such as 
for example cervical cap with spermicide jelly. 
•
Vasectomy (with a negative sperm post-vasectomy semen 


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analysis) at least 6 months previously and 1 additional 
acceptable contraception method.  
•
Male subjects must not donate sperm from the Screening Visit 
through 3 months after the last dose of study drug.
Note also that  
–
Male condom cannot be used with female condom due to risk 
of tearing. 
–
The use of birth-control methods does not apply if the female 
partner has a bilateral oophorectomy, hysterectomy, or is 
postmenopausal (as defined above). 
EXCLUSION CRITERIA 1. Active bacterial or mycotic infection requiring antimicrobial 
treatment; 
2. Pregnancy or nursing;   
3. A clinically significant QTc prolongation at baseline (e.g. repeated 
demonstration of a QTc interval  450 msec); 
4. Use of concomitant medications known to prolong the QT/QTc 
interval;  
5. Clinically significant cardiovascular disease including:  
a) Uncontrolled 
hypertension 
despite 
medical 
treatment, 
myocardial infarction, unstable angina within 6 months from 
study start; 
b) New York Heart Association (NYHA) Grade II or greater 
congestive heart failure;  
c) History of any cardiac arrhythmia requiring medication 
(irrespective of its severity);   
d) A history of additional risk factors for TdP (e.g. heart failure, 
hypokalemia, family history of Long QT Syndrome);  
6. Known positivity for HIV; 
7. Known active HBV and/or HCV infection; 
8. Platelet count < 100 x 109/L within 14 days before enrolment (i.e. 
the receipt of the Patient ID); 
9. Absolute neutrophil count < 1.2 x 109/L within 14 days before 
enrolment (i.e. the receipt of the Patient ID); 
10. Serum creatinine > 2 x ULN; 
11. Total serum bilirubin > 1.5 x ULN except in case of Gilbert’s 
disease; 
12. Serum 
aspartate 
aminotransferase/alanine 
aminotransferase 
(AST/ALT) > 3 x ULN; 


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13. History of other diseases (including active tumours), metabolic 
dysfunctions, physical examination findings, or clinical laboratory 
findings giving reasonable suspicion of a disease or condition that 
contraindicates use of an investigational drug or that might affect 
interpretation of the results of the study or render the subject at 
high risk from treatment complications; 
14. Prior treatment with a JAK2 or HDAC inhibitor or participation in 
an interventional clinical trial for cMPN, including PV, ET or MF; 
15. Systemic treatment for cMPN other than aspirin/cardio aspirin;  
16. Hydroxyurea within 28 days before enrolment (i.e. the receipt of 
the Patient ID); 
17. Interferon alpha within 14 days before enrolment (i.e. the receipt of 
the Patient ID); 
18. Anagrelide within 7 days before enrolment (i.e. the receipt of the 
Patient ID); 
19. Any other investigational drug or device within 28 days before 
enrolment (i.e. the receipt of the Patient ID); 
20. Patient with known hypersensitivity to the components of study 
therapy. 
Of note, a repeated demonstration of a QTc interval  450 msec (i.e. 
exclusion criterion n. 3) means that, if the first ECG evaluation 
demonstrates a prolonged QTc interval (i.e. a QTc interval  450 
msec), two additional ECG evaluations over a brief period of time 
(i.e. 5 minutes between each recording) must be performed. The 
averaged value of these three ECG evaluations has to be used for 
the evaluation of the QTc interval requested by the exclusion 
criterion n. 3. In the CRF all the performed ECG evaluations have 
to be entered as well as the average value of multiple ECG 
evaluation, if necessary.
Note that an any other investigational drug or device (i.e. exclusion 
criterion n. 19) includes any investigational drug or device not 
already mentioned and detailed in the exclusion criteria n. 14, 15, 
16 17 and/or 18.
DURATION OF 
TREATMENT  
The study (both Part A and Part B) will last up to a maximum of 24 
weeks of treatment.  
However, after completion of the trial, all patients achieving clinical 


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benefit will be allowed to continue treatment with Givinostat (at the 
same dose and schedule) in a long-term study (Study N.: 
DSC/11/2357/44), provided that the long-term study has already 
received all necessary approvals in that specific country and site, 
and the study has been already initiated in that particular site.
CONCOMITANT 
TREATMENT 
Patients must NOT receive the following treatments during the study: 
a) Other investigational drugs while on this study; 
b) Cytotoxic agents, interferons or other approved treatment for 
cMPN other than aspirin/cardio-aspirin; 
c) Any drug known to provoke TdP. 
Other concomitant medications (e.g. symptomatic treatment of 
pruritus) and significant non-drug therapy (e.g. phlebotomy, blood 
transfusion) are permitted.  
CRITERIA FOR 
RESPONSE 
Criteria for assessing clinico-haematological improvement 
Disease response will be evaluated according to the following clinico- 
haematological ELN criteria after 3 and 6 cycles of treatment with 
Givinostat both in Part A (secondary endpoints) and in Part B (primary 
and secondary endpoints, respectively).  
•
Complete response:  
1.
HCT<45% without phlebotomy, and 
2.
platelets  400 x109/L, and 
3.
WBC 10 x109/L, and 
4.
Normal spleen size, and 
5.
no disease-related systemic symptoms (i.e. pruritus, 
headache, microvascular disturbances). 
•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1.
HCT <45% without phlebotomy, or  
2.
response in 3 or more of the other criteria. 
•
No response: any response that does not satisfy  partial response.
As an exploratory endpoint, disease response will be evaluated also 
according to the following “new” ELN criteria (i.e. the revised ELN 
response criteria) after 6 cycles of treatment with Givinostat in Part B. 
•
Complete remission:  
1. Durable resolution of disease-related signs including 
palpable hepato-splenomegaly improvement, and large 


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symptoms improvement, and 
2. Durable peripheral blood count remission, defined as HCT < 
45% without phlebotomies, and PLT count  400 x109/L, 
and WBC count < 10 x109/L, and 
3. No progressive disease, and absence of any hemorrhagic or 
thrombotic event, and 
4. Bone marrow histological remission defined as the presence 
of age-adjusted normo-cellularity, and disappearance of tri-
linear hyperplasia, and absence of grade > 1 reticulin 
fibrosis. 
•
Partial remission:  
1. Durable resolution of disease-related signs including 
palpable 
hepato-splenomegaly, 
and 
large 
symptoms 
improvement, and 
2. Durable peripheral blood count remission, defined as HCT < 
45% without phlebotomies, and PLT count  400 x109/L, 
and WBC count < 10 x109/L, and 
3. No progressive disease, and absence of any hemorrhagic or 
thrombotic event, and 
4. No bone marrow histological remission defined as 
persistence of tri-linear hyperplasia. 
•
No response: any response that does not satisfy  partial 
remission. 
•
Progressive Disease: transformation into post-PV myelofibrosis, 
myelodysplastic syndrome or acute leukemia (according to the 
IWG-MRT criteria for the diagnosis of post-PV myelofibrosis 
and according to WHO criteria for the diagnosis of 
myelodysplastic syndrome and acute leukemia). 
Please note that according to the “new” ELN criteria (i.e. the revised 
ELN response criteria): 
1) Molecular response is not required for assignment as Complete 
Remission or Partial Remission. Molecular response evaluation 
requires analysis in peripheral blood granulocytes. Complete 
response is defined as eradication of a pre-existing abnormality. 
Partial response applies only to patients with at least 20% 
mutant allele burden at baseline. Partial response is defined as  
 50% decrease in allele burden. 
2) “Durable” is defined as lasting at least 12 weeks. 
3) “Large symptom improvement” is defined as  10 points of 


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decrease in MPN-SAF Total Symptom Score. 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled 
in 3 months) and the eligibility for this part of the study may be 
expanded to all patients with cMPN, disease response for this part of 
the study will be evaluated according to the ELN and EUMNET 
criteria after 3 and 6 cycles of treatment with Givinostat, in ET and MF 
patients, respectively. 
For ET (from the clinico-hematological ELN response criteria): 
•
Complete response:  
1.
platelets  400 x109/L, and 
2.
no disease related systemic symptoms (i.e. pruritus, 
headache, microvascular disturbances), and 
3.
normal spleen size, and 
4.
WBC 10 x109/L. 
•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1.
Platelet count < 600 x 109/L, or  
2.
Platelet count decrease > 50% from baseline. 
•
No response: any response that does not satisfy  partial response.
In all cases, both for PV and ET patients, all phlebotomies performed 
in the first 3 weeks of treatment will not be counted to assess the 
clinico-haematological response. 
For MF (from EUMNET response criteria)  
•
Complete 
response: 
complete 
response 
in 
anemia, 
splenomegaly, constitutional symptoms, platelet and leukocyte 
count.
1.
Complete response in anaemia: Haemoglobin  12 g/dL 
for transfusion-independent patients or  11 g/dL for 
transfusion-dependent patients (applicable only for patients 
with baseline haemoglobin level of < 10 g/dL); 
2.
Complete response in splenomegaly: Spleen not palpable; 
3.
Complete response in constitutional symptoms: Absence of 


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constitutional symptoms (fever, drenching night sweats, or 
 10% weight loss); 
4.
Complete response in platelet count: Platelet count 150-
400 x109/L; 
5.
Complete response in leukocyte count: Leukocyte count 4-
10 x109/L. 
•
Major response: Any response in both anaemia and 
splenomegaly without progression in constitutional symptoms 
or complete response in anaemia without progression in 
splenomegaly or partial response in anaemia in a baseline 
transfusion-dependent patient combined with response in 
constitutional symptoms without progression in splenomegaly 
or any response in splenomegaly combined with response in 
constitutional symptoms without progression in anaemia.
1.
Partial response in anaemia: Increase of Hb > 2 g/dL 
(but Hb < 12 g/dL) for non-RBC transfusion –dependent 
patients; or reduction > 50% of transfusion requirement 
for RBC transfusion-dependent patients. 
2.
Partial response in splenomegaly: Either  50% 
decrease in spleen size if baseline  10 cm from left 
costal margin (LCM) or  30% decrease if baseline > 10 
cm from LCM. 
3.
Partial response in platelet count: A  50% decrease in 
platelet count if baseline > 800 x109/L or platelet count 
increase by   50% x 109/L if baseline < 100 x109/L. 
4.
Partial response in leukocyte count: A  50% decrease 
in leukocyte count of baseline >  20 x109/L or leukocyte 
count increase by  1 x109/L if baseline < 4 x109/L 
5.
Progression in anaemia: A hemoglobin decrease of  2 
g/dL  or  a 50% increase in transfusion requirement or 
becoming transfusion dependent 
6.
Progression in splenomegaly: A  50% increase in 
spleen size if baseline  10 cm from LCM or a  30% 
increase if baseline > 10 cm from LCM. 
7.
Progression in constitutional symptoms: Appearance of
constitutional symptoms. 
•
Moderate response: Complete response in anaemia with 
progression in splenomegaly or partial response in anaemia 
without progression in  splenomegaly or any response in 


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splenomegaly without progression in   anaemia and 
constitutional symptoms.  
•
Minor response: Any leukocyte- or platelet-based response 
without progression in anaemia, splenomegaly, or constitutional 
symptoms.
•
No response: Any response that does not qualify at least as 
minor response.
In all cases (PV, ET and MF patients), the disease-related systemic 
symptoms will be evaluated directly by patients according to MPN-
SAF QOL questionnaire.  
Criteria for determination of MTD  
Once all patients enrolled in Part A have been treated for at least 1 
cycle, the study team will determine the MTD to be used in Part B
based on the safety and tolerability profile of Givinostat observed as 
well as the PK and PD data, if applicable. No intra-patient dose 
escalation will be permitted prior to determining the MTD.  
At that time, patients on treatment at lower dose levels may be 
allowed to escalate their Givinostat dose up to the MTD for the 
remainder part of the study (Part A) at the discretion of the 
Investigator and after the written authorization of Italfarmaco 
S.p.A.. Of note, patients initially dosed at lower dose levels that are 
allowed to escalate their Givinostat dose up to the MTD for the 
remainder part of the study (Part A), will follow the dose 
modification rules of Part B.
Criteria for characterization of PK 
Plasma concentrations from Parts A and B will be evaluated by dose 
and time point for all patients and time points with at least 1 PK 
assessment.  
DOSE MODIFICATIONS 
RULES, TREATMENT 
INTERRUPTION AND 
TREATMENT 
DISCONTINUATION
For patients who do not tolerate the protocol-specified dosing 
schedule, dose adjustments are permitted in order to allow the 
patients to continue the treatment with the study drug. 
Dose modification criteria in Part A  
In the Cycle 1 of Part A dose modifications will not be allowed. 
Patients receiving subsequent cycles of treatment in Part A may 
have up to two dose modifications for drug related DLT’s. The 
first dose modification should be one dose level below the current 


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dose, the second modification should be two dose levels below. 
Study drug may be resumed at lower dose level once the event 
resolves to at least grade 1 or baseline values. If toxicities meeting 
modification criteria occur after the second dose reduction, 
therapy must be discontinued.  
Patients with unresolved toxicities lasting 2 weeks or longer will 
not be permitted to continue on study.  
Patients experiencing Grade 3 or 4 unmanageable toxicity will 
require immediate dose interruption and notification to the 
Sponsor. Treatment for each new cycle will be delayed until dose 
limiting toxicities that are clearly not related to disease progression 
have resolved to at least Grade 1 or the patient’s baseline.  
Dose modification criteria in Part B   
Dose adjustments are permitted for patients who do not tolerate 
the protocol-specified dosing schedule, in order to allow to these 
patients to continue the treatment with Givinostat. The objective of 
the Givinostat dose adjustment rules is to optimize the response for 
each individual patient, avoiding specific drug-related toxicities. 
Therefore, dose reductions or interruptions will be mandatory for 
specific toxicities and dose increases after an initial dose reduction 
will be allowed in the case of inadequate efficacy at the reduced 
dosage in absence of specific toxicities.  
The severity of the above mentioned events will be graded 
according to NCI Common Terminology Criteria for AE (CTCAE 
v. 4.03, 14th June 2010). 
Each dose modification has to be recorded on the CRF.    
Patients initially dosed at lower dose levels in Part A that, after the 
definition of MTD, are allowed to escalate their Givinostat dose up 
to the MTD for the remainder part of the study (Part A) at the 
discretion of the Investigator and after the written authorization of 
Italfarmaco S.p.A., will follow the dose modifications criteria for 
Part B. 
Total daily dose may never exceed the MTD defined in Part A (i.e. 
100 mg b.i.d.). 
Treatment interruption and treatment discontinuation in Parts A
and B  
In some circumstances, it may be necessary to temporarily 


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interrupt treatment as a result of adverse experiences that may 
have an unclear relationship to study drug. Study drug may be 
withheld by the Investigator at any time if there is concern about 
patient safety and for all aspects of the conduct of the protocol, 
since the safety of the individual patient is paramount. Treating 
Investigator may employ any means necessary to ensure patient 
safety, particularly in medical circumstances not anticipated by 
this protocol.  
Dose adjustments are permitted for patients who do not tolerate 
the protocol-specified dosing schedule, in order to allow to these 
patients to continue the treatment with Givinostat. The objective of 
the Givinostat dose adjustment rules is to optimize the response for 
each individual patient, avoiding specific drug-related toxicities.  
If the patient inadvertently misses a drug dose, no additional trial 
medication should be taken that day or in the next days in the 
effort to replace the material that has been missed.  
If vomiting occurs, no additional trial medication should be taken 
that day in an effort to replace the material that has been vomited. 
If the study drug is interrupted for any reason for more than 4 
weeks continuously, dosing may be not be restarted.  
Patients have the right to withdraw from the study at any time for 
any reason. The Investigator has the right to withdraw patients 
from the study due to medical reasons according to his/her 
discretion.  
If a pregnancy occurs, the patient will be replaced and another 
patient in that DL should be recruited. 
If the patient discontinues the study because of an adverse event 
whether or not drug related, he/she must be followed until 
resolution or stabilization of the event, whichever occurs first. 
In case of lack of compliance or in case the patient is found not 
eligible, the patient discontinuation have to be discussed between 
Investigator and Sponsor.    
If 
the 
patient 
discontinues 
for 
any 
reason 
(including 
discontinuation for pregnancy), with drug related adverse event 
ongoing at study end, he/she must be followed until resolution or 
stabilization of the event or until it is reasonable to consider the 
event not drug related any more or until the start of a new 
treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications 
included in list of “Drugs with risk of Torsades de Pointes”, the 
treatment with Givinostat is to be promptly discontinued and the 


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patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for 
toxicity), “adverse events” should be indicated as the primary 
reason whenever applicable. All relevant information related to the 
reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after 
the last drug intake for any patient permanently discontinuing 
study treatment. Should any drug-related AE still be ongoing 
beyond the last scheduled visit, this must be followed at subsequent 
follow-up visits until recovery. If a patient does not return for a 
scheduled visit, every effort should be made to contact the patient. 
In any circumstance every effort should be made to complete and 
report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation 
including contributory factors must be included on the CRF.
Patients have the right to withdraw from the study at any time for any 
reason. The Investigator has the right to withdraw patients from the 
study due to medical reasons according to his/her discretion.  
Patients experiencing Grade 3 or 4 unmanageable toxicity will require 
immediate dose interruption and notification of the Sponsor. Treatment 
for each new cycle will be delayed until dose limiting toxicities that are 
clearly not related to disease progression have resolved to at least 
Grade 1 or the patient’s baseline.  
In the Cycle 1 of Part A dose modifications will not be allowed. 
Patients receiving subsequent cycles of treatment in Part A may have 
up to  two dose modifications for drug related DLT’s. The first dose 
modification should be one dose level below the current dose, the 
second modification should be two dose levels below. Study drug may 
be resumed at lower dose level once the event resolves to at least grade 
1 or baseline values. Patients with unresolved toxicities lasting 2 weeks 
or longer will not be permitted to continue on study.  
Patients enrolled in Part B of the study may have up to two dose 
modifications for DLT’s or other drug related toxicities which interfere 
in the opinion of the investigator with continued safe and tolerable 
administration of therapy.  
If toxicities meeting modification criteria occur after the second dose 
reduction, therapy must be discontinued. 
Note that if a pregnancy occurs, the patient will be replaced and 
another patient in that DL should be recruited. 
Criteria for temporarily discontinuation  


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Study drug should be temporarily stopped in Cycles 2 and beyond of  
Part A of and in all Part B for any drug related grade 2 toxicity, despite 
adequate supportive care (where applicable). 
In such cases, the following apply: 
treatment with Givinostat must be promptly discontinued and the 
patient remains untreated until recovery of the observed toxicities to 
the level identified, as mandatory for treatment continuation;  
in any event if recovery from previous toxicities takes 4 weeks or 
more, the experimental treatment shall not be restarted and the patient 
must discontinue the study. 
Note that these temporary stopping rules will be applied only to drug-
related AE’s. 
If vomiting occurs, no additional trial medication should be taken that 
day in an effort to replace the material that has been vomited. 
If the patient inadvertently misses a drug dose, no additional trial 
medication should be taken that day or in the next days in the effort to 
replace the material that has been missed. 
STATISTICAL 
METHODS 
This is a two-part, multicenter, open label, non-randomized, phase Ib/II 
study. 
A standard 3+3 design adopting a modified Fibonacci escalation 
schema will be used  in Part A.  
Sample size for Part B was discussed for the primary endpoint defined 
as the Overall Response Rate after 3 cycles. A Simon’s 2-stage design 
will be employed enrolling up to 28 patients in Part B with the aim of 
testing the “null hypothesis” that RR  0.50 versus the “alternative” 
that RR  0.75. Response rate will be assessed as defined in the 
Criteria for Response section. Overall up to 28 patients will need to be 
recruited, 12 patients being enrolled in Stage-1. Futility will be 
assessed after 12 patients enrolled (Stage 1). Please note that PV 
patients enrolled at the MTD in Part A may be counted towards Stage 
1. Under the “null hypothesis” (if RR = 0.50), the expected total 
sample size is of 18.2 patients, the probability of early termination at 
the end of Stage-1 is 0.613 and the probability of rejecting the “null 
hypothesis” is 0.081 (the target for the type-I error being 0.100). Under 
the “alternative hypothesis” (if RR = 0.75), the probability of rejecting 
the “null hypothesis” in favour of the “alternative” is 0.902 (the type-II 
error being 0.098). After testing the treatment on 12 patients in Stage-
1, if 6 or fewer patients respond to the treatment the trial will be 
terminated rejecting the “alternative” that RR  0.75. Otherwise, the 
trial goes on to Stage-2 enrolling further 16 patients to a total of 28 
patients. If at the end of Stage-2, a total of 17 or fewer patients respond 


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to the treatment the “alternative hypothesis” that RR  0.75 will be 
rejected; alternatively, if 18 or more patients respond, the “null 
hypothesis” that RR  0.50 will be rejected. Estimations are obtained 
from proprietary software (based on SAS ® 9.2) according to the 
algorithm proposed by R. Simon. 
Summary statistics will be calculated for all variables. For each 
continuous variable, the mean, standard deviation, median, minimum 
value and maximum value will be computed. For each discrete variable 
the number of patients in each category with non-missing values in 
relation to all patients with non-missing values of that variable will be 
provided. Results will be displayed within each cohort and overall, 
where applicable. Statistical calculations will be carried-out by 
resorting to SAS version 9.2 (or later). Both continuous and categorical 
data will be summarized and tabulated in 2-way tables (variable-by-
visit).  
The main purpose of this phase Ib/II study consists in providing 
accurate estimates of clinically relevant variables and measures. From 
the statistical viewpoint this translates in estimating confidence 
intervals (CIs) with adequate precision where precision represents the 
degree of uncertainty. 
The two tailed 95% CIs of the sample estimates will be computed 
using parametric approaches if deemed appropriate. Otherwise the 
StatXact-4 
software 
will 
be 
used 
in 
order 
to 
compute 
Exact/Nonparametric 95% CIs.      
Sub-groups analyses will be performed mainly for exploratory 
purposes. Since these analyses will be used to promote  hypothesis 
rather than confirm them, no adjustments for type I error inflation due 
to multiplicity of the tests will be considered. Moreover post-hoc and 
data-driven analyses will be carefully considered and ranked according 
to their biological plausibility. 
The following analysis sets will be defined:  
- Safety analysis set (SAF): The Safety analysis set will include all 
recruited patients who receive at least one dose of study 
medication. All safety analyses will be conducted on this 
population. 
- Intent-to-treat analysis set (ITT): The Intent-to-treat analysis set 
will include all recruited patients who receive at least one dose of 
study medication and from whom at least one post-baseline 
efficacy measurement is obtained. All efficacy analyses will be 
conducted on this population. All efficacy analyses will be 


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conducted on this population and they will be based on the 
effective/actual DL/daily doses of Givinostat at which each 
patient has been treated.   
- Per Protocol analysis set (PP): In order to assess the robustness of 
the efficacy analysis, the analysis of the efficacy endpoints could be 
repeated in the Per Protocol (PP) analysis set. The Per-protocol 
analysis set will include all ITT patients who receive at least 14 
daily doses without interruptions, and without any major deviation 
from the protocol procedures.  
- MTD analysis set: The MTD analysis set will include all patients 
who experienced a DLT in Cycle 1 or received at least 90% of the 
doses of study medication in cycle 1. The first cycle data from this 
analysis set will be used to determine MTD. Patients who didn’t 
experience a DLT and missed more than 10% of the doses in Cycle 
1 of Part A will be replaced.  
- PK Analysis set: will consist of all SAF patients who with at least 1 
PK assessment. This analysis set will be used for PK analysis. 
The number and percentage of the patients included in the analysis 
populations will be reported in a table showing the reason of exclusion 
for all patients enrolled into the study. A listing of reasons of exclusion 
from analysis population will be provided. 
Italfarmaco S.p.A. will perform a preliminary analysis of data after the 
completion of the first cycle of treatment from all patients recruited 
in Part A, in order to assess the MTD to be used for Part B.  
Moreover, a preliminary analysis will be performed on the 12 patients 
of the stage I (Part B). If six or fewer responses will be observed 
during the first stage then the study will be stopped. If seven or more  
responses will be observed in stage I, further 16 patients will be 
enrolled in Part B. In this case, a final statistical analysis will be 
performed considering all patients enrolled in the two study phases. In 
addition, Italfarmaco S.p.A. can perform a preliminary analysis of data 
in case of necessary safety and efficacy updates (e.g. to update 
regulatory documents and/or the drug safety profile, to revise the 
development program). 


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1.1 Medical indication and current treatments  
Polycythemia Vera (PV), also termed Polycythemia rubra vera, together with Essential 
Thrombocythemia (ET) and Myelofibrosis (MF) belongs to a distinct group of Ph-chromosome-
negative chronic myeloproliferative neoplasms (cMPN) characterized by clonal proliferation of 
multipotent haematopoietic stem cells leading to thrombocytosis, leukocytosis, erythrocytosis 
and bone marrow fibrosis [1, 2]. PV is characterized by a tri-lineage expansion of 
morphologically normal red cells, white cells, and platelets [3]. Generally, in PV it is possible to 
recognise two phases: (a) an initial proliferative polycythaemic phase, associated with increased 
red cell mass, which results in an increased propensity to thromboembolic events leading to 
significant morbidity and mortality, and (b) a “spent”, or post-polycythaemic phase, in which 
cytopenias, including anaemia, are associated with ineffective haematopoiesis, bone marrow 
fibrosis and hypersplenism. The course of the disease is associated with a tendency to transform 
to myelofibrosis and leukaemia, events which may be influenced by treatment [4].  
In 2005 the acquired mutation of the JAK2 kinase (JAK2V617F) was discovered in PV patients [5, 
6, 7, 8]. The JAK2 kinase, through its association with cytokine receptors and receptor tyrosine 
kinases, play a central role in cytokine signalling and signal transduction. The JAK2V617F
mutation, that is present in about 90-95% of PV patients, results in expression of a constitutively 
activated JAK2 tyrosine kinase that confers growth factors independence and hypersensitivity to 
blood cell lines [5, 6, 8, 9].  
PV is diagnosed in asymptomatic patients during the routine blood cell count analysis or, more 
commonly, on the basis of skin and mucous membrane redness or splenomegaly. Pruritus 
(aquagenic or not), fatigue, headache, vision disturbances, paraesthesia, erythromelalgia (acral 
dysesthesia and erythema) are the most common disease symptoms, that are present in the 
majority of patients and often severely deteriorate their quality of life [10, 11].  
The long-term prognosis of PV patients is variable. Particularly without treatment, about half of 
the people who have PV with symptoms die in less than 2 years, while with treatment, median 
survival in PV is 15 years. The 10-year risk of developing either myelofibrosis (MF) or acute 
myeloid leukaemia (AML) is 10% and 6%, respectively. The primary causes of morbidity and 
mortality in PV patients are thrombosis, haematological transformation, and haemorrhage, 
responsible for 41%, 13% and 4% of deaths, respectively [12].  
The first step in PV patient management is risk-stratification. The main two factors to be 
considered for risk-stratification are an age > 60 years and/or a history of thrombosis. Other 
factors, such as haematocrit, leukocytes and/or platelets counts and generic cardiovascular risk 
factors, are taken into account for risk stratification but their significance is still controversial.


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In low risk patients, it is recommended to control the erythrocytosis by phlebotomy and, when no 
contraindication exists, to administer low-dose aspirin [2, 13]. In patients with intermediate risk 
of thrombosis, phlebotomy should be offered to keep the haematocrit below appropriate values 
and in general it is recommended to add a low daily dose of aspirin. When platelet counts are > 
1000 x 109/L, additional myelosuppressive treatment should be considered. High-risk PV 
patients require cytoreductive therapy, even if the first step in the disease management is always 
phlebotomy plus low-dose aspirin [2]. 
Standard front-line therapy for high risk PV is hydroxycarbamide (formerly known as 
hydroxyurea, HU), the first choice cytoreductive agent [10, 13] authorised for PV therapy (both 
in Europe than in USA). Hydroxycarbamide is an antimetabolite that inhibits the enzyme 
ribonucleotide diphosphate reductase which has a rate-limiting role in DNA synthesis. It controls 
blood counts and reduces the rate of thromboembolic events. In general, hydroxycarbamide is 
well tolerated and has good clinical effect [4, 10], but its use is burdened by a not negligible rate 
of neoplastic transformation of the disease [14, 15].  
In addition to hydroxycarbamide, PV patients can be also treated with alkylating agents 
(pipobroman and busulfan) authorised in Europe for treatment of PV. Pipobroman is a piperazine 
derivative and is available for clinical use in some European countries (France and Italy). The 
role of pipobroman in inducing the neoplastic transformation of PV has been recently 
emphasized as it appears to be even greater than that of hydroxycarbamide [14, 15]. Busulphan 
has been reported to be effective in controlling blood counts in PV since the 50’s, but an 
extensive use of the drug is limited by its leukemogenic potential [4, 16]. In current clinical 
practice, pipobroman and busulfan are considered as second line therapies in hydroxycarbamide-
intolerant or refractory cases [2].  
Further to cytoreductive and anti-thrombotic therapy, very often patients are candidate to receive 
symptomatic treatments to control systemic symptoms, such as pruritus, headache, microvascular 
disturbances and fatigue, which can severely impair the patients’ quality of life. 
Recently, a JAK inhibitor was authorized both in Europe (i.e. Jakavi, INN: ruxolitinib) and 
in US (Jakafi, INN: ruxolitinib) for the treatment of adult patients with PV who are 
resistant to or intolerant of hydroxyurea.   
The clinical course of PV and ET is marked by significant thrombotic complications and a 
variable risk to evolve into myelofibrosis and eventually to acute myeloid leukemia. Randomized 
clinical trials performed in USA and Europe have shown that cytoreductive treatment of blood 
hyperviscosity, chemotherapy and low-dose aspirin have dramatically reduced the number of 
thrombo-hemorrhagic episodes and substantially improved survival.  
As compared to PV and ET, MF has the worst prognosis with a median survival or 3-5 years. A 
prognostic score system was developed where the presence of leukocytosis, leukopenia or 
anaemia was used to identify three groups of patients with different survival, from 1 to 8 years. 


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Conventional therapies in this disease were palliative and include many drugs in addition to 
supportive therapy to improve anaemia, thrombocytopenia and progressive splenomegaly.  
Recently, a JAK inhibitor was authorized for the treatment of disease-related splenomegaly 
or symptoms in adult patients with MF in Europe (i.e. Jakavi, INN: ruxolitinib) and to 
treat intermediate or high-risk MF patient in US (i.e. Jakafi, INN: ruxolitinib).
1.2 Rationale  
Polycythemia Vera (PV) is a myeloproliferative disorder which is considered to be a clonal 
disease derived from a transformed pluripotent hematopoietic stem cell. This cell is thought to 
lead to overactive hematopoiesis, driven by a constitutively active JAK-STAT signalling 
pathway, caused by V617F mutations within exons 12 and 14 of the JAK2 gene [17]. The 
clinical course of PV is marked by significant thrombotic complications with an estimated 
incidence of 18x1000 person-years, accounting for 45% of all deaths; myelofibrosis and 
transformation into AML may occur in a small percentage of cases (5x1000 person-years) [18].  
The mainstay of current therapy is aimed at reducing the number of these disease related 
complications by reducing blood hyperviscosity. Cytoreductive agents have been proven 
efficacious in this regard, but concerns regarding acceleration of disease transformation remain, 
thereby substantiating the need for novel therapies [2].  
Recently, small molecule inhibitors of the JAK2 kinase have at least partially validated the 
importance of this molecule in the clinical setting and several JAK2 inhibitors are currently 
under clinical development in PV. Recently, a JAK inhibitor was authorized both in Europe 
(i.e. Jakavi, INN: ruxolitinib) and in US (Jakafi, INN: ruxolitinib) for the treatment of 
adult patients with PV who are resistant to or intolerant of hydroxyurea.   
Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin and play a 
key role in the epigenetic regulation of gene expression.  
Givinostat (ITF2357) is a potent, orally available small molecule inhibitor of HDACs and it has 
shown to interfere with the JAK/STAT signalling pathway in preclinical studies. 
1.3 Preclinical rationale 
Completed and updated data following described are reported in the Section 5 “Non-clinical 
studies” of the current Investigator Brochure Dossier related to ITF2357.  
Givinostat has an anti-proliferative effect for tumor cellsbroad antitumor activity on both solid 
and hematological tumors. Its efficacy in  hematological tumors bearing the JAK2V617F 


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mutation is remarkableAmongst the latter, it has remarkable anti-proliferative activity against 
tumor cells bearing the JAK2V617F mutation, showing an IC50 of 95 nM for SET-2 and 175 nM 
for HEL cell lines which are hetero- and homozygous for the mutant protein, respectively. These 
values are two- to three-fold lower than the ones observed for a JAK2 wild type tumor cell such 
as the erythroleukemic cell line K562, for which the IC50 is 350 nM [19, 20]. Combination 
benefit of Givinostat and hydroxyurea was observed in in-vitro cytotoxicity assays conducted in 
HEL and UKE cells. 
1.4 Clinical studies 
Completed and updated data following described are reported in the Section 6 “Effects in 
humans” of the current Investigator Brochure Dossier related to ITF2357. 
Givinostat has been tested in a number of clinical studies. Threewo major indications have been 
explored with Givinostat, inflammatory disease, neuromuscular disorders and oncology. The 
most common AEs observed were thrombocytopenia as well as gastrointestinal toxicities. AEs 
were generally mild to moderate and reversible upon discontinuation of study drug. The 
maximum administered dose was a single dose of 600 mg in healthy volunteers and up to 400 
mg once per week in patients with multiple myeloma. Doses up to approximately 100 mg b.i.d. 
were generally very well tolerated. At higher doses of Givinostat transient reduces 
haematological parameters (particularly platelets) and diarrhoea as well as nausea and vomiting 
were observed. 
1.4.1 Givinostat in chronic myeloproliferative neoplasms  
Givinostat is an HDACi and, as such, it has been investigated for its inhibitory activity on the 
autonomous proliferation of cells obtained by PV and ET patients carrying the JAK2V617F
mutation and to elucidate the mechanism of action of this inhibition. Cells obtained from PV or 
ET patients carrying the JAK2V617F mutation are sensitive in colony assays to a 100-500 lower 
dose of Givinostat as compared to cells bearing un-mutated JAK2. Moreover, Givinostat 
promotes the outgrowth of normal colonies over that of JAK2V617F mutated cells in vitro and 
induces down-modulation of the JAK2V617F but not JAK2 wild type protein. JAK2V617F inhibition 
by Givinostat takes place at the post-transcriptional level and is followed by down-modulation of 
the phosphorylated STAT5 protein and PRV-1 gene expression.  


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Two phase II study were conducted in patients with JAK2V617F positive cMPN. A phase II of 
Givinostat monotherapy, was completed with positive results in patients with JAK2V617F positive 
PV, ET and MF (Study N.: DSC/07/2357/28) [22]. Another phase II study combining Givinostat 
with hydroxyurea, was recently completed with positive results in patients with JAK2V617F
positive PV not responding to the maximum tolerated dose of hydroxyurea monotherapy (Study 
N. DSC/08/2357/38); a total of 44 PV patients received Givinostat doses of either 50 or 100 mg 
per day and were treated for up to 24 weeks [23]. The ELN response criteria [21] were used to 
assess the primary endpoint after 12 weeks of treatment. Complete or partial responses were 
observed in approximately 50% of patients across both dose levels. 
At the time being, a multicenter, open label, long-term study testing the long term safety, 
tolerability and efficacy of Givinostat in patients with cMPN following core protocols and/or 
patient-named compassionate use program is ongoing (Study N. DSC/11/2357/44).  
After completion of this current trial (Study N. DSC/12/2357/45), all patients achieving clinical 
benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in 
the above mentioned long-term study (Study N.: DSC/11/2357/44), provided that the long-
term study has already received all necessary approvals in that specific country and site 
and the study was initiated in that particular site. 
4.1 
Overall study design 
This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety 
and tolerability, MTD and preliminary efficacy of Givinostat in patients with JAK2V617F positive 
PV.  
Part A is the dose escalation portion of the study and, once the MTD has been established, Part 
B will commence where the preliminary efficacy of Givinostat in PV patients will be established. 
Patients will be enrolled either in Part A or Part B and transition from one part to the other is not 
allowed. Only PV patients from Part A assigned to the dose selected for Part B (MTD) may be 
counted towards the efficacy assessment in Part B. 
Eligible patients for this study will have a confirmed diagnosis of PV according to the revised 
WHO criteria and the JAK2V617F positivity. Only if the enrolment in Part A is slow (i.e. < 5 
patients enrolled in 3 months), eligibility for this part of the study may be expanded to all 
patients with cMPN.  
After providing informed written consent before undertaking any protocol-related procedure, a 
unique patient identification code (i.e. patient screening ID which will be a combination of 
his/her site ID, study part ID and patient screening number, e.g. IT01-A01) will be assigned to 
each patient and it will identify the patient within his/her enrolment confirmation by Italfarmaco 
S.p.A. or its designee and never be reused in case of screening failure. After the enrolment 
confirmation and the assignation of the dose level before the first drug intake, a unique patient 
identification code (i.e. patient ID which will be a combination of patient screening number ID 


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and dose level ID, e.g. IT01-A01-DL1) will be assigned to each patient and it will identify the 
patient throughout his/her participation in the study and never be reused in case of premature 
drop-out. 
Study therapy will be administered in 28 day cycles. In fact, the “cycle” is defined as 4 weeks of 
treatment. 
Disease response will be evaluated according to the clinico-haematological ELN criteria [21] 
after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both 
parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be 
counted to assess the clinico-haematological response. 
The study will last up to a maximum of 24 weeks of treatment. However, after completion of the 
trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat 
(at the same dose and schedule) in a long-term study (Study N.: DSC/11/2357/44), provided 
that the long-term study has already received all necessary approvals in that specific 
country and site, and the study has been already initiated in that particular site. 
Safety will be monitored at each visit throughout the entire duration of the study. Treatment will 
be administered on an outpatient basis and patients will be followed regularly with physical and 
laboratory tests, as specified in the protocol (see Appendix A and paragraph 4.5.4); in case of 
hospitalization, the treatment will be continued or interrupted according to the Investigators’ 
decision. 
4.1.1.2 Study team definition 
The study team will include: selected Principal Investigator/s (i.e. Chairman and/or Principal 
Investigator/s who recruited the patients under discussion), the CRO Medical Monitor, 
Italfarmaco’ Medical Expert/s, Italfarmaco’ Clinical ScientistProject Manager and any other 
additional personnel, if necessary. 
4.1.1.5 Definition of MTD 
If 2 or more patients per dose level experience a DLT, dose escalation will terminate and the 
MTD is the next lower dose level if no more than one out of 6 patients had a DLT at that level. 
Once all patients enrolled in Part A have been treated for at least 1 cycle, the study team will 
determine the MTD to be used in Part B based on the safety and tolerability profile of Givinostat 
observed as well as the PK and PD data, if applicable.  
No intra-patient dose escalation will be permitted prior to determining the MTD.  


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At that time, continuing patients on treatment at lower dose levels may be allowed to escalate 
their Givinostat dose up to the MTD for the remainder part of the study (Part A) at the discretion 
of the Investigator and after the written authorization of Italfarmaco S.p.A.Sponsor. Of note, 
patients initially dosed at lower dose levels that are allowed to escalate their Givinostat dose 
up to the MTD for the remainder part of the study (Part A), will follow the dose 
modification rules of Part B (see paragraph 4.3.3.2). Total daily dose may never exceed the 
MTD defined in Part A (i.e. 100 mg b.i.d.). 
4.1.2 Part B 
Part B is a multicenter, open label, non-randomized, phase II, cohort expansion study to assess 
the preliminary clinical efficacy of Givinostat at the MTD in patients with JAK2V617F positive 
PV. 
Approximately twenty eight patients will be enrolled in Part B starting at the MTD defined in 
Part A (i.e. 100 mg b.i.d.), according to an optimized Simon’s 2-stage design [30]. 
The dose of Givinostat will be modified for protocol specified toxicities (see paragraph 
4.3.3.2). Patients experiencing severe toxicity will have their treatment interrupted until recovery 
of the toxicity and then restarted at a reduced dose level (see  and ). After the second occurrence 
of dose limiting toxicity patients will be permanently withdrawn from the study. 
4.2 
Trial organization 
The conduct of this study will be committed to a Contract Research Organization (CRO). In any 
case, Italfarmaco S.p.A. remains responsible for the development, writing and finalization of the 
study 
protocol, 
the 
investigational 
medicinal 
product 
(IMP) 
production 
and 
the  
Pharmacovigilance activities. 
For all study activities, with the exception above mentioned, the designated CRO or them 
delegates (e.g. a Contact Manufacturing Organization (CMO) delegated for the IMP 
secondary packaging and management) can will apply internal standard operating procedures 
(SOPs). 
Trial activities will be supervised by Italfarmaco S.p.A. through regular contacts with the staff of 
the designated CRO or their delegates and/or Investigators, as necessary. 


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4.3.1 Inclusion criteria 
Patients must meet the following criteria to be eligible for study entry: 
1. Patients must be able to provide informed consent through the signature of an informed 
consent form; 
2. Patients must have an age 18 years; 
3. Patients must have a confirmed diagnosis of PV according to the revised WHO criteria; 
4. Patients must have JAK2V617F positive disease; 
5. Patients must have an active/not controlled disease defined as  
a) HCT  45% or HCT <45% in need of phlebotomy, and
b) PLT counts > 400 x109/L, and
c) WBC > 10 x109/L; 
6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 
[28]  1 in Part A, ECOG performance status  2 in Part B, within 7 days of initiating 
study drug; 
7. Female patient of childbearing potential has a negative serum or urine pregnancy test 
within 72 hours of the first dose of study therapy; please note that a borderline urine 
pregnancy test must be followed with a serum pregnancy test; 
8. Use of an effective means of contraception for women of childbearing potential and men 
with partners of childbearing potential;  
9. Adequate and acceptable organ function within 7 days of initiating study drug; 
10. Willingness and capability to comply with the requirements of the study. 
Note that if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months), eligibility 
for this part of the study may be expanded to all patients with cMPN. In this case, the 
inclusion criteriaon n. 5 will be modified as following only for Part A:
5. Patients must have an active/not controlled disease defined as: 
a) ET patients: PLT counts > 600 x109/L; 
b) MF patients: no response according to EUMNET criteria [29].
Note that an effective means of contraception for women of childbearing potential and men with 
partners of childbearing potential (i.e. inclusion criteriaon n. 5) is defined as following described 
based on different subject subgroups:   
A. Female subjects of childbearing potential: acceptable non-hormonal, contraceptive methods 
must be used from the 28 days before first dose of study drug through 3 months after the last 
dose of study drug and include the following: 


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•
True abstinence (absence of any sexual intercourse), when in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods 
of contraception. 
•
Double barrier contraception such as diaphragm or a barrier method of contraception 
in conjunction with spermicidal jelly such as for example cervical cap with 
spermicide jelly and the male partner must use a condom with spermicide. 
•
Intra-uterine device (non-hormone-releasing) in place for at least 90 days previously 
and the male partner must use a condom with spermicide. 
•
Tubal ligation at least 6 months previously and 1 additional acceptable contraception 
method. 
•
Vasectomy of the male partner (with a negative sperm post-vasectomy semen 
analysis) at least 6 months previously and 1 additional acceptable contraception 
method. 
B. Female subjects of non-childbearing potential must meet at least 1 of the following criteria: 
•
Postmenopausal: Female subjects, less than 60 years of age, who have been 
amenorrheic for at least 2 years and have a serum FSH level within the laboratory’s 
reference range for postmenopausal females. Female subject who are 60 years of age 
or older who are amenorrheic for greater than 2 years will be assume to be 
postmenopausal. 
•
Documented hysterectomy or bilateral oophorectomy or both aAll other female 
subjects (including subjects with tubal ligations and subjects that do not have a 
documented hysterectomy) will be considered to be of childbearing potential. 
C. Male Subjects, acceptable contraceptive methods must be used from Screening Visit through 
3 months after the last dose of study drug, and include the following: 
•
True abstinence (absence of any sexual intercourse), when in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods 
of contraception. 
•
Condom with spermicide and the female partner must use an acceptable method of 
contraception, such as an oral, transdermal, injectable or implanted steroid-based 
contraceptive, or a diaphragm or a barrier method of contraception in conjunction 
with spermicidal jelly such as for example cervical cap with spermicide jelly. 
•
Vasectomy (with a negative sperm post-vasectomy semen analysis) at least 6 months 
previously and 1 additional acceptable contraception method.  
•
Male subjects must not donate sperm from the Screening Visit through 3 months after the 
last dose of study drug. 


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Note also that  
–
Male condom cannot be used with female condom due to risk of tearing. 
–
The use of birth-control methods does not apply if the female partner has a bilateral 
oophorectomy, hysterectomy, or is postmenopausal (as defined above). 
4.3.2 Exclusion criteria 
Patients must NOT meet any of the following criteria to be eligible for study entry: 
1. Active bacterial or mycotic infection requiring antimicrobial treatment; 
2. Pregnancy or nursing;   
3. A clinically significant QTc prolongation at baseline (e.g. repeated demonstration of a QTc 
interval  450 msec); 
4. Use of concomitant medications known to prolong the QT/QTc interval;  
5. Clinically significant cardiovascular disease including:  
a) Uncontrolled hypertension
despite medical treatment, myocardial infarction, unstable 
angina within 6 months from study start; 
b) New York Heart Association (NYHA) Grade II or greater congestive heart failure;  
c) History of any cardiac arrhythmia requiring medication (irrespective of its severity);   
d) A history of additional risk factors for TdP (e.g. heart failure, hypokalemia, family 
history of Long QT Syndrome);  
6. Known positivity for HIV; 
7. Known active HBV and/or HCV infection; 
8. Platelet count < 100 x109/L within 14 days before enrolment (i.e. the receipt of the Patient 
ID); 
9. Absolute neutrophil count < 1.2 x109/L within 14 days before enrolment (i.e. the receipt of 
the Patient ID); 
10. Serum creatinine > 2 x ULN; 
11. Total serum bilirubin > 1.5 x ULN except in case of Gilbert’s disease; 
12. Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 3 x ULN; 
13. History of other diseases (including active tumours), metabolic dysfunctions, physical 
examination findings, or clinical laboratory findings giving reasonable suspicion of a disease 
or condition that contraindicates use of an investigational drug or that might affect 
interpretation of the results of the study or render the subject at high risk from treatment 
complications; 


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14. Prior treatment with a JAK2 or HDAC inhibitor or participation in an interventional clinical 
trial for cMPN, including PV, ET or MF; 
15. Systemic treatment for cMPN other than aspirin/cardio aspirin;  
16. Hydroxyurea within 28 days before enrolment (i.e. the receipt of the Patient ID); 
17. Interferon alpha within 14 days before enrolment (i.e. the receipt of the Patient ID); 
18. Anagrelide within 7 days before enrolment (i.e. the receipt of the Patient ID) 
19. Any other investigational drug or device within 28 days before enrolment (i.e. the receipt of 
the Patient ID); 
20. Patient with known hypersensitivity to the components of study therapy. 
Of note, a repeated demonstration of a QTc interval  450 msec (i.e. exclusion criterion n. 3) 
means that, if the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc 
interval  450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 
minutes between each recording) must be performed. The averaged value of these three 
ECG evaluations has to be used for the evaluation of the QTc interval requested by the 
exclusion criterion n. 3. In the CRF all the performed ECG evaluations have to be entered 
as well as the average value of multiple ECG evaluation, if necessary.  
Note that an any other investigational drug or device (i.e. exclusion criterion n. 19) includes 
any investigational drug or device not already mentioned and detailed in the exclusion 
criteria n. 14, 15, 16 17 and/or 18. 
4.3.3  Criteria for dose modifications, treatment interruption and treatment discontinuation   
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patients to continue the treatment with the study drug.  
Patients have the right to withdraw from the study at any time for any reason. The Investigator 
has the right to withdraw patients from the study due to medical reasons according to his/her 
discretion. When patients discontinue study medication, the reason must be categorized in the 
case report form (CRF) as one of the following:  
1. 
study completed; 
2. 
adverse event(s); 
3. 
disease progression; 
4. 
protocol violation; 
5. 
patient withdrew Informed Consent Form; 
6. 
lost at follow-up (despite every effort made to contact the patient); 
7. 
physician decision due to safety reasons; 


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8. 
sponsor decision (see paragraph 8.7); 
9. 
lack of compliance; 
10. 
patient found not eligible; 
11. 
death; 
12. 
pregnancy. 
If the patient discontinues the study because of an adverse event whether or not drug related, 
he/she must be followed until resolution or stabilization of the event, whichever occurs first. 
In case of lack of compliance or in case the patient is found not eligible, the patient 
discontinuation have to be discussed between Investigator and Sponsor.    
If the patient discontinues for any reason (including discontinuation for pregnancy), with drug 
related adverse event ongoing at study end, he/she must be followed until resolution or 
stabilization of the event or until it is reasonable to consider the event not drug related any more 
or until the start of a new treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications included in list of “Drugs with 
risk of Torsades de Pointes” (see Appendix C) the treatment with Givinostat is to be promptly 
discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” 
should be indicated as the primary reason whenever applicable. All relevant information related 
to the reason for treatment discontinuation including contributory factors must be included on the 
CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any 
patient permanently discontinuing study treatment. Should any drug-related AE still be ongoing 
beyond the last scheduled visit, this must be followed at subsequent follow-up visits until 
recovery. If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient. In any circumstance every effort should be made to complete and report the 
observations as thoroughly as possible. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
4.3.3.1 Dose modification criteria in Part A   
Patients experiencing Grade 3 or 4 unmanageable toxicity will require immediate dose 
interruption and notification of the Sponsor. Treatment for each new cycle will be delayed until 
dose limiting toxicities that are clearly not related to disease progression have resolved to at least 
Grade 1 or the patient’s baseline.  
In the Cycle 1 of Part A dose modifications will not be allowed. Patients receiving subsequent 
cycles of treatment in Part A may have up to two dose modifications for drug related DLT’s (see 
paragraph 4.1.1.1 for the DLT definition). The first dose modification should be one dose level 
below the current dose, the second modification should be two dose levels below. Study drug 
may be resumed at lower dose level once the event resolves to at least grade 1 or baseline values. 


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If toxicities meeting modification criteria occur after the second dose reduction, therapy 
must be discontinued. Figure 1 outlines the dose modifications scheme for all DLs of 
Givinostat monotherapy, with exception of DL0 (i.e. 50 b.i.d.) and DL1 (i.e. 100 mg b.i.d.) 
represented by Figures 2 and 3, respectively. Patients with unresolved toxicities lasting 2 weeks 
or longer will not be permitted to continue on study.  
Patients experiencing Grade 3 or 4 unmanageable toxicity will require immediate dose 
interruption and notification of the Sponsor. Treatment for each new cycle will be delayed 
until dose limiting toxicities that are clearly not related to disease progression have 
resolved to at least Grade 1 or the patient’s baseline.  
Patients enrolled in Part B of the study may have up to two dose modifications for DLT’s or 
other drug related toxicities which interfere in the opinion of the investigator with continued safe 
and tolerable administration of therapy.  
If toxicities meeting modification criteria occur after the second dose reduction, therapy must be 
discontinued. 
Note that if a pregnancy occurs, the patient will be replaced and another patient in that DL 
should be recruited. 
Figure 1 - Criteria for dose modifications  
DLT is a Dose Limiting Toxicity. DLx represents a Dose Level with the exception of DL0 (i.e. 50 mg b.i.d.) and DL1 
(i.e. 100 mg b.i.d.), represented by Figures 2 and 3, respectively. DLx-1 represents the next lower Dose Level (first 
dose reduction). DLx-2 represents the next lower dose level after a first dose reduction (second dose reduction). 
Grade  1 represents the severity of AE. 


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Figure 2 - Criteria for dose modifications for patients treated in DL0  
DLT is a Dose Limiting Toxicity. Grade  1 represents the severity of AE. 
Figure 3 - Criteria for dose modifications for patients treated in DL1 
DLT is a Dose Limiting Toxicity. Grade  1 represents the severity of AE. 


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4.3.3.1 Dose modification criteria in Part B   
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 
Givinostat. The guidelines described here below (i.e. see paragraph 3.3.3.2.1 and paragraph 
3.3.3.2.2) need to be followed. The objective of the Givinostat dose adjustment rules 
described below is to optimize the response for each individual patient, avoiding specific 
drug-related toxicities. Therefore, dose reductions or interruptions will be mandatory for 
specific toxicities (see paragraph 3.3.3.2.1) and dose increases after an initial dose reduction 
will be allowed in the case of inadequate efficacy at the reduced dosage in absence of 
specific toxicities (see paragraph 3.3.3.2.2).  
The severity of the above mentioned events will be graded according to NCI Common 
Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010). 
Each dose modification has to be recorded on the CRF.     
Of note, the dose modification criteria described in this paragraph (i.e. see paragraph 
3.3.3.2.1 and paragraph 3.3.3.2.2 for details) will be followed also by patients initially dosed 
at lower dose levels in Part A that, after the definition of MTD, are allowed to escalate their 
Givinostat dose to the MTD for the remainder part of the study (Part A) at the discretion of 
the Investigator and after written authorization of Italfarmaco S.p.A..  
4.3.3.1.1 Dose adjustments for safety reasons in Part B
In Part B, the initial dose of Givinostat will be the MTD defined in Part A (i.e. 100 mg 
b.i.d.).  
Based on evaluations performed as part of the visit procedures of the Day 28 of each Cycle 
up to the Cycle 5 (i.e. Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, Cycle 4 Day 28, 
Cycle 5 Day 28) and/or in any necessary additional study visit, the Givinostat doses have to 
be decreased in case of the occurrence of at least one of the toxicities described in the Table 
3.  
The objective of these guidelines is to consider the patient’s data, prior clinic-
haematological response and dose tolerability, in order to achieve an optimized dose for 
each individual patient, or a balancing between the tolerable dose and the clinico-
haematological response, that also take into account the natural course of the disease.  
Reductions in Givinostat total daily dose for patients that meet dose reduction criteria (see 
Table 3 for details) will be achieved by adjusting the morning and evening administered 
dose level, since the total daily dose is equally divided between the morning and evening 
administration.     


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Table 3 - Dose reduction rules in Part B
Observed values/data 
Action 
Grade 1 thrombocytopenia  
(i.e. PLTs count < local LLN but  75 x 109/L)
Total daily dose must be reduced of 50 mg/die: 
•
For patients that are receiving the daily dose 
of 100 mg b.i.d., daily dose must be reduced to 
75 mg b.i.d.. 
•
For patients that are receiving a reduced daily 
dose of 75 mg b.i.d. or 50 mg b.i.d., daily dose 
must be evaluated based on the Investigator’s 
decision and after discussion with the 
Sponsor’s representative(s).
Grade 2 thrombocytopenia  
(i.e. PLTs count < 75 x 109/L but  50 x 109/L) 
or 
Grade 2 anemia 
(i.e. Hb value < 10 g/dL but  8 g/dL) 
or 
Grade  3 non-haematological toxicities with 
exception of: 
a) Grade 3 diarrhoea without adequate 
supportive care lasting  less than 3 days, 
and 
b) Grade 3 nausea or vomiting without 
adequate supportive care lasting less than 
3 days. 
Total daily dose must be reduced of 50 or 100  
mg/die, based on the Investigator’s decision 
and after discussion with the Sponsor’s 
representative(s): 
•
For patients that are receiving the daily dose 
of 100 mg b.i.d., daily dose should be reduced 
to 75 mg b.i.d. or 50 mg b.i.d., based on the 
Investigator’s decision and after  discussion 
with the Sponsor’s representative(s).
•
For patients that are receiving a reduced daily 
dose of 75 mg b.i.d. or 50 mg b.i.d., daily dose 
must be evaluated based on the Investigator’s 
decision and after discussion with the 
Sponsor’s representative(s). 
Grade 3 thrombocytopenia  
(i.e. PLTs count < 50 x 109/L but  25 x 109/L)
or 
Grade 3 anemia 
(i.e. Hb value < 8 g/dL; transfusion indicated) 
or 
Grade 3 febrile neutropenia  
(i.e.  ANC < 1.0 x 109/L with a single temperature 
of > 38.3°C / 101° F, or a sustained temperature 
38°C / 100.4°F for more than one hour)
Immediate temporary discontinuation of the 
treatment with Givinostat. 
The treatment will be interrupted for at least 
one week. Anyway,  the treatment for each 
new cycle will be delayed until the observed 
toxicity that is clearly not related to disease 
progression, has resolved to at least Grade 1 
or the patient’s baseline value.  
Daily dose has to be restarted at 75 mg b.i.d. 
or 50 mg b.i.d., based on the Investigator’s 


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decision and after  discussion with the 
Sponsor’s representative(s). 
Patients with unresolved toxicities lasting 4 
weeks or longer will not be permitted to 
continue on study.
Table 3 - Dose reduction rules in Part B (continue)
LLN is the Lower Limit of Normality of the value reported in each evaluation performed at local laboratory of 
each investigational site.  
The severity of the above mentioned events will be graded according to NCI Common 
Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010). 
Patients with unresolved toxicities lasting 4 weeks or longer will not be permitted to 
continue on study. 
In order follow the evolution of the observed abnormalities up to its stabilization and/or 
normalization (i.e. event resolved to at least Grade 1 or baseline values) and also to provide 
sufficient data to make dose adjustment decisions, it is strictly recommended to perform 
additional study visits at least on bi-weekly basis upon occurrence of the following 
toxicities:  
- 
Grade 1 thrombocytopenia (i.e. PLTs count < local LLN but  75 x 109/L); 
- 
Grade 1 anemia (i.e. Hb value < local LLN but  10 g/dL),  
Observed values/data 
Action 
Grade 4 thrombocytopenia  
(i.e. PLTs count  25 x 109/L) 
or 
Grade 4 anemia 
(i.e. 
life-threatening 
consequences; 
urgent 
intervention indicated) 
or 
Grade 4 febrile neutropenia  
(i.e. 
life-threatening 
consequences; 
urgent 
intervention indicated) 
or 
Grade  3 unmanageable toxicity 
Immediate temporary discontinuation of 
the treatment with Givinostat. 
The treatment will be interrupted for at 
least one week. Anyway,  the treatment 
for each new cycle will be delayed until 
the observed toxicity that is clearly not 
related to disease progression, 
has 
resolved to at least Grade 1 or the patient’s 
baseline value.  
The continuation of the study - and the 
study drug dosage - should be evaluated 
based on the Investigator’s decision and 
Sponsor’s recommendation.  
Patients with unresolved toxicities lasting 
4 weeks or longer will not be permitted 
to continue on study. 


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- 
ANC < 2.0 x 109/L; 
- 
Grade 2 non-haematological toxicities; 
- 
Any SAE (if feasible).  
In addition, additional study visits at least on weekly basis should be performed upon 
occurrence of the following toxicities: 
- 
Grade  2 thrombocytopenia (i.e. PLTs count < 75 x 109/L); 
- 
Grade  2 anemia (i.e. Hb value < 10 g/dL),  
- 
ANC  1.5 x 109/L; 
- 
Drug-related Grade  3 non-haematological toxicities; 
- 
Drug-related SAE (if feasible).  
Of note, the lowest dosage of Givinostat that can be dispensed to the patients in Part B is 50 
mg b.i.d., i.e. a dosage that has been previously shown to be well tolerated. Of note, patients 
will self-administer daily Givinostat capsules at home at morning and at the evening (i.e. 
after 12 hours) with fluids and between meals (i.e. to take the study drug at least 2 two 
hours after the last meal, or no less than 1 hour before the meal). 
4.3.3.1.2 Dose increase for inadequate efficacy in Part B
In Part B, the initial dose of Givinostat will be the MTD defined in Part A (i.e. 100 mg 
b.i.d.).  
Based on evaluations performed as part of the visit procedures of the Day 28 of each Cycle 
up to the Cycle 5 (i.e. Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, Cycle 4 Day 28, 
Cycle 5 Day 28) and/or in any necessary additional study visit, the Givinostat doses have to 
be decreased in case of the occurrence specific toxicities (see paragraph 4.3.3.2.1).  
After a dose reduction, dosing may be restarted and then increased following recovery of 
the observed toxicity(ies) to controlled levels. The objective for restarting and then 
escalating after a reduction for safety reasons is to find the highest safe dose regimen of 
Givinostat for each patient that is necessary to obtain a clinico-haematological response, 
with increase in dose not more than the MTD defined in Part A (i.e. 100 mg b.i.d.). 
After a dose reduction and in order to optimize the response for each individual patient 
avoiding specific drug-related toxicities, the Givinostat dosage may be increased for 
patients who meet all the following criteria, based on evaluations performed as part of the 
visit procedures of the Day 28 of each Cycle up to the Cycle 5 (i.e. Cycle 1 Day 28, Cycle 2 
Day 28, Cycle 3 Day 28, Cycle 4 Day 28, Cycle 5 Day 28):  
1. Inadequate efficacy as demonstrated by one or more of the following points: 
a) HCT  45%, or HCT < 45% but at least 1 phlebotomy performed after the first 
3 weeks of treatment, or HCT < 45% but at least three point higher than the 


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HCT obtained at baseline (i.e. HCT at baseline (in %) plus at least a value of 
3%), or 
b) WBCs count > 10 x 109/L, or
c) PLTs count > 400 x 109/L, and   
2. PLTs count > local LLN, and 
3. Hb value  12 g/dL, and 
4. ANC  1.5 x 109/L.  
Table 4 summarizes the dose increase rules to be apply for Givinostat dosage at the end (i.e. 
Day 28) of each Cycle of Part B up to Cycle 5 (i.e. Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 
Day 28, Cycle 4 Day 28, Cycle 5 Day 28). The objective of these guidelines is to consider the 
patient’s data, prior clinico-haematological response and dose tolerability, in order to 
achieve an optimized dose for each individual patient, or a balancing between the tolerable 
dose and the clinico-haematological response, that also take into account the natural course 
of the disease.  
Table 4 - Dose increase for inadequate efficacy in Part B
Observed values/data 
Action 
1. Inadequate efficacy as demonstrated by 
one or more of the following points: 
d) HCT  45%, or HCT < 45% but at 
least 1 phlebotomy performed after the 
first 3 weeks of treatment, or HCT < 
45% but at least three point higher 
than the HCT obtained at baseline (i.e. 
HCT at baseline (in %) plus at least a 
value of 3%), or 
e) WBCs count > 10 x 109/L, or
f)
PLTs count > 400 x 109/L, and   
2. PLTs count > local LLN, and 
3. Hb value  12 g/dL, and 
4. ANC  1.5 x 109/L.  
Total daily dose may be increased of 50 
mg/die:
•
For patients that are receiving a reduced 
daily dose of 75 mg b.i.d.,  daily dose 
must be increased to 100 mg b.i.d.. 
•
For patients that are receiving a reduced 
daily dose of 50 mg b.i.d., daily dose must 
be increased to 75 mg b.i.d.. 
•
Only for patients of Part A that are 
receiving a reduced daily dose of 50 mg 
o.d., daily dose must be increased to 50 
mg b.i.d..   


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The total daily dose increase may be no greater than an increase of 50 mg/die, since the 
following dose increase rules will apply as detailed in the Table 4: 
- For patients that are receiving a reduced daily dose of 75 mg b.i.d., the dose increase 
criteria allow to receive a maximum dosage of 100 mg b.i.d.; 
- For patients that are receiving a reduced daily dose of 50 mg b.i.d., the dose increase 
criteria allow to receive a maximum dosage of 75 mg b.i.d.. 
- Only for patients of Part A that are receiving a reduced daily dose of 50 mg o.d., the dose 
increase criteria allow to receive a maximum dosage of 50 mg b.i.d.. 
Therefore, total daily dose may never exceed the MTD defined in Part A (i.e. 100 mg b.i.d.). 
4.3.3.2
Treatment interruption and treatment discontinuation in Parts A and B  
In some circumstances, it may be necessary to temporarily interrupt treatment as a result 
of adverse experiences that may have an unclear relationship to study drug. Study drug 
may be withheld by the Investigator at any time if there is concern about patient safety and 
for all aspects of the conduct of the protocol, since the safety of the individual patient is 
paramount. Treating Investigator may employ any means necessary to ensure patient 
safety, particularly in medical circumstances not anticipated by this protocol.  
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 
Givinostat (see paragraph 4.3.3.1 and paragraph 4.3.3.2). The objective of the Givinostat 
dose adjustment rules described below is to optimize the response for each individual 
patient, avoiding specific drug-related toxicities.  
If the patient inadvertently misses a drug dose, no additional trial medication should be 
taken that day or in the next days in the effort to replace the material that has been missed.  
If vomiting occurs, no additional trial medication should be taken that day in an effort to 
replace the material that has been vomited. 
If the study drug is interrupted for any reason for more than 4 weeks continuously, dosing 
may be not be restarted.  
Patients have the right to withdraw from the study at any time for any reason. The 
Investigator has the right to withdraw patients from the study due to medical reasons 
according to his/her discretion.  
Note that these temporary stopping rules will be applied only to drug-related AE’s. 
If vomiting occurs, no additional trial medication should be taken that day in an effort to replace 
the material that has been vomited. 
If the patient inadvertently misses a drug dose, no additional trial medication should be taken that 
day or in the next days in the effort to replace the material that has been missed.  


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When patients discontinue study medication, the reason must be categorized in the case 
report form (CRF) as one of the following: 
1. study completed; 
2. adverse event(s); 
3. disease progression; 
4. protocol violation; 
5. patient withdrew Informed Consent Form; 
6. lost at follow-up (despite every effort made to contact the patient); 
7. physician decision due to safety reasons; 
8. sponsor decision (see paragraph 8.7); 
9. lack of compliance; 
10. patient found not eligible; 
11. death; 
12. pregnancy. 
If a pregnancy occurs, the patient will be replaced and another patient in that DL should 
be recruited. 
If the patient discontinues the study because of an adverse event whether or not drug 
related, he/she must be followed until resolution or stabilization of the event, whichever 
occurs first. 
In case of lack of compliance or in case the patient is found not eligible, the patient 
discontinuation have to be discussed between Investigator and Sponsor.    
If the patient discontinues for any reason (including discontinuation for pregnancy), with 
drug related adverse event ongoing at study end, he/she must be followed until resolution 
or stabilization of the event or until it is reasonable to consider the event not drug related 
any more or until the start of a new treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications included in list of “Drugs 
with risk of Torsades de Pointes” (see Appendix C) the treatment with Givinostat is to be 
promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-up 
visits until recovery. If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient. In any circumstance every effort should be made to complete 


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and report the observations as thoroughly as possible. All relevant information related to 
the reason for treatment discontinuation including contributory factors must be included 
on the CRF. 
When patients discontinue study medication, the reason must be categorized in the case report 
form (CRF) as one of the following:  
1. 
study completed; 
2. 
adverse event(s); 
3. 
disease progression; 
4. 
protocol violation; 
5. 
patient withdrew Informed Consent Form; 
6. 
lost at follow-up (despite every effort made to contact the patient); 
7. 
physician decision due to safety reasons; 
8. 
sponsor decision (see paragraph 8.7); 
9. 
lack of compliance; 
10. 
patient found not eligible; 
11. 
death; 
12. 
pregnancy. 
If the patient discontinues the study because of an adverse event whether or not drug related, 
he/she must be followed until resolution or stabilization of the event, whichever occurs first. 
In case of lack of compliance or in case the patient is found not eligible, the patient 
discontinuation have to be discussed between Investigator and Sponsor.    
If the patient discontinues for any reason (including discontinuation for pregnancy), with drug 
related adverse event ongoing at study end, he/she must be followed until resolution or 
stabilization of the event or until it is reasonable to consider the event not drug related any more 
or until the start of a new treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications included in list of “Drugs with 
risk of Torsades de Pointes” (see Appendix C) the treatment with Givinostat is to be promptly 
discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” 
should be indicated as the primary reason whenever applicable. All relevant information related 
to the reason for treatment discontinuation including contributory factors must be included on the 
CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any 
patient permanently discontinuing study treatment. Should any drug-related AE still be ongoing 
beyond the last scheduled visit, this must be followed at subsequent follow-up visits until 
recovery. If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient. In any circumstance every effort should be made to complete and report the 


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observations as thoroughly as possible. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
4.4.1 Investigational Medicinal Product (IMP) 
Completed and updated data following described are reported in the Section 4 “Physical, 
chemical and pharmaceutical properties and formulation” of the current Investigator Brochure 
Dossier related to ITF2357.  
Givinostat is a histone-deacetylases inhibitor.  
For the purpose of this document the name “Givinostat” is used to indicate the whole study drug 
name “Givinostat hydrochloride monohydrate” (also known as ITF2357, i.e. its Italfarmaco 
S.p.A. research code). Therefore, the dosages/concentrations of the study drug are expressed as 
Givinostat hydrochloride monohydrate.  
The product will be supplied as hard gelatine capsules for oral administration at the strength of 
50 mg and/or 75 mg and/or 100 mg each.  
Each capsule contains a granulate (obtained by wet granulation) composed of ITF2357, sodium 
starch glycolate, hydroxypropyl methyl cellulose (HPMC), sodium lauryl sulphate, lactose, 
magnesium stearate and colloidal silica. 
4.4.1.1 Dosage and administration 
In Part A patients will be treated in DLs at the following starting daily doses of Givinostat:  
•
50 mg b.i.d.;
•
100 mg b.i.d.;
•
150 mg b.i.d.;
•
200 mg b.i.d.;
•
150 mg t.i.d.;
•
200 mg t.i.d.. 
Intermediate Dose Levels (IDLs) and, consequently, additionally DLs may be used to establish 
the MTD (for more details, see paragraph 4.1.1.3). 
In Part B patients will be treated at the MTD of Givinostat established in Part A (i.e. 100 mg 
b.i.d.).  
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 


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Givinostat (see paragraph 4.3.3.1 and paragraph 4.3.3.2). The objective of the Givinostat 
dose adjustment rules described below is to optimize the response for each individual 
patient, avoiding specific drug-related toxicities.  
Both in Part A and in Part B, patients will self-administer daily Givinostat capsules at home 
as instructed by the Investigator (see paragraph 4.4.7.2 and paragraph 4.4.7.4), except for 
the first drug administration (i.e. Day 1 of the Cycle 1). Patients will not take the morning 
dose of Givinostat on the day selected for their timed PK and PD assessments (see 
paragraph 4.5.3.2 and paragraph 4.5.3.3). Study drug will be administered in the clinic for 
these specific visits, in order to obtain pre- and/or post-dose plasma levels of Givinostat. On 
all the other days corresponding to study visits, patients will take the morning dose of study 
drug prior to the visit. 
In Part A, the lowest dosage of Givinostat that can be dispensed to the patients is 50 mg 
o.d.. In this case, the patient should take the study drug each day at the morning with fluids 
and between meals (i.e. to take the study drug at least 2 two hours after the last meal, or no 
less than 1 hour before the meal). In all other possible dosage (i.e. 50 mg b.i.d, or 100 mg 
b.i.d., or 150 mg/die), patients will self-administer daily Givinostat capsules at home at 
morning and at the evening (i.e. after 12 hours) with fluids and between meals (i.e. to take 
the study drug at least 2 two hours after the last meal, or no less than 1 hour before the 
meal). 
In Part B, the lowest dosage of Givinostat that can be dispensed to the patients is 50 mg 
b.i.d., while the highest dosage of Givinostat that can be dispensed to the patients is 100 mg 
b.i.d.. In all the possible dosage (i.e. 50 mg b.i.d., 75 mg b.i.d., 100 mg b.i.d.), patients will 
self-administer daily Givinostat capsules at home at morning and at the evening (i.e. after 
12 hours) with fluids and between meals (i.e. to take the study drug at least 2 two hours 
after the last meal, or no less than 1 hour before the meal).  
Dose adjustments are permitted for patients who do not tolerate the protocol-specified 
dosing schedule, in order to allow to these patients to continue the treatment with 
Givinostat. The guidelines described here above (i.e. see paragraph 4.3.3.2.1 and paragraph 
4.3.3.2.2) need to be followed. The objective of the Givinostat dose adjustment rules are to 
optimize the response for each individual patient, avoiding specific drug-related toxicities. 
Therefore, dose reductions or interruptions will be mandated for specific toxicities (see 
paragraph 4.3.3.2.1) and dose increases after an initial dose reduction will be allowed in the 
case of inadequate efficacy at the reduced dosage. 
Each dose modification has to be recorded on the CRF.     
4.4.1.2 Criteria for temporarily discontinuation  
Study drug should be temporarily stopped in Cycles 2 and beyond of  Part A of and in all Part B 
for any drug related grade 2 toxicity, despite adequate supportive care (where applicable). 
In such cases, the following apply: 


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•
treatment with Givinostat must be promptly discontinued and the patient remains untreated 
until recovery of the observed toxicities to the level identified, as mandatory for treatment 
continuation;  
•
in any event if recovery from previous toxicities takes 4 weeks or more, the experimental 
treatment shall not be restarted and the patient must discontinue the study. 
Note that these temporary stopping rules will be applied only to drug-related AE’s. 
If vomiting occurs, no additional trial medication should be taken that day in an effort to replace 
the material that has been vomited. 
If the patient inadvertently misses a drug dose, no additional trial medication should be taken that 
day or in the next days in the effort to replace the material that has been missed. 
4.4.3 Patient numbering and screening  
Each patient will be identified in the study by a patient code. 
During the screening period (i.e. after the informed consent form signature and before the 
recruitment confirmation by the Italfarmaco S.p.A. or its designee), the patient code will be 
named patient screening ID and will be a combination of his/her site ID, study part ID and 
patient screening number. 
Both the site ID and the study part ID (i.e. “A” or “B” for Part A or Part B, respectively) will be 
assigned by the Sponsor or its designee to the investigator site.  
Upon signing the informed consent form, the patient screening number will be assigned by the 
Investigator. At each site, the first patient will be assigned patient number “01”, and subsequent 
patients will be assigned consecutive numbers (e.g. the second patient will be assigned patient 
number “02”, the third patient will be assigned patient number “03”, etc. etc.).   
When a study site has a patient ready to enrol, prior to dosing the site will compile a request for 
registration Form and send it to Italfarmaco S.p.A. or its designee in order to obtain the patient 
ID. The request for registration contains the site ID, the study part ID, the assigned patient 
screening number, a checklist related to the inclusion/exclusion criteria to verify the eligibility of 
the patient and collect some other information (e.g. date of birth, date of informed consent 
obtained). If the patient is eligible, Italfarmaco S.p.A. or its designee will confirm the enrolment 
of the patient assigning the related dose level and the patient ID (i.e. the patient code after the 
enrolment confirmation) which will be a combination of patient screening ID and dose level ID. 
Once assigned, both the patient screening ID and the patient ID must not be reused for any other 
patient. 


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The following scheme will resume the  patient identification process: 
If the patient will fail to be enrolled for any reason, the reason will be entered in the study CRF 
within 2 days that the patient is not enrolled. 
According to ICH-GCP guidelines, the Investigator will maintain a patient identification list, 
which ensures a distinctive identification of the patients by their name to screening numbers, 
date of birth, sex and date of inclusion. 
4.4.6 Treatment compliance 
The Investigator will record in the CRF the assigned dose of Givinostat and any dose reduction 
(if applicable) to allow the evaluation of compliance to treatment. 
At each visit, patients will bring back to the study site all drug bottles previously received (i.e.
used, partially used and unused) and receive a new supply. The number of residual capsules in 
the dispensed bottles will be counted by the Investigator and reported in the CRF.  
Then the bottles used, partially used and unused will be collected and sent back to Italfarmaco 
S.p.A. or their designee periodically or at the end of the study. 
Compliance with Givinostat treatment will be calculated by Italfarmaco S.p.A. or its designee 
based on the drug accountability documented by the site staff and monitored by Italfarmaco 


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S.p.A. or its designee (i.e. capsule counts). A patient will be considered sufficiently compliant 
with Givinostat treatment if he/she has taken at least 80% of the prescribed dose over the total 
duration of study drug dosing. 
4.4.7 Drug supply 
4.4.7.1 Packaging 
The packaging will consist of HDPE plastic bottles - closed with a PP screw cap, tamper evident 
- containing hard gelatine capsules of Givinostat. Each bottle  contains: 
- 
30 capsules of 50 mg of Givinostat, or 
- 
30 capsules of 75 mg of Givinostat, or 
- 
15 capsules of 100 mg of Givinostat.  
Depending on the need of supply of each Centre (e.g. number of treated patients) a variable 
number of bottles will be packed in a carton box for shipping. 
At each visit, patients will receive a number of bottles sufficient to cover the period between two 
visits. 
4.4.7.2 Labelling 
The IMP will be appropriately labelled at Italfarmaco S.p.A. or their designee (e.g. external 
providers when requested by the local law, CMO). 
Label of the bottles will comply with the legal requirements of each country and will be printed 
in the local language.  
The labels will show all the information requested according to the Annex 13 to the Good 
Manufacturing Practice (published by the Commission in The rules governing medicinal 
products in the European Community, Volume 4) and the local drug law (if any) and the local 
regulatory requirements. Only the patient specific bottle will be labelled with a tear-off label.  
The label of the medicinal product includes in the local language at least the following data: 
•
Sponsor’s study code;  
•
EudraCT No.;  
•
Patient ID;  
•
Name, address and telephone number of the Sponsor or/and the CRO or their delegates
(if applicable);  
•
Name of the Investigator;  
•
Name and strength of the medicinal product;  
•
Pharmaceutical dosage form;  


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•
Route of administration; 
•
Quantity of dosage units; 
•
Visit in which the patient receive the study drug; 
•
Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the trial patient or person administering the product);  
•
Batch number; 
•
Expiry date;  
•
Declaration of the intended purpose (e.g. for clinical trial use only);  
•
Storage conditions;  
•
The wording “Keep out of reach of children”. 
The patient ID and the visit in which the patient receive the study drug will be reported on every 
label by the Investigator. 
The Investigator will also provide the patient with written instructions on the number of capsules 
to be taken at each administration (i.e. dosage schedule). 
4.4.7.3 Storage 
The IMP will be appropriately stored at Italfarmaco S.p.A. or their its designee (e.g. external 
providers when requested by the local law, CMO) until distribution to the investigational sites. 
The investigational site will store the IMP under the same conditions, as specified in the label, 
ensuring that it is not accessible to unauthorized persons till its dispensing to patients.  
Detailed instructions for the IMP storage and management will be provided in a separate and 
specific IMP handling instruction manual. 
4.4.7.4 IMP dispensing  
All IMP supplies are to be used only for this protocol and not for any other purpose.  
Investigator will be responsible for the delivery of IMP to the patient according to the protocol 
and to instruct the patient to take the IMP as per protocol.  
Patients will be administered the IMP on an outpatient basis. 
At each visit, the Investigator will supply the patients with the appropriate number of bottles 
sufficient to cover the period between two visits. 
The Investigator will also provide the patient with written instructions on the number of capsules 
to be taken at each administration. 


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4.4.7.5 IMP accountability 
The Investigator will maintain accurate records of the disposition of all IMP received, distributed 
to patients (including date and time) and accidentally destroyed. Drug accountability will be 
noted by the field monitor during site visits and at the completion of the study. At each visit, 
patients will bring back to the study site all drug bottles previously received (used, partially used 
and unused) and receive a new IMP supply.  
At the study close-out, and, as appropriate during the course of the study, the Investigator will 
return all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A.,  - Dipartimento di Tecnica Farmaceutica,  Viale Fulvio Testi, 330, 20126 
Milan (MI), Italy or its designee (e.g. CMO).  
Only in some particular cases, after the authorization of Italfarmaco S.p.A. (or after a signed 
agreement between the investigational site and Italfarmaco S.p.A.), these materials can be 
destroyed locally. 
4.5.1 Laboratory evaluations and vital signs assessment  
The laboratory examinations (haematology, blood chemistry and urinalysis) will be performed in 
the local laboratory of each site. In addition, the vital signs assessment, the ECG 
assessment/evaluation and the QTc determination (according with Bazett’s correction formula, 
Appendix D) will be performed at each investigational site.  
All these results will be transcribed into the CRF and the original signed and dated laboratory 
print-out/tracings, including the ECG and source document, will be monitored and stored at the 
study site. Of note, if the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a 
QTc interval  450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 
minutes between each recording) must be performed. The averaged value of these three 
ECG evaluations has to be used for the evaluation of the QTc interval of the related visit. 
In the CRF all the performed ECG evaluations have to be entered as well as the average 
value of multiple ECG evaluation, if necessary. 
The laboratory examinations, the vital signs assessment, the ECG evaluation including the QTc 
determination are listed below: 
1) Haematology 
 
 Red blood cells (RBC) count, haematocrit (HCT), haemoglobin (Hb), mean corpuscular 
volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin 
concentration (MCHC), white blood cells (WBC) count (full and differential), platelets 
(PLT) count.  


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2) Blood chemistry 
ALT/SGPT, 
AST/SGOT, 
alkaline 
phosphatase 
(ALP), 
total 
bilirubin, 
lactic 
dehydrogenase (LDH), creatinine, blood urea nitrogen (BUN) or Urea (see Appendix F to 
convert Urea to BUN), glucose, sodium (Na), potassium (K), calcium (Ca), chloride (Cl), 
magnesium (Mg), albumin, eGFR determination (according with the Mayo Clinic 
Quadratic Equation). 
3) Urinalysis 
pH, specific gravity, protein, glucose. 
4) Vital signs 
Respiratory rate, pulse rate and sitting blood pressure will be measured after 5 minutes of 
rest. 
5) ECG and QTc 
ECG assessment and evaluation, QTc determination (according with Bazett’s correction 
formula, Appendix D). Of note, if the first ECG evaluation demonstrates a prolonged 
QTc interval (i.e. a QTc interval  450 msec), two additional ECG evaluations over 
a brief period of time (i.e. 5 minutes between each recording) must be performed. 
The averaged value of these three ECG evaluations has to be used for the evaluation 
of the QTc interval of the related visit. In the CRF all the performed ECG 
evaluations have to be entered as well as the average value of multiple ECG 
evaluation, if necessary. 
4.5.3.1 Spleen evaluation  
The spleen evaluation must be performed at the study centre according to the visit schedule 
outlined in the flow-chart (Appendix A). 
The spleen evaluation will be performed during the study according to institutional guidelines 
and site-specific clinical practice (i.e. MRI or CT scan). The same imaging technique and the 
same instrument to assess spleen dimension (i.e. MRI or CT scan) should be used on a patient 
throughout the study, if possible.  
If possible, the spleen dimension will be evaluated as longitudinal diameter (hereafter “A”), 
antero-posterior diameter (hereafter “B”), transversal diameter (hereafter “C”) and Splenic 
Volumetric Index (hereafter “SVI”): 
SVI = (A x B x C) / 27 
No spleen evaluation will be performed in splenectomised patients. 


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4.5.3.2 PK characterization  
Approximately 5.0 mL of blood for pharmacokinetic assessment will be collected as following 
described:  
1) Day 1 of Cycle 1 of Parts A and B: before the first Givinostat dose (pre-dose) and 2, 3 
and 8 (before the second Givinostat dose) hours after the first drug administration 
(Appendix A).  
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 1 (pre-dose) of 
Cycle 1 of Parts A and B and after that the patient will take the first drug administration 
(e.g. at 8.00 a.m.); then, the patient will perform the PK post-dose evaluations at 10.00 
a.m. (hour 2), 11.00 a.m. (hour 3) and at 16.00 p.m. (hour 8). 
2) Day 28 of the Cycle 1 of Part A: before the first daily Givinostat dose (pre-dose) and 1, 2, 
4 and 8 (before the second Givinostat dose) after the first daily drug administration 
(Appendix A).  
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 28 of Cycle 1 
(pre-dose) of Part A and after that the patient will take the first daily drug administration 
(e.g. at 8.00 a.m.); then, the patient will perform the PK post-dose evaluations at 9.00 
a.m. (hour 1), 10.00 a.m. (hour 2), 12.00 p.m. (hour 4) and at 16.00 p.m. (hour 8). 
3) Day 28 of the Cycles 2, 3, 4, 5, and 6 of Part A: before the first daily Givinostat dose 
(pre-dose) (Appendix A).  
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 28 of Cycle 2 and 
beyond Cycles (i.e. Cycles 3, 4, 5 and 6) of Part A (pre-dose) and after that the patient 
will take the first daily drug administration (e.g. at 8.00 a.m.). 
4) Day 28 of Cycle 2 of Part B: before the first daily Givinostat dose (pre-dose) and 1, 2, 4 
and 8 (before the second Givinostat dose) hours after the first daily drug administration 
(Appendix A). 
e.g.: the PK pre-dose evaluation will be performed at 7.45 a.m. of Day 28 of Cycle 2 
(pre-dose) of Part B and after that the patient will take the first daily drug administration 
(e.g. at 8.00 a.m.); then, the patient will perform the PK post-dose evaluations at 9.00 
a.m. (hour 1), 10.00 a.m. (hour 2), 12.00 a.m. (hour 4) and at 16.00 p.m. (hour 8). 
The PK samples should be drawn as closely to the predefined time as possible. 
The exact timing of PK sampling could be adjusted based on emerging clinical and preclinical 
data. 
For all time points an additional PK blood sample will be collected as back-up sample. 
This assessment is mandatory and will be performed by a central laboratory. The exact date and 
time of the PK blood draws will be recorded along with the date and time of the last dose of 
study drug preceding the blood draw. Additional information about the PK time points, 
instructions for sample preparation and shipment will be provided in the related study handling 
manual. 


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After evaluation of preliminary results and data exploration, some additional analyses may 
be performed to identify and quantify other molecular parameters of interest in term of 
improving of the knowledge of cMPN and the activity of the drug in these disorders.  
4.5.3.3 PD characterization  
Approximately 4.0 mL of blood for pharmacodynamic markers will be collected before the first 
Givinostat dose (pre-dose) and 12 hours after the first Givinostat dose (post-dose) at Day 1 of 
Cycle 1 both in Part A and in Part B for measurement of levels of molecular markers, to evaluate 
the pharmacodynamic effect of Givinostat and to identify markers predictive of clinical benefit 
of Givinostat (Appendix A). In addition, pharmacodynamic evaluations will be performed 
also using an aliquot of the PK samples collected at time points described in the paragraph 
4.5.3.2 [34]. The molecular markers to be measured may include mRNA levels of JAK2, 
STAT5A, BclXL, PIM1, NFE2, LMO2, cMyc as well as HDAC3, STAT4, MYBL1, MEGF9, 
GLRX, FAM49A. The final list of pharmacodynamic markers to be measured will depend on 
ongoing scientific developments as well as availability of assays and other business 
considerations.  
For all time points an additional PD blood sample will be collected as back-up sample. 
This assessment is mandatory and will be performed by a central laboratory. The exact date and 
time of the PD blood draws will be recorded along with the date and time of the last dose of 
study drug preceding the blood draw. Instructions for sample preparation and shipment will be 
provided in a separate and specific laboratory manual. 
After evaluation of preliminary results and data exploration, some additional analyses may be 
performed to identify and quantify other molecular parameters of interest in term of improving of 
the knowledge of cMPN and the activity of the drug in these disorders.  
4.5.3.4 JAK2V617F characterization  
JAK2V617F characterization (i.e. JAK2V617F allele burden evaluated by quantitative RT-PCR) will 
be performed in a central laboratory (Appendix E). Detailed instructions for sample preparation 
and shipment will be provided in a separate and specific laboratory manual.  
For all time points a blood sample will be collected as back-up sample. 
After evaluation of preliminary results and data exploration, some additional analyses may 
be performed to identify and quantify other molecular parameters of interest in term of 
improving of the knowledge of cMPN and the activity of the drug in these disorders.  


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4.5.4.1.1 Pre-treatment evaluations (up to 4 weeks: -28 to Day -1) 
The following procedures will be performed at the pre-treatment visit of Cycle 1 of  Part A as 
reported below: 
•
Informed consent signing; 
•
Demographic data (race, sex and date of birth); 
•
Adverse event recording; 
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Medical history;  
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), height, weight, 
body temperature and ECOG performance status;  
•
Pregnancy test (if indicated);  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or 
Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula);  
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F 
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire; 
•
Request of enrolment and receipt of patient ID. 
Appendix A (in particular, paragraph 10.1.1.1) summarize timing information. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 
[28]  1 within 7 days of initiating study drug. 
The pregnancy test (if indicated) has to be performed within 72 hours before the first Givinostat 
dose. The test can be performed by urine or serum pregnancy test. In case of a borderline-
positive urine pregnancy test, this must be confirmed with a serum pregnancy test and the result 
recorded in the CRF. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status [28] 
1 within 7 days of initiating study drug. 
If the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 


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evaluations has to be used for the evaluation of the QTc interval requested by the exclusion 
criterion n. 3. In the CRF all the performed ECG evaluations have to be entered as well as 
the average value of multiple ECG evaluation, if necessary.  
Patients with splenomegaly will perform the spleen evaluation as per site-specific clinical 
practice. Therefore, patients with splenomegaly before the treatment start will be followed 
according to institutional guidelines (i.e. MRI or CT scan). The same imaging technique and the 
same instrument should be used on a patient throughout the study, if possible. No spleen 
evaluation will be performed in splenectomised patients. 
Pre-treatment evaluations will be performed at one or more clinic visit to determine eligibility for 
the study. Pre-treatment evaluations must be performed up to 4 weeks before the treatment start 
within ± 7 days. 
If all eligibility criteria are met at the pre-treatment visit, the treatment with Givinostat can start.  
After the check that all eligibility criteria are met by the patient and in any case before the 
treatment start, all patients with an uncontrolled HCT (i.e. HCT  45%) have to perform at least 
one phlebotomy to normalize (if possible) the HCT value (i.e. HCT <45%).  
In case of patients phlebotomy-dependent, all efforts have to be afforded by Investigators to 
record all phlebotomies witch recruited patients experienced at least 6 months before the 
treatment start. 
4.5.4.1.2 Cycle 1 
Appendix A (in particular, paragraph 10.1.1.1) summarize timing information. 
Patients can take drug at home, except for the first drug administration.
If the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval. In the CRF all the 
performed ECG evaluations have to be entered as well as the average value of multiple 
ECG evaluation, if necessary. 
Day 1 
The following procedures must be performed exactly at Day 1 of Cycle 1 of Part A as reported 
below:  
1) Pre-dose evaluations: 
The following procedures will be performed before the first Givinostat dose as reported 
below: 


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•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable); 
•
Physical examination, weight, body temperature and ECOG performance status; 
•
Vital signs (blood pressure, pulse rate, respiratory rate);  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, 
BUN or Urea (as per site-specific clinical practice; see Appendix F to convert 
Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination 
(according with the Mayo Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula);  
•
PD sample collection; 
•
PK sample collection and preparation, in order to allow to perform both the 
PK and PD evaluations starting from the same sample [34].  
2) Post-dose evaluations: 
The following procedures will be performed after the first Givinostat dose as reported 
below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable); 
•
Vital signs (blood pressure, pulse rate, respiratory rate) 4 hours after the first 
Givinostat dose;  
•
ECG, QTc determination (according with Bazett’s correction formula) 3 hours 
after the first Givinostat dose; 
•
PD sample collection 12 hours after the first Givinostat dose; 
•
PK sample collection (2, 3 and 8 hours post-dose) and preparation, in order to 
allow to perform both the PK and PD evaluations starting from the same 
sample [34]; 
•
First Givinostat dose and accountability. 


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Day 2 
The following procedures will be performed exactly at Day 2 of Cycle 1 of Part A as reported 
below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Used/unused/partially used Givinostat supply return, Givinostat administration and 
Givinostat accountability.
Days 3 and 4 
The following procedures will be performed exactly at Days 3 and 4 of Cycle 1 of Part A as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Used/unused/partially used Givinostat supply return, Givinostat administration and 
Givinostat accountability. 
Days 8, 15 and 22 
The following procedures will be performed at Days 8, 15 and 22 of Cycle 1 of Part A (within ±
3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 


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•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Used/unused/partially used Givinostat supply return, Givinostat administration and 
Givinostat accountability. 
Day 10 
The following procedures will be performed at Day 10 of Cycle 1 of Part A (within ± 3 days) as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Used/unused/partially used Givinostat supply return, Givinostat administration and 
Givinostat accountability. 
Days 28 
The following procedures will be performed at Day 28 of Cycle 1 of Part A (within ± 3 days) as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  


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•
PK sample collection (pre-dose and 1, 2, 4 and 8 hours post-dose) and preparation, in 
order to allow to perform both the PK and PD evaluations starting from the same 
sample [34]; 
•
Used/unused/partially used Givinostat supply return, Givinostat administration and 
Givinostat accountability. 
End of Study 
In case of the patient drops-out of the study, the following procedures will be performed 7 days 
after last drug intake (within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN response 
criteria [21] (see paragraph 4.6.1); 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire; 
•
Used/unused/partially used Givinostat supply return and Givinostat accountability. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until it is 
reasonable to consider the event not drug related any more or until the start of a new 
treatment, whichever occurs first.  


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If the patient needs to take one of the concomitant medications included in list of “Drugs 
with risk of Torsades de Pointes” (see Appendix C) the treatment with Givinostat is to be 
promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-up 
visits until recovery. If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient. In any circumstance every effort should be made to complete 
and report the observations as thoroughly as possible. All relevant information related to 
the reason for treatment discontinuation including contributory factors must be included 
on the CRF. 
At study close-out, and as appropriate during the course of the study, the Investigator will return 
all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A., - Dipartimento di Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126 
Milan (MI), Italy, or their designee.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed 
agreement between the investigational site and Italfarmaco S.p.A.), these materials can be 
destroyed locally. 
4.5.4.1.3 Cycles 2, 3, 4, 5 and 6 
Appendix A (in particular, paragraph 10.1.1.2) summarize timing information. 
Patients with splenomegaly will perform the spleen evaluation as per site-specific clinical 
practice. Therefore, patients with splenomegaly before the treatment start will be followed 
according to institutional guidelines (i.e. MRI or CT scan). The same imaging technique and the 
same instrument should be used on a patient throughout the study, if possible. No spleen 
evaluation will be performed in splenectomised patients. The spleen evaluation must be 
performed at the study centre according to the visit schedule outlined in the flow-chart 
(Appendix A). 
If the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval. In the CRF all the 


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performed ECG evaluations have to be entered as well as the average value of multiple 
ECG evaluation, if necessary. 
Day 1 
The following procedures will be performed at Day 1 of Cycles 2, 3, 4, 5 and 6 of Part A (within 
± 3 days) as reported below: 
•
First Givinostat dose of the related cycle and accountability. 
Day 28 of Cycles 2, 4 and 5 
The following procedures will be performed at Day 28 of Cycles 2, 4 and 5 of Part A (within ± 3 
days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
PK sample collection (pre-dose) and preparation, in order to allow to perform both 
the PK and PD evaluations starting from the same sample [34]; 
•
Used/unused/partially used Givinostat supply return, Givinostat administration and 
Givinostat accountability. 
Day 28 of Cycles 3 and 6 
The following procedures will be performed at Day 28 of Cycles 3 and 6 of Part A (within ± 3 
days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 


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•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
PK sample collection (pre-dose) and preparation, in order to allow to perform both 
the PK and PD evaluations starting from the same sample [34]; 
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN response 
criteria [21] (see paragraph 4.6.1); 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire; 
•
Givinostat administration (only for cycle 3); 
•
Used/unused/partially used Givinostat supply returnGivinostat administration and 
Givinostat accountability. 
All phlebotomies performed in the first 3 weeks of treatment will be not counted to assess the 
clinico-haematological response according to the clinico-haematological ELN response criteria 
[21] (see paragraph 4.6.1);. 
End of Study 
The following procedures will be performed at the end of study visit (in case of completed study) 
or 7 days after last drug intake (in case of the patient drops-out of the study) (within ± 3 days) as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 


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•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN response 
criteria [21] (see paragraph 4.6.1); 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire; 
•
Used/unused/partially used Givinostat supply return and accountability. 
In case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can be 
counted for the End of Study visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations 
requested to be done at the Day 28 of Cycle 6) and she/he is eligible to continue the study 
drug treatment in the long-term study (i.e. Study DSC/11/2357/44), the evaluation 
performed at the Cycle 6 Day 28 visit of this study can be also counted for the pre-
treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluation is present between the two studies (e.g. haematological and biochemical 
evaluations). No additional Givinostat study (i.e. Study DSC/12/2357/45)-specific 
assumption has to be done at the completion of the Day 28 of Cycle 6. Indeed, in case the 
patient completes the study (i.e. performs all the evaluations requested to be done at the 
Day 28 of Cycle 6 of this study), she/he is eligible to continue the study drug treatment in 
the long-term study (i.e. Study DSC/11/2357/44) and she/he receive the written 
authorization of the treatment from the Sponsor of their designee (i.e. a patient’s 
confirmation form that includes the patient ID to use into the Study DSC/11/2357/44), the 
patient will continue the study drug treatment into the Study DSC/11/2357/44, receiving the 
study (i.e. Study DSC/11/2357/44)-specific drug to be taken. 


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                                 Study N.:       DSC/12/2357/45
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As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until it is 
reasonable to consider the event not drug related any more or until the start of a new 
treatment, whichever occurs first.  
If the patient needs to take one of the concomitant medications included in list of “Drugs 
with risk of Torsades de Pointes” (see Appendix C) the treatment with Givinostat is to be 
promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-up 
visits until recovery. If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient. In any circumstance every effort should be made to complete 
and report the observations as thoroughly as possible. All relevant information related to 
the reason for treatment discontinuation including contributory factors must be included 
on the CRF. 
At study close-out, and as appropriate during the course of the study, the Investigator will return 
all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A., Dipartimento di Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126 Milan 
(MI), Italy, or theirits designee.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed 
agreement between the investigational site and Italfarmaco S.p.A.), these materials can be 
destroyed locally. 
4.5.4.2 Part B
Appendix A (in particular, paragraph 10.1.2) summarize timing information. 
Patients should be told to arrive after an overnight fast of at least 8 hours at all study visits 
that request a blood test. However, the study visits should still be conducted even if the 
patient does not adhere to fasting requirements and this will not be considered a protocol 
violation. In these cases, this information (i.e. not fasting condition) has to be noted by the 
Investigator in the medical chart and reported in CRF, in order to avoid any 
misunderstanding of the collected data (e.g. glucose value is influenced by fasting/ not 
fasting conditions).    


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If the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval. In the CRF all the 
performed ECG evaluations have to be entered as well as the average value of multiple 
ECG evaluation, if necessary. 
The spleen evaluation Patients with splenomegaly will be performed during the study 
according to institutional guidelines and the spleen evaluation as per site-specific clinical 
practice (i.e. MRI or CT scan). Therefore, patients with splenomegaly before the treatment 
start will be followed according to institutional guidelines (i.e. MRI or CT scan). The same 
imaging technique and the same instrument should be used on a patient throughout the study, if 
possible. No spleen evaluation will be performed in splenectomised patients. 
Patients can take drug at home, except for the first drug administration. 
4.5.4.2.1 Pre-treatment evaluations (up to 4 weeks: -28 to Day -1) 
The following procedures will be performed at the pre-treatment visit of Part B as reported 
below: 
•
Informed consent signing; 
•
Demographic data (race, sex and date of birth); 
•
Adverse event recording; 
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Medical history;  
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), height, 
weight, body temperature and ECOG performance status;  
•
Pregnancy test (if indicated);  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Urinalysis: pH, specific gravity, protein, glucose;


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•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire [24, 
32]; 
•
Bone marrow histological evaluation, in patients who have consented to this optional 
exploratory research, who haven’t this assessment in the month before the 1 month before 
the study start (i.e the signature of the Informed Consent Form, and that have not any 
medical contraindication to bone marrow sampling as judged by the Investigator); 
•
Request of enrolment and receipt of patient ID. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance 
status [28]  2 within 7 days of initiating study drug. 
The pregnancy test (if indicated) has to be performed within 72 hours before the first 
Givinostat dose. The test can be performed by urine or serum pregnancy test. In case of a 
borderline-positive urine pregnancy test, this must be confirmed with a serum pregnancy test 
and the result recorded in the CRF. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status [28] 
 2 within 7 days of initiating study drug. 
Patients with splenomegaly will perform the spleen evaluation as per site-specific clinical 
practice. Therefore, patients with splenomegaly before the treatment start will be followed 
according to institutional guidelines (i.e. MRI or CT scan). The same imaging technique and 
the same instrument should be used on a patient throughout the study, if possible. 
Pre-treatment evaluations will be performed at one or more clinic visit to determine 
eligibility for the study. Pre-treatment evaluations must be performed up to 4 weeks before 
the treatment start within ± 7 days.  
Please note that, in case the patient performs the bone marrow histological evaluation as 
requested by the “new” ELN criteria (i.e. the revised ELN response criteria) [33] (see 
paragraph 4.8.7) – i.e. bone marrow evolution including the assessment of the presence of 
age adjusted normocellularity and/or trilinear hyperplasia - 1 month before the study start (i.e 
the signature of the Informed Consent Form), this examination has not to be repeated for this 
study in order to limit the discomfort for the patient. In any case, the results of this test will 


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be transcribed into the CRF and the original signed and dated laboratory print-out/tracings, 
including the assessment of the presence of age adjusted normocellularity and/or trilinear 
hyperplasia, will be monitored and stored at the study site. 
In case the patient refuses to provide this written consent to perform the bone marrow 
evaluation, this patient can be anyway recruited in Part B. However, this patient will not be 
counted to assess the related exploratory endpoints (i.e. overall response rate of Givinostat at 
the MTD after 6 cycles according to the revised ELN response criteria [33], and the 
evaluation of the effect of Givinostat on each single response parameter according to the 
revised ELN response criteria [33]).   
If all eligibility criteria are met at the pre-treatment visit, the treatment with Givinostat can 
start. 
After the check that all eligibility criteria are met by the patient and in any case before the 
treatment start, all patients with an uncontrolled HCT (i.e. HCT  45%) have to perform 
phlebotomy(ies) to normalize the HCT value (i.e. HCT <45%).  
In case of patients who are phlebotomy-dependent, all efforts have to be made by 
Investigators to record all phlebotomies witch recruited patients experienced at least 6 
months before the treatment start. 
4.5.4.2.2 Day 1 of Cycle 1 
The following procedures must be performed exactly at Day 1 of Cycle 1 of Part B as reported 
below:  
1) Pre-dose evaluations: 
The following procedures will be performed before the first Givinostat dose as reported 
below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable); 
•
PD sample collection; 
•
PK sample collection and preparation, in order to allow to perform both the 
PK and PD evaluations starting from the same sample [34] (if requested). 


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2) Post-dose evaluations: 
The following procedures will be performed after the first Givinostat dose as reported 
below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if 
applicable); 
•
PD sample collection 12 hours after the first Givinostat dose; 
•
PK sample collection (2, 3 and 8 hours post-dose) and preparation, in order to 
allow to perform both the PK and PD evaluations starting from the same 
sample [34] (if requested); 
•
First Givinostat dose and accountability. 
4.5.4.2.3 Day 28 of Cycles 1, 2, 4 and 5 
The following procedures will be performed at Day 28 of Cycles 1, 2, 4 and 5 of Part B (within 
± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Used/unused/partially used Givinostat supply return, Givinostat administration and 
Givinostat accountability; 


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                                 Study N.:       DSC/12/2357/45
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•
Only at Cycle 2: PK sample collection (pre-dose and 1, 2, 4 and 8 hours post-dose) and 
preparation, in order to allow to perform both the PK and PD evaluations starting 
from the same sample [34] (if requested)at Cycle 2 only;.
•
Givinostat administration and accountability. 
4.5.4.2.4 Day 28 of Cycles 3 and 6 
The following procedures will be performed at Day 28 of Cycles 3 and 6 of Part B (within ± 3 
days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable);
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire [24, 
32]; 
•
Bone marrow histological evaluation (only for cycle 6) in patients who have consented to 
this optional exploratory research and that have not any medical contraindication to bone 
marrow sampling as judged by the Investigator; 
•
Therapeutic response evaluation according to the clinico-haematological ELN response 
criteria [21] (see paragraph 4.6.1); 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
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•
Therapeutic response evaluation according to the “new” ELN criteria (i.e. revised ELN 
response criteria) [33] (see paragraph 4.8.7) (only for cycle 6); 
•
Only for Cycle 3: Givinostat administration; 
•
Used/unused/partially 
used 
Givinostat 
supply 
return,
and 
Givinostat 
admistrationccountability and accountability (only for cycle 3). 
All phlebotomies performed in the first 3 weeks of treatment will be not counted to assess the 
therapeutic response. 
4.5.4.2.5 End of study 
The following procedures will be performed at the end of study visit (in case of completed study) 
or 7 days after last drug intake (in case of the patient drops-out of the study) (within ± 3 days) as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN), 
glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation); 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
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•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire [24, 
32]; 
•
Bone marrow histological evaluation, in patients who have consented to this optional 
exploratory research, and that have not any medical contraindication to bone marrow 
sampling as judged by the Investigator; 
•
Therapeutic response evaluation according to the clinico-haematological ELN response 
criteria [21] (see paragraph 4.6.1); 
•
Therapeutic response evaluation according to the “new” ELN criteria (i.e. revised ELN 
response criteria) [33] (see paragraph 4.8.7); 
•
Used/unused/partially used Givinostat supply return and Givinostat accountability. 
In case the patient drops-out the study during the first 3 Cycles (i.e. before the Day 28 of Cycle 
3), the bone marrow histological evaluation is has not to be performed at End of Study visit. 
In case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can be 
counted for the End of Study visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations 
requested to be done at the Day 28 of Cycle 6) and she/he is eligible to continue the study 
drug treatment in the long-term study (i.e. Study DSC/11/2357/44), the evaluation 
performed at the Cycle 6 Day 28 visit of this study can be also counted for the pre-
treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluation is present between the two studies (e.g. haematological and biochemical 
evaluations). No additional Givinostat study (i.e. Study DSC/12/2357/45)-specific 
assumption has to be done at the completion of the Day 28 of Cycle 6. Indeed, in case the 
patient completes the study (i.e. performs all the evaluations requested to be done at the 
Day 28 of Cycle 6 of this study), she/he is eligible to continue the study drug treatment in 
the long-term study (i.e. Study DSC/11/2357/44) and she/he receive the written 
authorization of the treatment from the Sponsor of their designee (i.e. a patient’s 
confirmation form that includes the patient ID to use into the Study DSC/11/2357/44), the 
patient will continue the study drug treatment into the Study DSC/11/2357/44, receiving the 
study (i.e. Study DSC/11/2357/44)-specific drug to be taken. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until it is 
reasonable to consider the event not drug related any more or until the start of a new 
treatment, whichever occurs first.  


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                                 Study N.:       DSC/12/2357/45
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If the patient needs to take one of the concomitant medications included in list of “Drugs 
with risk of Torsades de Pointes” (see Appendix C) the treatment with Givinostat is to be 
promptly discontinued and the patient must leave the study. 
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-up 
visits until recovery. If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient. In any circumstance every effort should be made to complete 
and report the observations as thoroughly as possible. All relevant information related to 
the reason for treatment discontinuation including contributory factors must be included 
on the CRF. 
At study close-out, and as appropriate during the course of the study, the Investigator will return 
all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A., - Dipartimento di Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126 
Milan (MI), Italy or their designee.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed 
agreement between the investigational site and Italfarmaco S.p.A.), these materials can be 
destroyed locally. 
4.6.1 Criteria for assessing clinico-haematological improvement 
Disease response will be evaluated according to the following clinico-haematological ELN 
criteria [21] (see paragraph 4.6.1) after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of 
treatment with Givinostat both in Part A (exploratory endpoints) and in Part B (primary and 
secondary endpoints, respectively).  
•
Complete response:  
1. HCT<45% without phlebotomy, and 
2. Pplatelets  400 x109/L, and 
3. WBC 10 x109/L, and 
4. Normal spleen size, and 
5. Nno disease-related systemic symptoms (i.e. pruritus, headache, microvascular 
disturbances). 


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•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1. HCT <45% without phlebotomy, or  
2. Rresponse in 3 or more of the other criteria. 
•
No response: any response that does not satisfy partial response. 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months) and the 
eligibility for this part of the study may be expanded to all patients with cMPN, disease response 
for this part of the study will be evaluated according to the clinico-haematological ELN and 
EUMNET criteria [29] after 3 and 6 cycles of treatment with Givinostat, in ET and MF patients, 
respectively. 
For ET (from the clinico-hematological ELN response criteria): 
•
Complete response:  
1. Pplatelets  400 x109/L, and 
2. Nno disease related systemic symptoms (i.e. pruritus, headache, microvascular 
disturbances), and 
3. Nnormal spleen size, and 
4. WBC 10 x109/L. 
•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1. Platelet count < 600 x 109/L, or  
2. Platelet count decrease > 50% from baseline. 
•
No response: any response that does not satisfy partial response. 
Both for PV and ET patients, all phlebotomies performed in the first 3 weeks of treatment will 
not be counted to assess the clinico-haematological response. 
For MF (from EUMNET response criteria)  
•
Complete response: complete response in anemia, splenomegaly, constitutional 
symptoms, platelet and leukocyte count.
1. Complete response in anaemia: Haemoglobin  12 g/dL for transfusion-independent 
patients or  11 g/dL for transfusion-dependent patients (applicable only for patients 
with baseline haemoglobin level of < 10 g/dL); 
2. Complete response in splenomegaly: Spleen not palpable; 
3. Complete response in constitutional symptoms: Absence of constitutional symptoms 
(fever, drenching night sweats, or  10% weight loss); 
4. Complete response in platelet count: Platelet count 150-400 x109/L; 
5. Complete response in leukocyte count: Leukocyte count 4-10 x109/L. 


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•
Major response: Any response in both anaemia and splenomegaly without progression in 
constitutional symptoms or complete response in anaemia without progression in 
splenomegaly or partial response in anaemia in a baseline transfusion-dependent patient 
combined with response in constitutional symptoms without progression in splenomegaly 
or any response in splenomegaly combined with response in constitutional symptoms 
without progression in anaemia.
1. Partial response in splenomegaly: Either  50% decrease in spleen size if baseline 
10 cm from left costal margin (LCM) or  30% decrease if baseline > 10 cm from 
LCM. 
2. Partial response in platelet count: A  50% decrease in platelet count if baseline > 
800 x109/L or platelet count increase by   50% x 109/L if baseline < 100 x109/L. 
3. Partial response in leukocyte count: A  50% decrease in leukocyte count of baseline 
>  20 x109/L or leukocyte count increase by  1 x109/L if baseline < 4 x109/L 
4. Progression in anaemia: A hemoglobin decrease of  2 g/dL  or  a 50% increase in 
transfusion requirement or becoming transfusion dependent 
5. Progression in splenomegaly: A  50% increase in spleen size if baseline  10 cm 
from LCM or a  30% increase if baseline > 10 cm from LCM. 
6. Progression in constitutional symptoms: Appearance of constitutional symptoms. 
•
Moderate response: Complete response in anaemia with progression in splenomegaly or 
partial response in anaemia without progression in  splenomegaly or any response in 
splenomegaly without progression in   anaemia and constitutional symptoms.  
•
Minor response: Any leukocyte- or platelet-based response without progression in 
anaemia, splenomegaly, or constitutional symptoms.
•
No response: Any response that does not qualify at least as minor response. 
In all cases (PV, ET and MF patients), the disease-related systemic symptoms will be evaluated 
directly by patients according to MPN-SAF QOL questionnaire [24, 32]. 
In all cases, the response status of the patient may be reviewed by a panel of independent 
Investigators, if necessary. 
4.6.3 Criteria for characterization of PK 
Plasma concentrations from Parts A and B will be evaluated by dose and time point for all 
patients and time points with at least one 1 PK assessment. 
4.6.4 The Efficacy Population 
The analysis sets are defined in the paragraph 6.2.1.  


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Patients with a disease-related global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported in 
CRF as disease progression clinically assessed. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
The response status of the patient may be reviewed if necessary by a panel of independent 
investigators, if necessary. 
4.7.1 Laboratory evaluations  
The following laboratory examinations (haematology, blood chemistry and urinalysis) will be 
performed at each investigational unit by a local  laboratory co-operating with the Investigator 
following its own procedures:  
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
or Urea (as per site-specific clinical practice; see Appendix F to convert Urea to BUN) 
, glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with the Mayo 
Clinic Quadratic Equation);
•
Urinalysis: pH, specific gravity, protein, glucose.
The required amount of blood and urine will be collected at each visit as scheduled above.
Appendix A and paragraph 4.5.4 summarize timing information. 
All results of laboratory examinations will be entered into the appropriate CRF sections. The 
original laboratory print-outs will be filed in the patient file at the study site. 
Of note, if the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
 450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval of the related visit. In the 
CRF all the performed ECG evaluations have to be entered as well as the average value of 
multiple ECG evaluation, if necessary. 
4.7.2 Clinical safety assessments 
Clinical safety assessments will include a thorough physical examination, vital signs assessment 
(respiratory rate, pulse rate and sitting blood pressure will be measured after 5 minutes of rest), 


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weight, body temperature, ECOG performance status, ECG assessment and evaluation, QTc 
determination (according with Bazett’s correction formula, Appendix D).  
Appendix A and paragraph 4.5.4 summarize timing information. 
All results of the above mentioned clinical safety assessments will be entered into the appropriate 
CRF sections. The original print-outs related to these evaluations, including the ECG and QTc 
recording, will be filed in the patient file at the study site.  
Of note, if the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval 
 450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes 
between each recording) must be performed. The averaged value of these three ECG 
evaluations has to be used for the evaluation of the QTc interval of the related visit. In the 
CRF all the performed ECG evaluations have to be entered as well as the average value of 
multiple ECG evaluation, if necessary. 
4.7.3  Adverse events 
All AEs either observed by the Investigator, or reported by the patient spontaneously or in a 
response to a direct question must be evaluated by the Investigator and will be recorded on the 
AE section of the CRF. 
For AEs definitions, coding and reporting procedures see paragraph 5. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until it is 
reasonable to consider the event not drug related any more or until the start of a new 
treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-up 
visits until recovery. If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient. In any circumstance every effort should be made to complete 
and report the observations as thoroughly as possible. All relevant information related to 
the reason for treatment discontinuation including contributory factors must be included 
on the CRF. 
For AEs definitions, coding and reporting procedures see paragraph 5. 


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4.8.3 Spleen size assessment  
The spleen evaluation must be performed at the study centre according to the visit schedule 
outlined in the flow-chart (Appendix A). 
To evaluate the effects of Givinostat on spleen size (by MRI or CT scan) in patients with 
confirmed splenomegaly before the treatment start will be used MRI or CT scan.  
The spleen evaluation Patients with splenomegaly will be performed followed during the study 
according to institutional guidelines and site-specific clinical practice (i.e. MRI or CT scan). For 
this reason, it is strictly recommended to the sites  to provide the Sponsor or their designee 
with the local normal spleen values of the imaging performed for each patient according 
institutional guidelines and site-specific clinical practice (i.e. MRI or CT scan). 
The same imaging technique and the same instrument to assess spleen dimension (i.e. MRI or 
CT scan) should be used on a patient throughout the study, if possible.  
If possible, the spleen dimension will be evaluated as longitudinal diameter (hereafter “A”), 
antero-posterior diameter (hereafter “B”), transversal diameter (hereafter “C”) and Splenic 
Volumetric Index (hereafter “SVI”): 
SVI = (A x B x C) / 27 
4.8.4 Improvement of constitutional symptoms  
To evaluate the improvement of disease-related constitutional symptoms, the Myeloproliferative 
Neoplasm Symptom Assessment Form (MPN-SAF) questionnaire (about 20 items) will be used 
in Parts A and B,  in order to assess the most important clinical symptoms among patients with 
MPNs [24].  
In addition, starting from MPN-SAF questionnaire, in Part B also the MPN-SAF Total Symptom 
Score [32] will be assessed as requested by the “new” ELN criteria (i.e. revised ELN response 
criteria) [32].  
4.8.8 Evaluation of the effects of Givinostat on each single parameter of the revised ELN 
response criteria 
Each single parameter of the “new” ELN criteria (i.e. revised ELN response criteria) [33] (see 
paragraph 4.8.7) will be used to evaluate the effect of Givinostat in PV patients in Part B. 


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5. 
ADVERSE EVENTS 
The Investigator is responsible for the detection and documentation of AEs as defined in this 
protocol. AE data will be obtained at all study visits, based on information spontaneously 
provided by the patient and/or through questioning. Additionally, patients will be advised that 
they can contact the Investigator at any time to report or discuss AEs. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until it is 
reasonable to consider the event not drug related any more or until the start of a new 
treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-up 
visits until recovery. If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient. In any circumstance every effort should be made to complete 
and report the observations as thoroughly as possible. All relevant information related to 
the reason for treatment discontinuation including contributory factors must be included 
on the CRF. 
5.1.1 Adverse Event (AE) 
An Adverse Event is “any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment” (ICH E2A). 
AEs include: 
•
Onset of any clinical sign or symptom;
•
Worsening (change in nature, severity or frequency) of conditions present at the start of the 
trial;
•
Patient deterioration due to the primary illness;
•
Intercurrent illnesses; 
•
Drug interactions;


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•
Events related or possibly related to concomitant medications;
•
Abnormal laboratory values, as well as significant shifts from baseline within the range of 
normal, which the investigator considers to be clinically significant. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
5.1.2 Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established: “all noxious and unintended 
responses to a medicinal product related to any dose should be considered Adverse Drug 
Reaction”. 
The phrase "responses to a medicinal products" means that a causal relationship between 
a medicinal product and an adverse event is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
Regarding marketed medicinal products, a well-accepted definition of an adverse drug 
reaction in the post-marketing setting is found in WHO Technical Report 498 [1972] and 
reads as follows: ”a response to a drug which is noxious and unintended and which occurs 
at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for 
modification of physiological function.” 
The old term "side effect" has been used in various ways in the past, usually to describe 
negative (unfavourable) effects, but also positive (favourable) effects. It is recommended 
that this term no longer be used and particularly should not be regarded as synonymous 
with adverse event or adverse reaction. 
5.1.3 Unexpected Adverse Drug Reaction  
An Unexpected Adverse Drug Reaction is “aAn Adverse Drug Reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s Brochure 
for an unapproved investigational medicinal product or summary of product characteristics, SPC, 
for marketed products)”. 
All adverse events judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence 
or argument to suggest a causal relationship. 


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5.1.4 Serious Adverse Event (SAE) 
A Serious Adverse Event (experience) or reaction is “any untoward medical occurrence that at 
any dose: 
•
results is fatal (results in the outcome death); 
•
is life-threatening*; 
•
required in-patient hospitalisation or prolongation of existing hospitalisation; 
•
results in persistent or significant disability/incapacity; 
•
is a congenital anomaly/birth defect; 
•
is medically significant or requires intervention to prevent one or other of the outcomes listed 
above; 
•
consists in the transmission of an infective agent through the IMP.” 
*The term life-threatening refers to an event in which the patient is at risk of  death at the time of 
the event; it does not refer to an event which hypothetically may cause death if it is more 
severe. 
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious in other situations. Important adverse events/ reactions that are not immediately 
life-threatening or do not result in death or hospitalisation but may jeopardise the subject 
or may require intervention to prevent one of the other outcomes listed in the definition 
above, should also be considered serious. 
The pre-planned hospitalization or adverse reaction expected as part of the trial treatment 
(e.g. standard expected side effect of chemotherapy) should not considered as SAE. 
A Suspected Unexpected  Serious Adverse Reaction (SUSAR) is referred to an adverse 
drug reaction which comply with both the definitions of “serious” and “unexpected”. 
5.2 
AE Reporting 
The Investigators or their designees are requested to collect and asses any spontaneous AE 
reported by the patient and to question the patient about AEs and undercurrent illnesses at each 
visit during the treatment period and any follow-up visit performed to monitor any drug-
related AE that is still ongoing beyond the last scheduled visit until recovery. The 
questioning of patients regarding AEs is generalized such as “How have you been feeling since 
your last visit?” Any AE occurring after a patient has signed the Informed Consent form and up 
to the follow-up study visit, whether volunteered by the patient, discovered during general 


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questioning by the Investigators or detected through physical examination, laboratory test or 
other means, will be recorded on the specific section of the CRF. Each AE will be described by:  
- 
the seriousness; 
- 
the duration (start and end dates); 
- 
the severity; 
- 
the relationship with the IMP; 
- 
the action taken.  
The severity of AE should be assessed and graded according to the most recently published NCI 
Common Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010).  
The relationship with the IMP should be assessed as: 
- 
related to IMP; 
- 
not related to IMP; 
- 
unknown.  
The assessment of the relationship of an adverse event with the administration of IMP is a 
clinical decision based on all available information at the time of the completion of the CRF. 
An assessment of “Not related” would include the existence of a clear alternative explanation, or 
non-plausibility. 
An assessment of “Related” indicates that there is a reasonable suspicion that the adverse event 
is associated with the use of the IMP. 
An assessment “Unknown” indicates there is not a reasonable suspicion that the adverse 
event is associated with the use of the IMP and at the same time there is not the existence of 
a clear alternative explanation or non-plausibility. In this case, Investigator has to collect 
all possible information in order to assess the relationship with the IMP, particularly in 
case of Serious Adverse Events. 
Factors to be considered in assessing the relationship of the adverse event to study drug include: 
- 
The temporal sequence from IMP administration; 
- 
The recovery on discontinuation and recurrence on reintroduction; 
- 
The concomitant diseases; 
- 
The evolution of the treated disease; 
- 
The concomitant medication; 
- 
The pharmacology and pharmacokinetics of the IMP; 
- 
The presence of an alternative explanation. 


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5.2.1 Abnormal laboratory findings and other objective measurements 
Abnormal laboratory findings and other objective measurements should not be routinely 
captured and reported as AEs as they will be collected and analysed separately in the CRF. 
However, abnormal laboratory findings and other objective measurements that meet the criteria 
for an SAE, result in discontinuation of the IMP or require medical intervention, or are judged by 
the Investigator to be clinically significant changes from baselines values should be captured and 
reported on the AE pages of the CRF. 
As reported also in the paragraph 4.3.3, if the patient discontinues for any reason 
(including discontinuation for pregnancy), with drug related adverse event ongoing at 
study end, he/she must be followed until resolution or stabilization of the event or until it is 
reasonable to consider the event not drug related any more or until the start of a new 
treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse 
events” should be indicated as the primary reason whenever applicable. All relevant 
information related to the reason for treatment discontinuation including contributory 
factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for 
any patient permanently discontinuing study treatment. Should any drug-related AE still 
be ongoing beyond the last scheduled visit, this must be followed at subsequent follow-up 
visits until recovery. If a patient does not return for a scheduled visit, every effort should be 
made to contact the patient. In any circumstance every effort should be made to complete 
and report the observations as thoroughly as possible. All relevant information related to 
the reason for treatment discontinuation including contributory factors must be included 
on the CRF. 
When reporting an abnormal laboratory finding on the AE pages of the CRF, a clinical diagnosis 
should be recorded in addition to the abnormal value itself, if this is available (for example 
“anaemia” in addition to “haemoglobin = 10.5 g/dl”). 
5.3 
SAE Reporting  
Any SAE, including death from any cause that occurs after a patient has signed the Informed 
Consent and up to any the follow-up visit performed to monitor any drug-related AE that is 
still ongoing beyond the last scheduled visit until recovery (regardless of relationship to study 
drug) must be reported by the Investigators to Italfarmaco S.p.A. within 24 hours of learning of 
its occurrence. 


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Related SAEs MUST be collected and reported regardless of the time elapsed from the last study 
drug administration, even if the study has been closed. Anyway, no active subject monitoring 
by the Investigators is required. 
The Investigators are required to complete the SAE fForm, according with the procedures 
described in the study manual and within 24 hours of learning of its occurrence provided by 
Italfarmaco S.p.A.. Sufficient details must be provided to allow for a complete medical 
assessment of the AE and independent determination of possible causality. The Investigators are 
obliged to pursue and provide additional information as requested by Italfarmaco S.p.A. Drug 
Safety Manager, or Study Director, or their his designee(s). 
The Investigator must notify the SAE to the Drug Safety Unit (hereinafter “DSU”) of
Italfarmaco S.p.A. Drug Safety Unit (DSU) by sending faxing and/or mailing (only in case the 
mail will be automatically generated by the e-CRF) the SAE Fform, according with the 
procedures indicated in the study manual and within 24 hours of a SAE, at the number 
specified belowlearning of its occurrence. ; then, only in case the SAE will be faxed to the 
Italfarmaco S.p.A. DSU, the Investigator must confirm any SAE notifications by mailing to the 
mail address or phoning to the  phone number specified below:The details of the DSU are 
specified here below: 
Italfarmaco S.p.A. 
Drug Safety Unit 
Italfarmaco S.p.A. 
Via dei Lavoratori, 54 
20092 Cinisello Balsamo (MI), Italy 
Phone:  
Fax:   
Fax (back-up):+
Mobile: 
Fax:   
e-mail:  
The same procedure must be applied to the SAE follow-up information. 
All serious and unexpected AE that are associated with the use of the study drug (SUSARs) will 
be notified by Italfarmaco S.p.A. DSU rug Safety Manager to the competent authority within the 
required time and following procedures required by applicable laws. It is imperative that 
Italfarmaco S.p.A. be informed as soon as possible, so that reporting can be done within the 
required time frame.  
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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The SAEs will also be recorded in the dedicated AE section of the CRF. 
5.3.2 Pregnancy   
Female patients who have a positive pregnancy test during the pre-treatment evaluations 
assessment are not eligible for study participation. If a patient becomes pregnant while on study, 
the treatment shall be immediately stopped. The investigator is required to report the pregnancy 
to Italfarmaco S.p.A. Drug Safety Unit (DSU) within 24 hours of learning of its occurrence via 
telephone and/or fax and/or mail (only in case the mail will be automatically generated by the e-
CRF). If initially reported via telephone, this must be followed-up with a written report via fax 
and/or mail (only in case the mail will be automatically generated by the e-CRF) within 24 hours 
of the telephone report.  
Patients should be instructed to notify the investigator if, after completion of the study, it is 
determined that they became pregnant during the treatment phase or through 3 months after the 
last dose of study drug. 
Whenever possible, a pregnancy with an onset within the above defined time frame should be 
followed until termination, any premature termination should be reported, and the status of the 
mother and child should be reported to the sponsor after delivery. 
If the Investigator is made aware that the partner of a male patient who is participating to the 
study become pregnant, he/she is required to report the pregnancy to Italfarmaco S.p.A. DSU 
within 24 hours via telephone and/or fax and/or mail (only in case the mail will be automatically 
generated by the e-CRF). If initially reported via telephone, this must be followed-up with a 
written report via fax and/or mail (only in case the mail will be automatically generated by the e-
CRF) within 24 hours of the telephone report.  
Whenever possible, such pregnancy should be followed until termination, any premature 
termination should be reported, and the status of the mother and child should be reported to the 
sponsor after delivery. 
6.2 
Statistical methods to be employed 
Methods here represent the outline of the intended methods.  
A Statistical Analysis Plan (SAP) will be produced before the database lock and will contain full 
details of all planned summaries, listings and analyses. 


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A standard 3+3 design adopting a modified Fibonacci escalation schema will be used  in Part A
[25, 26, 27].  
Sample size for Part B was discussed for the primary end point defined as the Overall Response 
Rate after 3 cycles. Simon’s 2-stage design will be employed in Part B [30] with the aim of 
testing the “null hypothesis” that RR  0.50 versus the “alternative” that RR  0.75. Response 
rate will be assessed as defined in paragraph 6.2.5.2. Overall up to 28 patients will need to be 
recruited, 12 patients being enrolled in Stage-1. PV patients enrolled at the MTD in Part A may 
be counted towards Stage 1. Under the “null hypothesis” (if RR = 0.50), the expected total 
sample size is of 18.2 patients, the probability of early termination at the end of Stage-1 is 0.613 
and the probability of rejecting the “null hypothesis” is 0.081 (the target for the type-I error 
being 0.100). Under the “alternative hypothesis” (if RR = 0.75), the probability of rejecting the 
“null hypothesis” in favour of the “alternative” is 0.902 (the type-II error being 0.098). After 
testing the treatment on 12 patients in Stage-1, if 6 or fewer patients respond to the treatment the 
trial will be terminated rejecting the “alternative” that RR  0.75. Otherwise, the trial goes on to 
Stage-2 enrolling further 16 patients to a total of 28 patients. If at the end of Stage-2, a total of 17 
or fewer patients respond to the treatment the “alternative hypothesis” that RR  0.75 will be 
rejected; alternatively, if 18 or more patients respond, the “null hypothesis” that RR  0.50 will 
be rejected. Estimations are obtained from proprietary software (based on SAS ® 9.2) according 
to the algorithm proposed by R. Simon [30]. 
Summary statistics will be calculated for all variables. For each continuous variable, the mean, 
standard deviation, median, minimum value and maximum value will be computed. For each 
discrete variable the number of patients in each category with non-missing values in relation to 
all patients with non-missing values of that variable will be provided. Results will be displayed 
within each cohort and overall, where applicable.  Statistical calculations will be carried-out by 
resorting to SAS version 9.2 (or later). Both continuous and categorical data will be summarized 
and tabulated in 2-way tables (variable-by-visit). The main purpose of this phase Ib/II study 
consists in providing accurate estimates of clinically relevant variables and measures. From the 
statistical viewpoint this translates in estimating confidence intervals (CIs) with adequate 
precision where precision represents the degree of uncertainty. 
The two tailed 95% CIs of the sample estimates will be computed using parametric approaches if 
deemed appropriate. Otherwise the StatXact-4 software will be used in order to compute 
Exact/Nonparametric 95% CIs.      
Sub-groups analyses will be performed mainly for exploratory purposes. Since these analyses 
will be used to promote hypothesis rather than confirm them, no adjustments for type I error 
inflation due to multiplicity of the tests will be considered. Moreover post-hoc and data-driven 
analyses will be carefully considered and ranked according to their biological plausibility. 


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6.2.1 Analysis Sets 
The following analysis sets will be defined:  
- Safety analysis set (SAF): The Safety analysis set will include all recruited patients who 
receive at least one dose of study medication. All safety analyses will be conducted on this 
population. 
- Intent-to-treat analysis set (ITT): The Intent-to-treat analysis set will include all recruited 
patients who receive at least one dose of study medication and from whom at least one post-
baseline efficacy measurement is obtained. All efficacy analyses will be conducted on this 
population and will be based on the effective/actual DL/daily doses of Givinostat at 
which each patient has been treated. 
- Per Protocol analysis set (PP): In order to assess the robustness of the efficacy analysis, the 
analysis of the efficacy end-point could be repeated in the Per Protocol (PP) analysis set. The 
Per-protocol analysis set will include all ITT  patients who receive at least 14 daily doses 
without interruptions, and without any major deviation from the protocol procedures.  
- MTD analysis set: The MTD analysis set will include all patients who experienced  DLTs in 
Cycle 1 of Part A, or who received at least 90% of the doses of study medication in Cycle 1 
of Part A. The data regarding the Cycle 1 of Part A will be used to determine MTD from this 
analysis set.  
- PK Analysis set: will consist of all SAF patients who with at least 1 PK assessment. This 
analysis set will be used for PK analysis. 
The number and percentage of the patients included in the analysis populations will be reported 
in a table showing the reason of exclusion for all patients enrolled into study. A listing of reasons 
of exclusion from analysis population will be provided.  
6.2.9 Interim analyses 
Italfarmaco S.p.A. will perform a preliminary analysis of data after the completion of the first 
cycle of treatment from all patients recruited in Part A, in order to assess the MTD to be used 
for Part B.  
Moreover, a preliminary analysis will be performed on the 12 patients of the first stage of Part B: 
if six or fewer responses will be observed during the first stage then the study will be stopped; if 
seven or more  responses will be observed in the first stage of Part B, further 16 patients will be 
enrolled in the second stage of Part B. In this case, a final statistical analysis will be performed 
considering all patients enrolled in the two study phases. 


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In addition, Italfarmaco S.p.A. can perform a preliminary analysis of data in case of necessary 
safety and efficacy updates (e.g. to update regulatory documents and/or the drug safety profile, to 
revise the development program).  
8.4 
Auditing procedures 
Italfarmaco S.p.A. reserves the right to conduct auditing activities at any/all participating centres 
and contracted a CRO or their delegates in order to verify compliance with Italfarmaco S.p.A. 
internal SOPs, CRO and/or their delegates SOPs, the principles of GCP and all applicable laws. 
A Regulatory Authority may also wish to conduct an inspection (during the study or even after 
its completion). If an inspection is requested by a Regulatory Authority, the Investigator must 
inform Italfarmaco S.p.A. immediately that this request has been made. 
8.5 
Handling of study medication 
All study medication will be supplied to the pharmacy of the Centre by Italfarmaco S.p.A. or its 
designee. Drug supplies must be kept in an appropriate, secure area and stored in accordance 
with the conditions specified on the drug labels. The investigator must maintain an accurate 
record of the shipment and dispensing of the IMP in the drug accountability form.  An accurate 
record of the date and amount of study drug dispensed to each patient must be available for 
inspection at any time. Copies of the drug accountability form will be provided to Italfarmaco 
S.p.A. by the investigator. 
All drug supplies are to be used only for this protocol and not for any other purpose. The 
investigator must not destroy any partly-used or unused drug supply without authorization from 
Italfarmaco S.p.A.. At the conclusion of the study, and, as appropriate during the course of the 
study, the investigator will return all used and unused drug containers to Italfarmaco S.p.A., 
Dipartimento di Tecnica Farmaceutica,  Viale Fulvio Testi, 330, 20126 Milan (MI), Italy or 
their designee (e.g. CMO), and a copy of the completed IMP accountability form to the 
Italfarmaco S.p.A. monitor. 
8.6 
 Ownership of data, disclosure and confidentiality 
The investigator must assure that patients’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents submitted to the sponsor, 


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patients should not be identified by their names, but by an identification code. The investigator 
should keep an enrolment log showing codes, names and addresses. 
By signing the protocol, the Investigator agrees to keep all information provided by Italfarmaco 
S.p.A. in strict confidence and to request similar confidentiality from his/her staff and the 
IRB/ECs. Study documents provided by Italfarmaco S.p.A. (protocols, investigators' brochures, 
CRFs and other material) will be stored appropriately to ensure their confidentiality. The 
information provided by Italfarmaco S.p.A. to the Investigator may not be disclosed to others 
without direct written authorization from Italfarmaco S.p.A., except to the extent necessary to 
obtain informed consent from patients who wish to participate in the trial.  
Italfarmaco S.p.A assures that the key design items of the Protocol will be published in a 
publicly accessible database such as “Clinicaltrials.gov”. Moreover, upon completion of the 
Study and finalization of the Study report, the Results of these study will be submitted for 
publication or posted in a publicly accessible data base.  
By signing the protocol, the investigators and their co-workers accept to submit any intended 
communication (abstract, paper or oral presentation) to Italfarmaco S.p.A. reasonably in advance 
(at least 30 working days for an abstract or oral presentation and 60 working days for a 
manuscript). This is to allow Italfarmaco S.p.A. to review the communications for accuracy and 
confidentiality, to provide any relevant supplementary information and to allow establishment of 
co authorship and in no way has to be intended as a restriction of the sponsor to the investigators’ 
right to publish the results of the study. In case Italfarmaco S.p.A. identifies specific 
need/opportunity to patent any of the study findings, the Investigator will allow a six month 
time-window between his submission to Italfarmaco S.p.A. and the intended publication and 
actual submission/communication to third parties, in order to allow Italfarmaco S.p.A. to 
undertake appropriate patenting steps. 
9. 
REFERENCE LIST 
1. Tefferi A, Spivak JL., Polycythemia vera: scientific advances and current practice, 
Semin. Hematol. 2005 Oct; 42(4): 206-20. 
2. Tefferi A., Essential thrombocythemia, polycythemia vera, and myelofibrosis: current 
management and the prospect of targeted therapy, Am. J. Hematol. 2008 Jun; 83(6): 491-
7. 
3. Finazzi G, Barbui T., How I treat patients with polycythemia vera, Blood. 2007 Jun 15; 
109(12): 5104-11.  


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4. McMullin MF., A review of the therapeutic agents used in the management of 
polycythemia vera, Hematol. Oncol. 2007 Jun; 25(2): 58-65. 
5. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, 
Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome 
Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative 
disorders, Lancet. 2005 Mar 19-25; 365(9464): 1054-61. Erratum in: Lancet. 2005 Jul 9-
15; 366(9480): 122.  
6. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola 
M, Skoda RC., A gain-of-function mutation of JAK2 in myeloproliferative disorders, N. 
Engl. J. Med. 2005 Apr 28; 352(17): 1779-90. 
7. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJP, Boggon TJ, 
Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, 
D’Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, 
Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG., 
Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential 
thrombocythemia, and myeloid metaplasia with myelofibrosis, Cancer Cell. 2005; 7: 387–
397. 
8. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score J, Seear R, Chase AJ, 
Grand FH, White H, Zoi C, Loukopoulos D, Terpos E, Vervessou EC, Schultheis B, 
Emig M, Ernst T, Lengfelder E, Hehlmann R, Hochhaus A, Oscier D, Silver RT, Reiter 
A, Cross NC., Widespread occurrence of the JAK2 V617F mutation in chronic 
myeloproliferative disorders, Blood. 2005 Sep 15; 106(6): 2162-8.  
9. Levine RL, Gilliland DG., Myeloproliferative disorders, Blood. 2008 Sep 15; 112(6): 
2190-8. 
10. Penninga EI, Bjerrum OW., Polycythemia vera and essential thrombocythaemia: current 
treatment strategies, Drugs. 2006; 66(17): 2173-87. 
11. Mesa RA, Niblack J, Wadleigh M, Verstovsek S, Camoriano J, Barnes S, Tan AD, 
Atherton PJ, Sloan JA, Tefferi A., The burden of fatigue and quality of life in 
myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 
MPD patients, Cancer 2007 Jan 1; 109(1): 68-76. 
12. Squizzato A, Romualdi E, Middeldorp S., Antiplatelet drugs for polycythemia vera and 
essential thrombocythaemia, Cochrane Database Syst Rev. 2008 Apr 16; (2): CD006503. 
13. Mesa RA., New insights into the pathogenesis and treatment of chronic 
myeloproliferative disorders, Curr. Opin. Hematol. 2008 Mar; 15(2): 121-6. 
14. Kiladjian JJ, Gardin G, Renoux M, Bruno F, Bernard JF., Long-term outcomes of 
polycythemia vera patients treated with pipobroman as initial therapy, Hematol. J. 2003; 
4(3): 198-207 
15. Kiladjian JJ, Chevret S, Dosquet D, Fenaux P, Chomienne C, Rain JD., Long-Term 
Outcome in Polycythemia Vera (PV): Final Analysis of a Randomized Trial Comparing 
Hydroxyurea (HU) to Pipobroman (Pi), ASH congress 2008. 


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16. Green AR, Vassiliou GS, Curtin N, Campbell PJ., Management of the myeloproliferative 
disorders: distinguishing data from dogma, Hematol. J. 2004; 5 Suppl 3: S126-32. 
17. Scott LM, Tong W, Levine RL et al., JAK2 exon 12 mutations in polycythemia vera and 
idiopathic erythrocytosis, N. Engl. J. Med. 2007; 356: 459-68. 
18. Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T, 
European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. 
Efficacy and safety of low-dose aspirin in polycythemia vera, N. Engl. J. Med. 2004 Jan 
8; 350(2):114-24. 
19. Calzada et al., The HDAC inhibitor Givinostat modulates the hematopoietic transcription 
factors NFE2 and C-MYB in JAK2V617F myeloproliferative neoplasm cells, Exp. Hematol. 
2012; 40 (8): 634-45.
20. Guerini V, Barbui V, Spinelli O, Salvi A, Dellacasa C, Carobbio A, Introna M, Barbui T, 
Golay J, Rambaldi A., The histone deacetylase inhibitor ITF2357 selectively targets cells 
bearing mutated JAK2(V617F), Leukemia 2008 Apr; 22(4): 740-7.  
21. Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, 
Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Reilly JT, Vannucchi AM, 
Barbui T, Response criteria for essential thrombocythemia and polycythemia vera: result 
of a European LeukemiaNet consensus conference, Blood. 2009 May 14; 113(20): 4829-
33 
22. Rambaldi A, Dellacasa CM, Finazzi G et al., A pilot study of the Histone-Deacetylase 
inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative 
neoplasms, Br. J. Haematol. 2010; 150 (4): 446-55. 
23. Rambaldi et al., A phase II study of the HDAC inhibitor Givinostat in combination with  
hydroxyurea in patients with Polycythemia Vera resistant to hydroxyurea monotherapy, 
Poster at ASH 2011, Session Name: 634.Myeloproliferative Syndromes, Publication N.: 
1748, Submission ID: 40637, ClinicalTrial.gov Identifier: NCT00928707. 
24. Scherber et al., The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-
SAF): International Prospective Validation and Reliability Trial in 402 patients, Blood, 
2011 July 14; 118(2): 401-408. 
25. Le Tourneau C, Lee JJ, Siu LL, Dose Escalation Methods in Phase I Cancer Clinical 
Trials, JNCI, 2009 May 20; 101(10): 708–720. 
26. Rubinstein LV and Simon RM, Phase I clinical trial design, In Budman, Calvert, 
Rowinsky, (eds.), Handbook of Anticancer Drug Development, Elsevier, Amsterdam, 
297-308, 2003.  
27. Omura GA, Modified Fibonacci Search, J. Clin. Oncol., 2003 August 15; 21(16): 3177 – 
3177. 
28. Oken M.M., Creech R.H., Tormey DC et al., Toxicity and response Criteria of the 
eastern cooperative oncology group, Am. J. Clin. Oncol. 1982; 5: 649-655. 


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29. Barosi G, Bordessoule D, Briere J et al., Response criteria for myelofibrosis with myeloid 
metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET), 
Blood 2005; 106: 2849-53. 
30. Simon R., Optimal two-stage designs for phase II clinical trials, Controlled Clinical 
Trials, 1989; 10: 1-10. 
31. Lippert E., Girodon F., Hammond E., et al.: Concordance of assays designed for the 
quantification of JAK2V617F: a multicenter study, Haematologica 2008; 94: 8-45. 
32. Emanuel R.M., Dueck A.C., Geyer H.L. et al.: Myeloproliferative neoplasm (MPN) 
symptom assessment form total symptom score: prospective international assessment of 
an abbreviated symptom burden scoring system among patients with MPNs, JCO 
November 20, 2012; 30 (33): 4098-4103. 
33. Barosi G., Mesa R., Finazzi G. et al.: Revised response criteria for polycythemia vera and 
essential thrombocythemia: a ELN and IWG-MRT consensus project, Blood, 2013 June 
6; 121(23): 4778-81. 
34. Daniel J. De Angelo D. J.,1 Mesa R. A., Fiskus W., Tefferi A. et al.: Phase II trial of 
panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, 
post–essential thrombocythaemia, and post–polycythaemia vera myelofibrosis, British 
Journal of Haematology, 2013 August;162(3):326-35. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
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10.1.1.1 Flow-chart of Cycle 1 
Cycle Description 
Screening 
Cycle 1 
Cycle Day 
-28 to 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 
28 
EOS11
Treatment phase 
Pre-dose 
Pre-
dose 
Post-
dose 
TREATMENT 
Window 
± 7 days 
Not applicable 
± 3 days 
Visit at the investigational site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent Form signature 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications (drugs) 
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug therapies (e.g. 
phlebotomies, transfusions) 
X
X
X
X
X
X
X
X
X
X
X
X
Medical history 
X
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs 
(blood pressure, pulse rate, 
respiratory rate), height, weight, 
body temperature and ECOG 
performance status1
X
 
 
X
 
 
X
X
X
X
X
Physical examination, weight, 
body temperature and ECOG 
performance status 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate)  
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 4 hours after 
the first Givinostat dose
 
X 
 
 
 
 
 
 
 
 
 


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Cycle Description 
Screening 
Cycle 1 
Cycle Day 
-28 to 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 
28 
EOS11
Treatment phase 
Pre-dose 
Pre-
dose 
Post-
dose 
TREATMENT 
Window 
± 7 days 
Not applicable 
± 3 days 
Visit at the investigational site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (if indicated) 2 
X
 
 
 
 
 
 
 
 
 
 
 
Blood chemistry3 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
ECG, QTc determination 
(according with Bazett’s 
correction formula)  3 hours after 
the first Givinostat dose12
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
ECG, QTc determination 
(according with Bazett’s 
correction formula)12
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Urinalysis4 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Haematology5 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
PD sample collection* 
 
X 
 
 
 
 
 
 
 
 
 
 
PD sample collection 12 hours 
after the first Givinostat dose  *
 
 
X 
 
 
 
 
 
 
 
 
 

ǡ


͸ǡ*

X 
X 







X 

Spleen evaluation (by MRI or CT 
scan)7 
X 
 
 
 
 
 
 
 
 
 
 
X 
Therapeutic response evaluation 8 
 
 
 
 
 
 
 
 
 
 
 
X 
Collection of a blood sample for 
the quantitative RT-PCR 
evaluation of JAK2V617F
mutational status on peripheral 
blood (PB) granulocyte* 
X 
 
 
 
 
 
 
 
 
 
 
 


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                                 Study N.:       DSC/12/2357/45
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Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
 
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Cycle Description 
Screening 
Cycle 1 
Cycle Day 
-28 to 
Day -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
8 
Day 
10 
Day 
15 
Day 
22 
Day 
28 
EOS11
Treatment phase 
Pre-dose 
Pre-
dose 
Post-
dose 
TREATMENT 
Window 
± 7 days 
Not applicable 
± 3 days 
Visit at the investigational site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of disease-related 
symptoms using the MPN-SAF 
QOL Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
X 
Request of enrolment and receipt 
of patient ID 
X 
 
 
 
 
 
 
 
 
 
 
 
First Givinostat dose and 
accountability 
 
 
X 
 
 
 
 
 
 
 
 
 
Givinostat administration and 
accountability9
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Used/unused/partially used 
Givinostat supply return from 
patient(s) and Givinostat 
accountability10
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1   Height will be measured at the pre-treatment evaluations only.  
 Patients must have an ECOG  1  within 7 days of initiating study drug. 
2 Pregnancy test has to be performed within 72 hours before the first Givinostat dose. The test can be performed by 
urine or serum pregnancy test. In case of a  borderline-positive urine pregnancy test, this must be confirmed with a 
serum pregnancy test.
3 Blood Chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or Urea (according with 
the site-specific clinical practice), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with 
the Mayo Clinic Quadratic Equation). 
4 Urinalysis: pH, specific gravity, protein, glucose. 
5 Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and differential), PLT count. 
6 PK sample collection: as following summarize: 
- Day 1: pre-dose and 2, 3 and 8 hours post-dose; 
- Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose. 
Patients will not take the morning dose of Givinostat on the day selected for their timed PK  assessments. 
Study drug will be administered in the clinic for these specific visits, in order to obtain pre- and/or post-dose 


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                                 Study N.:       DSC/12/2357/45
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plasma levels of Givinostat.  On all the other days corresponding to study visits, patients will take the 
morning dose of study drug prior to the visit. 
7 Spleen evaluation as per site-specific clinical practise: Patients with splenomegaly will be followed according to 
institutional guidelines (i.e. MRI or CT scan). The same imaging technique and the same instrument should be 
used on a patient throughout the study, if possible. No spleen evaluation will be performed in splenectomised 
patients. 
8 Therapeutic response evaluation: for PV and ET (if any), according with the clinico-haematological ELN response 
criteria [21] (see paragraph 4.6.1); for MF (if any), according with EUMNET response criteria. 
9 Givinostat administration: patients can take drug at home, except for the first drug administration. 
10 IMP: at study close-out, and as appropriate during the course of the study, the Investigator will return all used and 
unused study drug, packaging, drug labels, and the completed drug forms to Italfarmaco S.p.A., Dipartimento di 
Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126, Milan (MI), Italy or their designee (e.g. CMO).  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed agreement between 
the investigational site and Italfarmaco S.p.A.), these materials can be destroyed locally. 
11 EOS: In case of the patient drops-out of the study, the end of Study (EOS) visit will be performed 7 days after last 
drug intake. 
Note that, as reported in the paragraph 4.3.3, if the patient discontinues for any reason (including 
discontinuation for pregnancy), with drug related adverse event ongoing at study end, he/she must be 
followed until resolution or stabilization of the event or until it is reasonable to consider the event not drug 
related any more or until the start of a new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” should be 
indicated as the primary reason whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any patient 
permanently discontinuing study treatment. Should any drug-related AE still be ongoing beyond the last 
scheduled visit, this must be followed at subsequent follow-up visits until recovery. If a patient does not 
return for a scheduled visit, every effort should be made to contact the patient. In any circumstance every 
effort should be made to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory factors must be 
included on the CRF. 
12 ECG: If the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), two 
additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) must be 
performed. The averaged value of these three ECG evaluations has to be used for the evaluation of the QTc 
interval. In the CRF all the performed ECG evaluations have to be entered as well as the average value of 
multiple ECG evaluation, if necessary. 
* For all time points a blood sample will be collected as back-up sample. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
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Version 1.0  – 29th  July 2015 
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10.1.1.2 Flow-chart of Cycle 2 and beyond 
Day 1 of 
each cycle 
Day 28 of 
cycles 2, 4 and 
5 
Day 28 of 
cycles 3 and 6 
End of study visit 
(in case of completed 
study) 
or 7 days after last drug 
intake (in case of the 
patient drops-out of the 
study)8
Treatment phase 
TREATMENT 
Window 
 
± 3 days 
Visit at the investigational site 
X 
X 
X 
Adverse event recording  
 
X
X
X
Concomitant medications (drugs) 
 
X
X
X
Non-drug therapies (e.g. phlebotomies, 
transfusions) 
 
X
X
X
Physical examination, vital signs (blood 
pressure, pulse rate, respiratory rate),  
weight, body temperature and ECOG 
performance status 
 
X 
X 
X 
Blood chemistry1 
 
X 
X 
X 
ECG, QTc determination (according with 
Bazett’s correction formula)9
 
X 
X 
X 
Haematology2 
 
X 
X 
X 
PK sample collection and preparation, in 
order to allow to perform both the PK and 
PD evaluations starting from the same 
sample 3, *
 
X 
X 
 
Spleen evaluation (by MRI or CT scan)4 
 
 
X 
X 
Therapeutic response evaluation5 
 
 
X 
X 
Collection of a blood sample for the 
quantitative RT-PCR evaluation of 
JAK2V617F mutational status on peripheral 
blood (PB) granulocyte*
 
 
X 
X 
Assessment of disease-related symptoms 
using the MPN-SAF QOL Questionnaire 
 
 
X 
X 
Givinostat administration6 
X 
X 
X10 
 
First Givinostat dose of the related cycle 
and accountability 
X 
 
 
 


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                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 2 
Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
 
Page 105of 111 
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Day 1 of 
each cycle 
Day 28 of 
cycles 2, 4 and 
5 
Day 28 of 
cycles 3 and 6 
End of study visit 
(in case of completed 
study) 
or 7 days after last drug 
intake (in case of the 
patient drops-out of the 
study)8 
Treatment phase 
TREATMENT 
Window 
 
± 3 days 
Visit at the investigational site 
X 
X 
X 
Used/unused/partially used Givinostat 
supply return from patient(s) and 
accountability7
 
X 
X 
X 
1 Blood Chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or Urea (according with 
the site-specific clinical practice), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with 
the Mayo Clinic Quadratic Equation). 
2 Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and differential), PLT count.  
3 PK sample collection: pre-dose. Patients will not take the morning dose of Givinostat on the day selected for 
their timed PK  assessments. Study drug will be administered in the clinic for these specific visits, in order 
to obtain pre- and/or post-dose plasma levels of Givinostat.  On all the other days corresponding to study 
visits, patients will take the morning dose of study drug prior to the visit. 
4 Spleen evaluation as per site-specific clinical practise: Patients with splenomegaly will be followed according to 
institutional guidelines (i.e. MRI or CT scan). The same imaging technique and the same instrument should be 
used on a patient throughout the study, if possible. No spleen evaluation will be performed in splenectomised 
patients. 
5 Therapeutic response evaluation: for PV and ET (if any), according with the clinico-haematological ELN criteria 
[21] (see paragraph 4.6.1); for MF (if any), according with EUMNET response criteria. 
6 Givinostat administration: patients can take drug at home. 
7 IMP: at study close-out, and as appropriate during the course of the study, the Investigator will return all used and 
unused study drug, packaging, drug labels, and the completed drug forms to Italfarmaco S.p.A., Dipartimento di 
Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126, Milan (MI), Italy or their designee (e.g. CMO). Only in 
some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed agreement between the 
investigational site and Italfarmaco S.p.A.), these materials can be destroyed locally. 
8 EOS: as reported in the paragraph 4.3.3, if the patient discontinues for any reason (including 
discontinuation for pregnancy), with drug related adverse event ongoing at study end, he/she must be 
followed until resolution or stabilization of the event or until it is reasonable to consider the event not drug 
related any more or until the start of a new treatment, whichever occurs first.   


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                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 2 
Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
 
Page 106of 111 
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In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” should be 
indicated as the primary reason whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any patient 
permanently discontinuing study treatment. Should any drug-related AE still be ongoing beyond the last 
scheduled visit, this must be followed at subsequent follow-up visits until recovery. If a patient does not 
return for a scheduled visit, every effort should be made to contact the patient. In any circumstance every 
effort should be made to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory factors must be 
included on the CRF. 
Of note, in case the patient completes the study (i.e. performs all the evaluations requested to be done at the 
Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can be counted for the End of Study 
visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations requested to be done at 
the Day 28 of Cycle 6) and she/he is eligible to continue the study drug treatment in the long-term study (i.e. 
Study DSC/11/2357/44), the evaluation performed at the Cycle 6 Day 28 visit of this study can be also 
counted for the pre-treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluation is present between the two studies (e.g. haematological and biochemical evaluations). No 
additional Givinostat study (i.e. Study DSC/12/2357/45)-specific assumption has to be done at the 
completion of the Day 28 of Cycle 6. Indeed, in case the patient completes the study (i.e. performs all the 
evaluations requested to be done at the Day 28 of Cycle 6 of this study), she/he is eligible to continue the 
study drug treatment in the long-term study (i.e. Study DSC/11/2357/44) and she/he receive the written 
authorization of the treatment from the Sponsor of their designee (i.e. a patient’s confirmation form that 
includes the patient ID to use into the Study DSC/11/2357/44), the patient will continue the study drug 
treatment into the Study DSC/11/2357/44, receiving the study (i.e. Study DSC/11/2357/44)-specific drug to 
be taken. 
9 ECG: If the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), two 
additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) must be 
performed. The averaged value of these three ECG evaluations has to be used for the evaluation of the QTc 
interval. In the CRF all the performed ECG evaluations have to be entered as well as the average value of 
multiple ECG evaluation, if necessary. 
10 Givinostat administration: Only for cycle 3. 
* For all time points a blood sample will be collected as back-up sample. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 2 
Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
 
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10.1.2 Flow-chart of Part B
Pre-treatment 
evaluations*** 
(up 
to 
4 
weeks:  
-28 to Day -1) 
Day 1 of the first 
Cycle***
Day 28 of 
Cycles 1, 2, 
4 and 5***
Day 28 
of  
Cycles 3 
and 6***
End of study visit  
(in case of completed study)  
or 7 days after last drug intake 
(in case of the patient drops-
out of the study)11, ***
Treatment phase 
Pre-dose 
Pre-dose 
Post-dose 
TREATMENT 
Windows 
± 7 days 
Not applicable 
± 3 days 
Visit at the investigational site 
X 
X 
X 
X 
X 
X 
Informed Consent Form signature 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Adverse event recording  
X
X 
X 
X
X
X
Concomitant medications (drugs) 
X
X 
X 
X
X
X
Non-drug therapies (e.g. 
phlebotomies, transfusions) 
X
X 
X 
X
X
X
Medical history 
X
 
 
 
 
 
Physical examination, vital signs 
(blood pressure, pulse rate, 
respiratory rate), height, weight, 
body temperature and ECOG 
performance status1
X
 
 
X 
X 
X 
Pregnancy test (if indicated) 2 
X
 
 
 
 
 
Blood chemistry3 
X
 
 
X 
X 
X 
ECG, QTc determination 
(according with Bazett’s 
correction formula)12
X
 
 
X 
X 
X 
Urinalysis4 
X 
 
 
 
 
 
Haematology5 
X
 
 
X 
X 
X 
PD sample collection before the 
first Givinostat dose*
 
X 
 
 
 
 
PD sample collection 12 hours 
after the first Givinostat dose *  
 
 
X 
 
 
 
PK sample collection6, *
and preparation, in order to 
allow to perform both the PK 
and PD evaluations starting 
from the same sample (if 
requested)
 
X 
X 
X 
 
 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 2 
Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
 
Page 108of 111 
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Pre-treatment 
evaluations  
(up to 4 weeks:  
-28 to  
Day -1)***
Day 1 of the first 
Cycle*** 
Day 28 of 
Cycles 1, 2, 
4 and 5 
Day 28 
of  
Cycles 3 
and 6 
End of study visit  
(in case of completed 
study)  
or 7 days after last drug 
intake (in case of the 
patient drops-out of the 
study)11
Treatment phase 
Pre-dose 
Pre-dose 
Post-dose 
TREATMENT 
Windows 
± 7 days 
Not applicable 
± 3 days 
Visit at the investigational site 
X 
X 
X 
X 
X 
X 
Spleen evaluation (by MRI or 
CT scan)7
X 
 
 
 
X 
X 
Collection of blood sample for 
quantitative RT-PCR evaluation 
of JAK2V617F mutational status 
on peripheral blood (PB) 
granulocyte *
X 
 
 
X 
X 
X 
Assessment of disease-related 
symptoms using the MPN-SAF 
QOL Questionnaire [24, 32] 
X 
 
 
 
X 
X 
Bone marrow histological 
evaluation in order to assess the 
presence of age adjusted 
normocellularity and/or trilinear 
hyperplasiaA
X 
 
 
 
XB 
XC
Therapeutic response 
evaluation8
 
 
 
 
X 
X 
Request of enrolment and 
receipt of patient ID 
X 
 
 
 
 
 
Givinostat administration9 
 
 
 
X 
X** 
 
First Givinostat dose and 
accountability 
 
 
X 
 
 
 
Used/unused/partially used 
Givinostat supply return from 
patient(s) and accountability10
 
 
 
X 
X 
X 
1   Height will be measured at the pre-treatment evaluations only.  
Patients must have an ECOG  2, within 7 days of initiating study drug. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 2 
Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
 
Page 109of 111 
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2 Pregnancy test has to be performed within 72 hours before the first Givinostat dose. The test can be performed by 
urine or serum pregnancy test. In case of a positive or borderline-positive urine pregnancy test, this must be 
confirmed with a serum pregnancy test.
3 Blood Chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or Urea (according with 
the site-specific clinical practice), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according with 
the Mayo Clinic Quadratic Equation). 
4 Urinalysis: pH, specific gravity, protein, glucose. 
5 Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and differential), PLT count. 
6 PK sample collection: as following summarize: 
- Day 1 of Cycle 1: pre-dose and 2, 3 and 8 hours post-dose; 
- Day 28 only of Cycle 2: pre-dose and 1, 2, 4 and 8 hours post-dose. 
Patients will not take the morning dose of Givinostat on the day selected for their timed PK  assessments. 
Study drug will be administered in the clinic for these specific visits, in order to obtain pre- and/or post-dose 
plasma levels of Givinostat.  On all the other days corresponding to study visits, patients will take the 
morning dose of study drug prior to the visit. 
7 Spleen evaluation as per site-specific clinical practise: Patient with splenomegalyThe spleen evaluation will be 
performed during the study followed according to institutional guidelines and site-specific clinical practice 
(i.e. MRI or CT scan). The same imaging technique and the same instrument should be used on a patient 
throughout the study, if possible. No spleen evaluation will be performed in splenectomised patients.
8 Therapeutic response evaluation: both according with the clinico-haematological ELN criteria [21] (see paragraph 
4.6.1) (both at cycle 3 and at cycle 6) and according with the “new” ELN criteria (i.e. revised ELN response 
criteria) [33] (see paragraph 4.8.7) (only at cycle 6).  
9 Givinostat administration: patients can take drug at home, except for the first drug administration. 
10 IMP: at study close-out, and as appropriate during the course of the study, the Investigator will return all used and 
unused study drug, packaging, drug labels, and the completed drug forms to Italfarmaco S.p.A.,  – Dipartimento di 
Tecnica Farmaceutica, Viale Fulvio Testi, 330, 20126, Milan (MI), Italy or their designee (e.g. CMO).  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed agreement between 
the investigational site and Italfarmaco S.p.A.), these materials can be destroyed locally. 
11 EOS: as reported in the paragraph 4.3.3, if the patient discontinues for any reason (including 
discontinuation for pregnancy), with drug related adverse event ongoing at study end, he/she must be 
followed until resolution or stabilization of the event or until it is reasonable to consider the event not drug 
related any more or until the start of a new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse events” should be 
indicated as the primary reason whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors must be included on the CRF. 
A complete end of study visit must be performed by 7 days after the last drug intake for any patient 
permanently discontinuing study treatment. Should any drug-related AE still be ongoing beyond the last 
scheduled visit, this must be followed at subsequent follow-up visits until recovery. If a patient does not 
return for a scheduled visit, every effort should be made to contact the patient. In any circumstance every 
effort should be made to complete and report the observations as thoroughly as possible. All relevant 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 2 
Version 1.0  – 29th  July 2015 
SOP 2 final version 12.09 
 
Page 110of 111 
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information related to the reason for treatment discontinuation including contributory factors must be 
included on the CRF. 
Of note, in case the patient completes the study (i.e. performs all the evaluations requested to be done at the 
Day 28 of Cycle 6), the evaluation performed at the Cycle 6 Day 28 visit can be counted for the End of Study 
visit. 
In addition, in case the patient completes the study (i.e. performs all the evaluations requested to be done at 
the Day 28 of Cycle 6) and she/he is eligible to continue the study drug treatment in the long-term study (i.e. 
Study DSC/11/2357/44), the evaluation performed at the Cycle 6 Day 28 visit of this study can be also 
counted for the pre-treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluation is present between the two studies (e.g. haematological and biochemical evaluations). No 
additional Givinostat study (i.e. Study DSC/12/2357/45)-specific assumption has to be done at the 
completion of the Day 28 of Cycle 6. Indeed, in case the patient completes the study (i.e. performs all the 
evaluations requested to be done at the Day 28 of Cycle 6 of this study), she/he is eligible to continue the 
study drug treatment in the long-term study (i.e. Study DSC/11/2357/44) and she/he receive the written 
authorization of the treatment from the Sponsor of their designee (i.e. a patient’s confirmation form that 
includes the patient ID to use into the Study DSC/11/2357/44), the patient will continue the study drug 
treatment into the Study DSC/11/2357/44, receiving the study (i.e. Study DSC/11/2357/44)-specific drug to 
be taken. 
12 ECG: If the ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval  450 msec), two 
additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) must be 
performed. The averaged value of these three ECG evaluations has to be used for the evaluation of the QTc 
interval. In the CRF all the performed ECG evaluations have to be entered as well as the average value of 
multiple ECG evaluation, if necessary.
* For all time points a blood sample will be collected as back-up sample. 
**  Only for cycle 3. 
*** Patients should be told to arrive after an overnight fast of at least 8 hours at all study visits that request a 
blood test.  However, the study visits should still be conducted even if the patient does not adhere to 
fasting requirements and this will not be considered a protocol violation. In these cases, this information 
(i.e. not fasting condition) has to be noted by the Investigator in the medical chart and reported in CRF, in 
order to avoid any misunderstanding of the collected data (e.g. glucose value is influenced by fasting/not 
fasting conditions).    
A Please note that, in case the patient performs the bone marrow histological evaluation as requested by the “new” 
ELN criteria (i.e. the revised ELN response criteria) [33] (see paragraph 4.8.7) – i.e. bone marrow evolution 
including the assessment of the presence of age adjusted normocellularity and/or trilinear hyperplasia - 1 month 
before the study start (i.e the signature of the Informed Consent Form), this examination has not to be repeated for 
this study in order to limit the discomfort for the patient. In any case, the results of this test will be transcribed into 
the CRF and the original signed and dated laboratory print-out/tracings, including the assessment of the presence 
of age adjusted normocellularity and/or trilinear hyperplasia, will be monitored and stored at the study site.  
Finally, in case the patient refuses to provide this written consent to perform the bone marrow evaluation, this 
patient can be anyway recruited in Part B. However, this patient will not be counted to assess the related 
exploratory endpoints (i.e. overall response rate of Givinostat at the MTD after 6 cycles according to the revised 
ELN response criteria [33], and the evaluation of the effect of Givinostat on each single response parameter 
according to the revised ELN response criteria [33]).   
B Only for cycle 6. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
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C In case the patient drops-out the study during the first 3 Cycles (i.e. before the Day 28 of Cycle 3) , this evaluation 
has not to be performed at End of Study visit.
10.5 Appendix E: JAK2V617F genotyping and quantification in granulocytes 
JAK2V617F genotyping and quantification will be performed in Part A at the screening, at  
during the pre-treatment evaluations, Day 28 of Cycle 3, at Day 28 of Cycle 6 and at the end of 
study, and in Part B at the screening, at Day 28 of each Cycle (i.e. Day 28 of the Cycles 1, 2, 
3, 4, 5 and 6)and at the end of study at the end of every year of treatment and at the end of the 
study (in case of completed study) or 7 days after last drug intake (in case of the patient drops-
out of the study). A sample of peripheral blood in EDTA (20 mL) will be obtained, and either 
granulocyte are separated in the same institution up to the freezing of a granulocyte pellet, or the 
blood sample is sent the same day with an O/N courier to the Central Laboratory. Granulocytes 
are prepared from peripheral blood (PB) samples using density-gradient centrifugation and 
residual erythrocyte lyses; granulocytes are frozen as a pellet. Frozen pellets from different 
patients can be sent in blocks to the Central Laboratory in dry ice. DNA is extracted using solid-
phase extraction. The presence and the mutation, and the allelic burden, are evaluated in 
triplicate in each sample, using a quantitative real-time PCR (RT-PCR) technique and standard 
curve with plasmids available the Central Laboratory [31].  


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 1 
Version 1.0  – 23rd  July 2013 
SOP 2 final version 12.09 
Page 1of 29 
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STUDY N.: DSC/12/2357/45 
EUDRACT N.:  2013-000860-27 
A two-part study to assess the safety and preliminary efficacy of 
Givinostat in patients with JAK2V617F positive Polycythemia Vera
Document type: 
Amendment 1 
Development Phase: 
Phase Ib/II 
Document status: 
Version 1.0 
Release: 23rd July 2013 
Sponsor:
ITALFARMACO S.p.A. 
Via dei Lavoratori, 54
20092 Cinisello Balsamo (MI), Italy
Tel.: 
  
Fax: 
Property of Italfarmaco 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Italfarmaco   
PPD
PPD


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 1 
Version 1.0  – 23rd  July 2013 
SOP 2 final version 12.09 
 
Page 2of 29 
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AMENDMENT 1 RATIONALE 
The clinical study protocol DSC/12/2357/45 has been amended for the following reasons: 
•
To clarify the meaning of an “effective means of contraception for women of childbearing 
potential and men with partners of childbearing potential” (i.e. inclusion criteria n. 5) 
mentioning that the contraceptive methods will be used for up to 3 months after stopping 
the study treatment, as requested by French Regulatory Authority; 
•
To update the patient numbering sections as per eCRF; 
•
To add as exploratory endpoint of Part B the evaluation of the preliminary efficacy of 
Givinostat according to the “new” ELN response criteria (i.e. the revised ELN response 
criteria, Barosi G., Mesa R., Finazzi G. et al.: Revised response criteria for polycythemia 
vera and essential thrombocythemia: a ELN and IWG-MRT consensus project, Blood, 
2013 June 6; 121(23): 4778-81). 
Further to what is reported above, with the present amendment some typographic mistakes 
existing in the clinical study protocol version 1.0 (dated 01st March 2013) have been put right.  
AMENDMENT 1 SUMMARY OF CHANGES 
Substantive additions to the protocol are denoted in bold. Substantive deletions are in 
strikethrough. 
2.1 Primary Objectives
Part A 
•
To characterize the safety, tolerability and MTD of Givinostat in patients with PV.  
Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD after 3 cycles  according 
to the clinico-haematological European LeukemiaNet (ELN) response criteria [21] 
(see paragraph 4.6.1). 
•
To determine the safety and tolerability of Givinostat at the MTD after 3 cycles. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
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Version 1.0  – 23rd  July 2013 
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2.2 Secondary Objectives
Part A 
•
To evaluate the preliminary efficacy of Givinostat after 3 and 6  cycles of treatment 
according to the clinico-haematological ELN response criteria [21] (see paragraph 
4.6.1). 
•
To characterize PK. 
Part B  
•
To evaluate the preliminary efficacy of Givinostat at the MTD after 6 cycles  according 
to the clinico-haematological ELN response criteria [21] (see paragraph 4.6.1). 
•
To determine the safety and tolerability of Givinostat at the MTD after 6 cycles. 
•
To characterize PK. 
2.3 Exploratory Objectives
Parts A and B 
•
To evaluate the effect of Givinostat on single parameters of the clinico-haematological
ELN response criteria [21] (see paragraph 4.6.1). 
•
To evaluate the effects of Givinostat on PD markers. 
•
To evaluate the effects of Givinostat on spleen size (by MRI or CT scan) in patients with 
confirmed splenomegaly at baseline. 
•
To evaluate the effects of Givinostat on disease-related quality of life. 
•
To evaluate the effect of Givinostat on JAK2V617F allele burden. 
•
To evaluate the reduction of the symptomatic treatment of pruritus. 
Part B  
•
To evaluate the preliminary efficacy of Givinostat after 6  cycles of treatment 
according to the “new” ELN response criteria (i.e. the revised ELN response 
criteria) [33] (see paragraph 4.8.7). 
•
To evaluate the effect of Givinostat on sigle parameters of the “new” ELN response 
criteria (i.e. the revised ELN response criteria) [33] (see paragraph 4.8.7). 
3.1 Primary endpoints 
Part A 
•
Safety and tolerability evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse events, graded according to 
Common Terminology Criteria for Adverse Events (CTCAE v. 4.03, 14th June 2010). 
•
Determination of the MTD of Givinostat based on cycle 1 DLT’s. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
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SOP 2 final version 12.09 
 
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Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - of 
Givinostat at the MTD after 3 cycles; the response will be evaluated according to the 
clinico-haematological European LeukemiaNet (ELN) response criteria [21] (see 
paragraph 4.6.1). 
•
Safety and tolerability of Givinostat at the MTD after 3 cycles evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse events, graded according to 
CTCAE v. 4.03. 
3.2 Secondary endpoints  
Part A 
•
Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - of 
Givinostat at the MTD after 3 and 6 cycles; the response will be evaluated according to 
the clinico-haematological ELN response criteria [21] (see paragraph 4.6.1). 
•
Individual Givinostat concentrations tabulated by dose cohort along with descriptive 
statistics. 
Part B  
•
Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - of 
Givinostat at the MTD after 6 cycles; the response will be evaluated according to the 
clinico-haematological ELN response criteria [21] (see paragraph 4.6.1). 
•
Safety and tolerability of Givinostat at the MTD after 6 cycles evaluated as following: 
- 
Number of patients experiencing adverse events; 
- 
Type, incidence, and severity of treatment-related adverse events, graded according to 
CTCAE v. 4.03. 
•
Individual Givinostat concentrations tabulated with descriptive statistics. 
3.3 Exploratory endpoints 
Part A and Part B  
•
To evaluate the effect of Givinostat on each single response parameter according to the 
clinico-haematological ELN response criteria [21] (see paragraph 4.6.1). 
•
To evaluate the effects of Givinostat on PD markers by mRNA analysis. 
•
To evaluate the effects of Givinostat on spleen size (by MRI or CT scan) in patients with 
confirmed splenomegaly at baseline. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 1 
Version 1.0  – 23rd  July 2013 
SOP 2 final version 12.09 
 
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•
Improvement of constitutional symptoms evaluated according to MPN-SAF QOL 
questionnaire [24, 32]. 
•
Reduction of the JAK2V617F allele burden, tested by quantitative RT-PCR. 
•
Reduction of the symptomatic treatment of pruritus in term of dosage and/or days of 
treatment. 
Part B  
•
Overall response rate - i.e. Complete Remission and Partial Remission - of 
Givinostat at the MTD after 6 cycles; the response will be evaluated according to the 
“new” ELN response criteria (i.e. the revised ELN response criteria [33], see 
paragraph 4.8.7). 
•
To evaluate the effect of Givinostat on each single response parameter according to 
the “new” ELN response criteria (i.e. the revised ELN response criteria [33], see 
paragraph 4.8.7). 
4.1 Overall study design
This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety 
and tolerability, MTD and preliminary efficacy of Givinostat in patients with JAK2V617F 
positive PV.  
Part A is the dose escalation portion of the study and, once the MTD has been established, Part B 
will commence where the preliminary efficacy of Givinostat in PV patients will be established. 
Patients will be enrolled either in Part A or Part B and transition from one part to the other is not 
allowed. Only PV patients from Part A assigned to the dose selected for Part B (MTD) may be 
counted towards the efficacy assessment in Part B. 
Eligible patients for this study will have a confirmed diagnosis of PV according to the revised 
WHO criteria and the JAK2V617F positivity. Only if the enrolment in Part A is slow (i.e. < 5 
patients enrolled in 3 months), eligibility for this part of the study may be expanded to all 
patients with cMPN.  
After providing informed written consent before undertaking any protocol-related procedure, a 
unique patient identification code (i.e. patient screening ID which will be a combination of 
his/her site ID, study part ID and patient screening number, e.g. IT01-A01) will be assigned
to each patient and it will identify the patient within his/her enrolment confirmation by 
Italfarmaco S.p.A. or its designee and never be reused in case of screening failure. After the 
enrolment confirmation and the assignation of the dose level before the first drug intake, a 
unique patient identification code (i.e. patient ID which will be a combination of patient 
screening number ID and dose level ID, e.g. IT01-A01-DL1) will be assigned to each patient 
and it will identify the patient throughout his/her participation in the study and never be reused in 
case of premature drop-out.


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Study therapy will be administered in 28 day cycles. In fact, the “cycle” is defined as 4 weeks of 
treatment. 
Disease response will be evaluated according to the clinico-haematological ELN criteria [21] 
after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both 
parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be 
counted to assess the clinico-haematological response. 
The study will last up to a maximum of 24 weeks of treatment. However, after completion of the 
trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat 
(at the same dose and schedule) in a long-term study (Study N.: DSC/11/2357/44).  
Safety will be monitored at each visit throughout the entire duration of the study. Treatment will 
be administered on an outpatient basis and patients will be followed regularly with physical and 
laboratory tests, as specified in the protocol (see Appendix A and paragraph 4.5.4); in case of 
hospitalization, the treatment will be continued or interrupted according to the Investigators’ 
decision.  
4.1.1.5 Definition of MTD
If 2 or more patients per dose level experience a DLT, dose escalation will terminate and the 
MTD is the next lower dose level if no more than one out of 6 patients had a DLT at that level. 
Once all patients enrolled in Part A have been treated for at least 1 cycle, the study team will 
determine the MTD to be used in Part B based on the safety and tolerability profile of Givinostat 
observed as well as the PK and PD data, if applicable.  
No intra-patient dose escalation will be permitted prior to determining the MTD. At that time, 
continuing patients at lower dose levels may be allowed to escalate their Givinostat dose to the 
MTD for the remainder part of the study (Part AB) at the discretion of the Investigator and 
Sponsor. 
4.3.1 Inclusion criteria
Patients must meet the following criteria to be eligible for study entry: 
1. Patients must be able to provide informed consent through the signature of an informed 
consent form; 
2. Patients must have an age 18 years; 
3. Patients must have a confirmed diagnosis of PV according to the revised WHO criteria; 
4. Patients must have JAK2V617F positive disease; 
5. Patients must have an active/not controlled disease defined as  
a) HCT  45% or HCT <45% in need of phlebotomy, and 
b) PLT counts > 400 x109/L, and 


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c) WBC > 10 x109/L; 
6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 
[28]  1 in Part A, ECOG performance status  2 in Part B, within 7 days of initiating 
study drug; 
7. Female patient of childbearing potential has a negative serum or urine pregnancy test 
within 72 hours of the first dose of study therapy; please note that a borderline urine 
pregnancy test must be followed with a serum pregnancy test; 
8. Use of an effective means of contraception for women of childbearing potential and men 
with partners of childbearing potential;  
9. Adequate and acceptable organ function within 7 days of initiating study drug; 
10. Willingness and capability to comply with the requirements of the study. 
Note that if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months), eligibility for 
this part of the study may be expanded to all patients with cMPN. In this case, the inclusion 
criteria 5 will be modified as following only for Part A: 
5. Patients must have an active/not controlled disease defined as: 
a) ET patients: PLT counts > 600 x109/L; 
b) MF patients: no response according to EUMNET criteria [29]. 
Note that an effective means of contraception for women of childbearing potential and men 
with partners of childbearing potential (i.e. inclusion criteria n. 5) is defined as following 
described based on different subject subgroups:   
A. Female subjects of childbearing potential: acceptable non-hormonal, contraceptive 
methods must be used from the 28 days before first dose of study drug through 3 
months after the last dose of study drug and include the following: 
•
True abstinence (absence of any sexual intercourse), when in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
•
Double barrier contraception such as diaphragm or a barrier method of 
contraception in conjunction with spermicidal jelly such as for example cervical 
cap with spermicide jelly and the male partner must use a condom with 
spermicide. 
•
Intra-uterine device (non-hormone-releasing) in place for at least 90 days 
previously and the male partner must use a condom with spermicide. 
•


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•
Tubal ligation at least 6 months previously and 1 additional acceptable 
contraception method 
•
Vasectomy of the male partner (with a negative sperm post-vasectomy semen 
analysis) at least 6 months previously and 1 additional acceptable contraception 
method. 
B. Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria: 
•
Postmenopausal: Female subjects, less than 60 years of age, who have been 
amenorrheic for at least 2 years and have a serum FSH level within the 
laboratory’s reference range for postmenopausal females. Female subject who 
are 60 years of age or older who are amenorrheic for greater than 2 years will be 
assume to be postmenopausal. 
•
Documented hysterectomy or bilateral oophorectomy or both All other female 
subjects (including subjects with tubal ligations and subjects that do not have a 
documented hysterectomy) will be considered to be of childbearing potential. 
C. Male Subjects, acceptable contraceptive methods must be used from Screening Visit 
through 3 months after the last dose of study drug, and include the following: 
•
True abstinence (absence of any sexual intercourse), when in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, postovulation methods) and withdrawal are not 
acceptable methods of contraception. 
•
Condom with spermicide and the female partner must use an acceptable method 
of contraception, such as an oral, transdermal, injectable or implanted steroid-
based contraceptive, or a diaphragm or a barrier method of contraception in 
conjunction with spermicidal jelly such as for example cervical cap with 
spermicide jelly. 
•
Vasectomy (with a negative sperm post-vasectomy semen analysis) at least 6 months 
previously and 1 additional acceptable contraception method  
•
Male subjects must not donate sperm from the Screening Visit through 3 months 
after the last dose of study drug 
Note also that  
–
Male condom cannot be used with female condom due to risk of tearing. 
–
The use of birth-control methods does not apply if the female partner has a bilateral 
oophorectomy, hysterectomy, or is postmenopausal (as defined above). 


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4.3.3 Criteria for dose modifications
... 
In case of multiple reasons (i.e.g. patient withdraws the consent for toxicity), “adverse events” 
should be indicated as the primary reason whenever applicable. All relevant information related 
to the reason for treatment discontinuation including contributory factors must be included on the 
CRF. 
... 
4.4.3 Patient numbering and screening 
Each patient will be identified in the study by a patient code ID which will be a combination of 
his/her site ID and patient number.  
During the screening period (i.e. after the informed consent form signature and before the 
recruitment confirmation by the Italfarmaco S.p.A. or its designee), the patient code will be 
named patient screening ID and will be a combination of his/her site ID, study part ID and 
patient screening number. 
Both tThe site ID and the study part ID (i.e. “A” or “B” for Part A or Part B, respectively) 
will be assigned by the Sponsor or its designee to the investigator site.  
Upon signing the informed consent form, the patient screening number will be assigned by the 
Investigator. At each site, the first patient will be assigned patient number 1, and subsequent 
patients will be assigned consecutive numbers (e.g. the second patient will be assigned patient 
number 2, the third patient will be assigned patient number 3, etc).   
When a study site has a patient ready to enrol, prior to dosing the site will compile a request for 
registration Form and send it to Italfarmaco S.p.A. or its designee in order to obtain the patient 
ID. The request for registration contains the site ID, the study part ID, the assigned patient 
screening number, a checklist related to the inclusion/exclusion criteria to verify the eligibility 
of the patient and collect some other information (e.g. date of birth, date of informed consent 
obtained). If the patient is eligible, Italfarmaco S.p.A. or its designee will confirm the 
enrolment of the patient assigning the related dose level and the patient ID (i.e. the patient 
code after the enrolment confirmation) which will be a combination of patient screening ID 
and dose level ID. 
Once assigned, both the patient screening ID and the patient IDnumber must not be reused for 
any other patient. 
The following scheme will resume the  patient identification process: 


ITALFARMACO S.p.A
                                               
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If the patient will fail to be en
within 2 days that the patient i
According to ICH-GCP guid
which ensures a distinctive i
date of birth, sex and date of i
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nrolled for any reason, the reason will be ent
is not enrolled.
delines, the Investigator will maintain a pat
dentification of the patients by their name 
nclusion.
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tered in the study CRF 
ient identification list, 
to screening numbers, 


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4.5.3 Spleen evaluation, PK and PD characterization, and molecular examinations and bone 
marrow histological evaluation
4.5.3.6 Bone marrow histological evaluation
A bone marrow histological evaluation will be performed to all patients recruited in Part B
in order to assess the presence of age adjusted normocellularity and/or trilinear 
hyperplasia as requested by the “new” ELN response criteria (i.e. the revised ELN 
response criteria) [33] (see paragraph 4.8.7).  
This examination will be performed in the local laboratory of each site. The results of this 
test will be transcribed into the CRF and the original signed and dated laboratory print-
out/tracings, including the assessment of the presence of age adjusted normocellularity 
and/or trilinear hyperplasia, will be monitored and stored at the study site. 
Please note that, in case the patient performs the bone marrow histological evaluation as 
requested by the “new” ELN criteria (i.e. the revised ELN response criteria) [33] (see 
paragraph 4.8.7) – i.e. bone marrow evolution including the assessment of the presence of 
age adjusted normocellularity and/or trilinear hyperplasia - 1 month before the study start 
(i.e the signature of the Informed Consent Form), this examination has not to be repeated 
for this study in order to limit the discomfort for the patient. In any case, the results of this 
test will be transcribed into the CRF and the original signed and dated laboratory print-
out/tracings, including the assessment of the presence of age adjusted normocellularity 
and/or trilinear hyperplasia, will be monitored and stored at the study site. 
In case the patient drops-out the study during the first 3 Cycles (i.e. before the Day 28 of 
Cycle 3), this evaluation has not to be performed at End of Study visit. 
Finally, in case the patient refuses to provide this written consent to perform the bone 
marrow evaluation, this patient can be anyway recruited in Part B. However, this patient 
will not be counted to assess the related exploratory endpoints (i.e. overall response rate of 
Givinostat at the MTD after 6 cycles according to the revised ELN response criteria [33], 
and the evaluation of the effect of Givinostat on each single response parameter according 
to the revised ELN response criteria [33]).   


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4.5.4.1.2 Cycle 1
… 
End of Study
In case of the patient drops-out of the study, the following procedures will be performed 7 days 
after last drug intake (within ± 3 days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
(see Appendix F to convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin; 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire; 
•
Used/unused/partially used Givinostat supply return and accountability. 
At study close-out, and as appropriate during the course of the study, the Investigator will return 
all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A. – Dipartimento di Tecnica Farmaceutica Viale Fulvio Testi, 330, 20126, 
Milan, Italy.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed 
agreement between the investigational site and Italfarmaco S.p.A.), these materials can be 
destroyed locally. 


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4.5.4.1.3 Cycles 2, 3, 4, 5 and 6
… 
Day 28 of Cycles 3 and 6
The following procedures will be performed at Day 28 of Cycles 3 and 6 of Part A (within ± 3 
days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
(see Appendix F to convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin; 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
PK sample collection (pre-dose); 
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire; 
•
Givinostat administration and accountability. 
All phlebotomies performed in the first 3 weeks of treatment will be not counted to assess the 
clinico-haematological response according to the clinico-haematological ELN response 
criteria [21] (see paragraph 4.6.1). 
End of Study
The following procedures will be performed at the end of study visit (in case of completed study) 
or 7 days after last drug intake (in case of the patient drops-out of the study) (within ± 3 days) as 
reported below: 
•
Adverse event recording;  


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•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
(see Appendix F to convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin; 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire; 
•
Used/unused/partially used Givinostat supply return and accountability. 
At study close-out, and as appropriate during the course of the study, the Investigator will return 
all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A. – Dipartimento di Tecnica Farmaceutica Viale Fulvio Testi, 330, 20126, 
Milan, Italy.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed 
agreement between the investigational site and Italfarmaco S.p.A.), these materials can be 
destroyed locally. 
4.5.4.2.1 Pre-treatment evaluations (up to 4 weeks: -28 to Day -1)
The following procedures will be performed at the pre-treatment visit of Part B as reported 
below: 
•
Informed consent signing; 
•
Demographic data (race, sex and date of birth); 
•
Adverse event recording; 
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Medical history;  
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), height, 
weight, body temperature and ECOG performance status;  
•
Pregnancy test (if indicated);  


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•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
(see Appendix F to convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin; 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Urinalysis: pH, specific gravity, protein, glucose;
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire [24, 
32]; 
•
Bone marrow histological evaluation, in patients who have consented to this 
optional exploratory research, who haven’t this assessment in the month before the 
1 month before the study start (i.e the signature of the Informed Consent Form, and 
that have not any medical contraindication to bone marrow sampling as judged by 
the Investigator; 
•
Request of enrolment and receipt of patient ID. 
The pregnancy test (if indicated) has to be performed within 72 hours before the first Givinostat 
dose. The test can be performed by urine or serum pregnancy test. In case of a borderline-
positive urine pregnancy test, this must be confirmed with a serum pregnancy test and the result 
recorded in the CRF. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status [28] 
2 within 7 days of initiating study drug.
Patients with splenomegaly will perform the spleen evaluation as per site-specific clinical 
practice. Therefore, patients with splenomegaly before the treatment start will be followed 
according to institutional guidelines (i.e. MRI or CT scan). The same imaging technique and the 
same instrument should be used on a patient throughout the study, if possible. 
Pre-treatment evaluations will be performed at one or more clinic visit to determine eligibility for 
the study. Pre-treatment evaluations must be performed up to 4 weeks before the treatment start 
within ± 7 days. Please note that, in case the patient performs the bone marrow histological 
evaluation as requested by the “new” ELN criteria (i.e. the revised ELN response criteria) 
[33] (see paragraph 4.8.7) – i.e. bone marrow evolution including the assessment of the 
presence of age adjusted normocellularity and/or trilinear hyperplasia - 1 month before the 
study start (i.e the signature of the Informed Consent Form), this examination has not to be 
repeated for this study in order to limit the discomfort for the patient.  


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In any case, the results of this test will be transcribed into the CRF and the original signed 
and dated laboratory print-out/tracings, including the assessment of the presence of age 
adjusted normocellularity and/or trilinear hyperplasia, will be monitored and stored at the 
study site. 
In case the patient refuses to provide this written consent to perform the bone marrow 
evaluation, this patient can be anyway recruited in Part B. However, this patient will not be 
counted to assess the related exploratory endpoints (i.e. overall response rate of Givinostat 
at the MTD after 6 cycles according to the revised ELN response criteria [33], and the 
evaluation of the effect of Givinostat on each single response parameter according to the 
revised ELN response criteria [33]).   
If all eligibility criteria are met at the pre-treatment visit, the treatment with Givinostat can start. 
After the check that all eligibility criteria are met by the patient and in any case before the 
treatment start, all patients with an uncontrolled HCT (i.e. HCT  45%) have to perform 
phlebotomy(ies) to normalize the HCT value (i.e. HCT <45%).  
In case of patients phlebotomy-dependent, all efforts have to be made by Investigators to record 
all phlebotomies witch recruited patients experienced at least 6 months before the treatment start.  
4.5.4.2.4 Day 28 of Cycles 3 and 6
The following procedures will be performed at Day 28 of Cycles 3 and 6 of Part B (within ± 3 
days) as reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
(see Appendix F to convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin; 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire [24, 
32]; 
•
Bone marrow histological evaluation (only for cycle 6), in patients who have 
consented to this optional exploratory research and that have not any medical 
contraindication to bone marrow sampling as judged by the Investigator; 
•


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•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Therapeutic response evaluation according to the “new” ELN criteria (i.e. revised 
ELN response criteria) [33] (see paragraph 4.8.7) (only for cycle 6); 
•
Givinostat administration and accountability (only for cycle 3). 
All phlebotomies performed in the first 3 weeks of treatment will be not counted to assess the 
clinico-haematologicaltherapeutic response. 
4.5.4.2.5 End of study
The following procedures will be performed at the end of study visit (in case of completed study) 
or 7 days after last drug intake (in case of the patient drops-out of the study) (within ± 3 days) as 
reported below: 
•
Adverse event recording;  
•
Concomitant medications (drugs); 
•
Significant non-drug therapies (e.g. phlebotomies, transfusions) recording (if applicable); 
•
Physical examination, vital signs (blood pressure, pulse rate, respiratory rate), weight, 
body temperature and ECOG performance status;  
•
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN 
(see Appendix F to convert Urea to BUN), glucose, Na, K, Ca, Cl, Mg, albumin; 
•
ECG, QTc determination (according with Bazett’s correction formula); 
•
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and 
differential), PLT count;  
•
Spleen evaluation by MRI or CT scan; 
•
Collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F
mutational status on peripheral blood (PB) granulocyte; 
•
Assessment of disease-related symptoms using the MPN-SAF QOL Questionnaire [24, 
32]; 
•
Bone marrow histological evaluation, in patients who have consented to this 
optional exploratory research, and that have not any medical contraindication to 
bone marrow sampling as judged by the Investigator;
•
Therapeutic response evaluation according to the clinico-haematological ELN 
response criteria [21] (see paragraph 4.6.1); 
•
Therapeutic response evaluation according to the “new” ELN criteria (i.e. revised 
ELN response criteria) [33] (see paragraph 4.8.7); 
•
Used/unused/partially used Givinostat supply return and accountability. 


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In case the patient drops-out the study during the first 3 Cycles (i.e. before the Day 28 of 
Cycle 3), this evaluation has not to be performed at End of Study visit. 
At study close-out, and as appropriate during the course of the study, the Investigator will return 
all used and unused study drug, packaging, drug labels, and the completed drug forms to 
Italfarmaco S.p.A. – Dipartimento di Tecnica Farmaceutica Viale Fulvio Testi, 330, 20126, 
Milan, Italy.  
Only in some particular cases, after the authorization of  Italfarmaco S.p.A. (or after a signed 
agreement between the investigational site and Italfarmaco S.p.A.), these materials can be 
destroyed locally. 
4.6.1 Criteria for assessing clinico-haematological improvement
Disease response will be evaluated according to the following clinico-haematological ELN 
criteria [21] (see paragraph 4.6.1) after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of 
treatment with Givinostat both in Part A (exploratory endpoints) and in Part B (primary and 
secondary endpoints, respectively).  
•
Complete response:  
1. HCT<45% without phlebotomy, and 
2. platelets  400 x109/L, and 
3. WBC 10 x109/L, and 
4. Normal spleen size, and 
5. no disease-related systemic symptoms (i.e. pruritus, headache, microvascular 
disturbances). 
•
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1. HCT <45% without phlebotomy, or  
2. response in 3 or more of the other criteria. 
•
No response: any response that does not satisfy partial response. 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months) and the 
eligibility for this part of the study may be expanded to all patients with cMPN, disease response 
for this part of the study will be evaluated according to the clinico-haematological ELN and 
EUMNET criteria [29] after 3 and 6 cycles of treatment with Givinostat, in ET and MF patients, 
respectively. 
... 


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4.8.1 Evaluation of the effects of Givinostat on each single parameter of the clinico-
haematological ELN response criteria
Each single parameter of the clinico-haematological ELN response criteria [21] (see paragraph 
4.6.1) will be used to evaluate the effect of Givinostat in PV patients. 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months) and the 
eligibility for this part of the study may be expanded to all patients with cMPN, in this part of the 
study each single parameter of the ELN and EUMNET criteria will be used to evaluate the effect 
of Givinostat in ET and MF patients, respectively. 
4.8.4 Improvement of constitutional symptoms 
To evaluate the improvement of disease-related constitutional symptoms the Myeloproliferative 
Neoplasm Symptom Assessment Form (MPN-SAF) questionnaire (about 20 items) will be used,  
in order to assess the most important clinical symptoms among patients with MPNs [24, 32].  
In addition, starting from MPN-SAF questionnaire, also the MPN-SAF Total Symptom 
Score [32] will be assessed  as requested by the “new” ELN criteria (i.e. revised ELN 
response criteria) [32].  
4.8.6 Reduction of the symptomatic treatment of pruritus in term of dosage and/or days of 
treatment.
To evaluate the reduction of the symptomatic treatment of pruritus, the dosage and/or the 
days of treatment of each concomitant medication taken by the patient to treat this 
symptom will be used. This assessment will be performed using the data entered by 
Investigators in the specific section of the CRF. 
4.8.7 Evaluation of preliminary efficacy according to the revised ELN criteria
Disease response will be evaluated also according to the following “new” ELN criteria (i.e. 
the revised ELN response criteria) after 6 cycles of treatment with Givinostat in Part B [33] 
(see paragraph 4.8.7). 


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•
Complete remission:  
1. Durable resolution of disease-related signs including palpable hepato-
splenomegaly improvement, and large symptoms improvement, and 
2. Durable peripheral blood count remission, defined as HCT < 45% without 
phlebotomies, and PLT count  400 x109/L, and WBC count < 10 x109/L, and 
3. No progressive disease, and absence of any hemorrhagic or thrombotic event, and 
4. Bone marrow histological remission defined as the presence of age-adjusted 
normo-cellularity, and disappearance of tri-linear hyperplasia, and absence of 
grade > 1 reticulin fibrosis. 
•
Partial remission:  
1. Durable resolution of disease-related signs including palpable hepato-
splenomegaly, and large symptoms improvement, and 
2. Durable peripheral blood count remission, defined as HCT < 45% without 
phlebotomies, and PLT count  400 x109/L, and WBC count < 10 x109/L, and 
3. No progressive disease, and absence of any hemorrhagic or thrombotic event, and 
4. No bone marrow histological remission defined as persistence of tri-linear 
hyperplasia. 
•
No response: any response that does not satisfy  partial remission. 
•
Progressive Disease: transformation into post-PV myelofibrosis, myelodysplastic 
syndrome or acute leukemia (according to the IWG-MRT criteria for the diagnosis 
of post-PV myelofibrosis and according to WHO criteria for the diagnosis of 
myelodysplastic syndrome and acute leukemia). 
Please note that according to the “new” ELN criteria (i.e. revised ELN response criteria) 
[33] (see paragraph 4.8.7): 
1) Molecular response is not required for assignment as Complete Remission or Partial 
Remission. Molecular response evaluation requires analysis in peripheral blood 
granulocytes. Complete response is defined as eradication of a pre-existing 
abnormality. Partial response applies only to patients with at least 20% mutant 
allele burden at baseline. Partial response is defined as   50% decrease in allele 
burden. 
2) “Durable” is defined as lasting at least 12 weeks. 
3) “Large symptom improvement” is defined as  10 points of decrease in MPN-SAF 
Total Symptom Score [32]. 


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4.8.8 Evaluation of the effects of Givinostat on each single parameter of the revised ELN 
response criteria
Each single parameter of the “new” ELN criteria (i.e. revised ELN response criteria) [33] 
(see paragraph 4.8.7) will be used to evaluate the effect of Givinostat in PV patients. 
5.3 SAE Reporting 
Any SAE, including death from any cause that occurs after a patient has signed the Informed 
Consent and up to the follow-up visit (regardless of relationship to study drug) must be reported 
by the Investigators to Italfarmaco S.p.A. within 24 hours of learning of its occurrence. 
Related SAEs MUST be collected and reported regardless of the time elapsed from the last study 
drug administration, even if the study has been closed.  
The Investigators are required to complete the SAE form provided by Italfarmaco S.p.A.. 
Sufficient details must be provided to allow for a complete medical assessment of the AE and 
independent determination of possible causality. The Investigators are obliged to pursue and 
provide additional information as requested by Italfarmaco S.p.A. Drug Safety Manager, or 
Study Director, or his designee. 
The Investigator must notify the SAE to the Italfarmaco S.p.A. Drug Safety Unit (DSU) by 
faxing and/or mailing (only in case the mail will be automatically generated by the e-CRF) the 
SAE form, within 24 hours of a SAE, at the number specified below; then, only in case the SAE 
will be faxed to the Italfarmaco S.p.A. DSU, the Investigator must confirm any SAE 
notifications by mailing to the mail address or phoning to the  phone number specified below: 
  
Drug Safety Unit 
Italfarmaco S.p.A. 
Via dei Lavoratori, 54  
20092 Cinisello Balsamo (MI), Italy  
Phone: 
Mobile: 
Fax:  
e-mail:  
  
The same procedure must be applied to the SAE follow-up information. 
All serious and unexpected AE that are associated with the use of the study drug (SUSARs) will 
be notified by Italfarmaco S.p.A. Drug Safety Manager to the competent authority within the 
required time and following procedures required by applicable laws.  
It is imperative that Italfarmaco S.p.A. be informed as soon as possible, so that reporting can be 
done within the required time frame.  
The SAEs will also be recorded in the dedicated AE section of the CRF. 
PPD
PPD
PPD
PPD
PPD


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5.3.2 Pregnacy
Female patients who have a positive pregnancy test during the pre-treatment evaluations 
assessment are not eligible for study participation. If a patient becomes pregnant while on study, 
the treatment shall be immediately stopped. The investigator is required to report the pregnancy 
to Italfarmaco S.p.A. Drug Safety Unit (DSU) within 24 hours via telephone and/or fax and/or 
mail (only in case the mail will be automatically generated by the e-CRF). If initially reported 
via telephone, this must be followed-up with a written report via fax and/or mail (only in case the 
mail will be automatically generated by the e-CRF) within 24 hours of the telephone report.  
Patients should be instructed to notify the investigator if, after completion of the study, it is 
determined that they became pregnant during the treatment phase or within the last follow up 
visit through 3 months after the last dose of study drug. 
Whenever possible, a pregnancy with an onset within the above defined time frame should be 
followed until termination, any premature termination should be reported, and the status of the 
mother and child should be reported to the sponsor after delivery. 
If the Investigator is made aware that the partner of a male patient who is participating to the 
study become pregnant, he/she is required to report the pregnancy to Italfarmaco S.p.A. DSU 
within 24 hours via telephone and/or fax and/or mail (only in case the mail will be automatically 
generated by the e-CRF). If initially reported via telephone, this must be followed-up with a 
written report via fax and/or mail (only in case the mail will be automatically generated by the e-
CRF) within 24 hours of the telephone report.  
Whenever possible, such pregnancy should be followed until termination, any premature 
termination should be reported, and the status of the mother and child should be reported to the 
sponsor after delivery. 
6.2.6.1 Part A
The following secondary efficacy parameters will be evaluated in Part A after 3 and 6 cycles of 
treatment (i.e. at the end of Cycles 3 and 6, respectively) based on ITT and PP: 
•
Preliminary efficacy of Givinostat (secondary endpoint) for PV/ET and MF patients, 
respectively (see paragraph 4.6.1 for more details): 
-
For PV and ET (if any): Complete response (CR) and partial response (PR) rate 
according to the clinico-haematological ELN response criteria [21] (see paragraph 
4.6.1); 
-
For MF (if any): Complete response (CR), major response, moderate response and 
minor response rate according to the EUMNET response criteria (see paragraph 
4.6.1). 
Note that only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months, the 
eligibility for this part of the study may be expanded to all patients with cMPN.  


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Frequency and percentage of patients in each response category (complete response (CR), partial 
response (PR), no response (NR) for PV and ET; Complete response (CR), major response, 
moderate response and minor response rate for MF) will be presented at each time point. In order 
to evaluate the response rate, subjects who discontinued prematurely the study for any reason 
(AE, consent withdrawal, lost to follow up) will be defined as ‘Non Responder’. Other missing 
data will not be replaced, if not otherwise specified. 
The following secondary parameter will be evaluated in Part A based on PK analysis set: 
–
Individual Givinostat concentrations tabulated by dose cohort along with descriptive 
statistics.  
The PK analysis will be conducted on the PK population.  
Plasma concentrations from Part A will be listed and tabulated by dose and time point for all 
patients and time points with at least 1 PK assessment.  
Descriptive statistics for all PK parameters for Part A will be calculated. These tables will 
include number of observations, mean, standard deviation, median, minimum and maximum and 
additionally the geometric mean and coefficient of variation (not for time to maximum plasma 
concentration). 
6.2.6.2 Part B
The following secondary efficacy parameter will be evaluated in Part B after 6 cycles of 
treatment (i.e. at the end of Cycle 6) based on ITT and PP: 
•
Preliminary effectiveness of Givinostat (secondary endpoint) after 6 cycles of treatment 
in Part B for PV/ET and MF patients, respectively (see paragraph 4.6.1 for more details): 
-
For PV and ET (if any): Complete response (CR) and partial response (PR) rate 
according to the clinico-haematological ELN response criteria [21] (see paragraph 
4.6.1); 
-
For MF (if any): Complete response (CR), major response, moderate response and 
minor response rate according to the EUMNET response criteria (see paragraph 
4.6.1). 
Note that only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 
months), the eligibility for this part of the study may be expanded to all patients with 
cMPN.  
Frequency and percentage of patients in each response category (complete response (CR), 
partial response (PR), no response (NR) for PV and ET; Complete response (CR), major 
response, moderate response and minor response rate for MF) will be presented at each 
time point. In order to evaluate the response rate, subjects who discontinued prematurely 
the study for any reason (AE, consent withdrawal, lost to follow up) will be defined as 
‘Non Responder’. Other missing data will not be replaced, if not otherwise specified. 


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The following secondary safety parameter will be evaluated in Part B after 6 cycles of treatment 
(i.e. at the end of Cycles 6, or including data related to Cycles 4, 5 and 6) based on safety 
population: 
•
Number of patients experiencing adverse events. 
•
Type, incidence, and severity of treatment-related adverse events, graded according to 
Common Terminology Criteria for Adverse Events (CTCAE v. 4.03, 14th June 2010). 
AEs will be coded using MedDRA dictionary (using the most updated version). Adverse events 
(AEs) will be reported on a per subject basis. If a patient has more than one AE for a treatment 
that coded to the same preferred term (PT), the patient will be counted only once for that 
preferred term. Similarly, if a patient has more than one AE for a treatment within a system 
organ class (SOC) category, the patient will be counted only once in that system organ class 
category. A patient with multiple CTCAE grades for an AE will be summarized under the 
maximum CTCAE grade recorded for the event.  
Any Adverse Events which started at or after the first administration of study treatment will be 
considered a treatment Emergent Adverse Event (TEAE). If the start date is missing for an AE, 
the AE will be considered to be treatment emergent.
TEAE included in this analysis are defined  as those starting after the  date of  the first 
administration of  Cycle 4. 
An overview of AEs including the number of subjects with at least one AE, at least one TEAE, at 
least one drug-related TEAE, at least one serious TEAE, any SAE, any AE leading to death, any 
TEAE leading to death, any TEAE leading to drug discontinuation, at least one grade  3 TEAE, 
will be presented. The following AE frequency tables will be also provided:  
•
incidence of TEAEs by primary SOC and PT; 
•
incidence of drug-related TEAEs by primary SOC and PT; 
•
incidence of TEAEs by maximum severity, primary SOC and PT; 
•
incidence of TEAEs by strongest relationship,  maximum severity, primary SOC and PT; 
•
incidence of TESAEs by primary SOC and PT; 
•
incidence of TEAEs leading to study drug discontinuation by primary SOC and PT; 
•
incidence of TEAEs leading to dose modification by primary SOC and PT. 


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The following secondary parameters will be evaluated in Part B based on PK analysis set: 
•
Individual Givinostat concentrations tabulated with descriptive statistics: plasma 
concentrations from Part B will be listed and tabulated by time point for all patients and 
time points with at least 1 PK assessment; descriptive statistics for all PK parameters for 
Part B will also be calculated; these tables will include number of observations, mean, 
standard deviation, median, minimum and maximum and additionally the geometric 
mean and coefficient of variation (not for time to maximum plasma concentration). 
6.2.7.1 Parts A and B
The following exploratory parameters will be evaluated using ad-hoc descriptive analysis in 
Parts A and B based on ITT and PP: 
•
The effect of Givinostat on each single response parameter according to the clinico-
haematological ELN (for PV and ET) [21] (see paragraph 4.6.1) and EUMNET 
response criteria (for MF); note that only in case the enrolment in Part A is slow (i.e. < 5 
patients enrolled in 3 months, the eligibility for this part of the study may be expanded to 
all patients with cMPN.  
•
Effects of Givinostat on PD markers. 
•
Effects of Givinostat on spleen size in patients with confirmed splenomegaly at baseline. 
•
Improvement of constitutional symptoms evaluated according to MPN-SAF QOL 
questionnaire [24, 320]. 
•
Reduction of the JAK2V617F allele burden, tested by quantitative RT-PCR. 
•
Reduction of the symptomatic treatment of pruritus in term of dosage and/or days of 
treatment. 
The following exploratory parameters will be evaluated using ad-hoc descriptive analysis in 
Part B based on ITT and PP: 
•
The preliminary efficacy of Givinostat after 6  cycles of treatment according to the 
“new” ELN criteria (i.e. revised ELN response criteria) [33] (see paragraph 4.8.7). 
•
The effect of Givinostat on single parameters of the “new” ELN criteria (i.e. revised 
ELN response criteria) [33] (see paragraph 4.8.7). 
Explorative endpoints will be summarized by descriptive methods. Default summary statistics 
and changes from baseline (where applicable) to each time point for all parameters will be 
produced. 


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6.3 Sample size and power considerations
The A standard 3+3 design adopting a modified Fibonacci escalation schema will be used  in 
Part A [25, 26, 27].  
Sample size for Part B was discussed for the primary end point defined as the Overall Response 
Rate after 3 cycles. Simon’s 2-stage design will be employed in Part B [30] with the aim of 
testing the “null hypothesis” that RR  0.50 versus the “alternative” that RR  0.75. Response 
rate will be assessed as defined in paragraph 6.2.5.2. Overall up to 28 patients will need to be 
recruited, 12 patients being enrolled in Stage-1. PV patients enrolled at the RP2DMTD in Part A 
may be counted towards Stage 1. Under the “null hypothesis” (if RR = 0.50), the expected total 
sample size is of 18.2 patients, the probability of early termination at the end of Stage-1 is 0.613 
and the probability of rejecting the “null hypothesis” is 0.081 (the target for the type-I error 
being 0.100). Under the “alternative hypothesis” (if RR = 0.75), the probability of rejecting the 
“null hypothesis” in favour of the “alternative” is 0.902 (the type-II error being 0.098). After 
testing the treatment on 12 patients in Stage-1, if 6 or fewer patients respond to the treatment the 
trial will be terminated rejecting the “alternative” that RR  0.75. Otherwise, the trial goes on to 
Stage-2 enrolling further 16 patients to a total of 28 patients. If at the end of Stage-2, a total of 17 
or fewer patients respond to the treatment the “alternative hypothesis” that RR  0.75 will be 
rejected; alternatively, if 18 or more patients respond, the “null hypothesis” that RR  0.50 will 
be rejected. Estimations are obtained from proprietary software (based on SAS ® 9.2) according 
to the algorithm proposed by R. Simon [30]. 
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8; 350(2):114-24. 
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Golay J, Rambaldi A., The histone deacetylase inhibitor ITF2357 selectively targets cells 
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Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Reilly JT, Vannucchi AM, 
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22. Rambaldi A, Dellacasa CM, Finazzi G et al., A pilot study of the Histone-Deacetylase 
inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative 
neoplasms, Br. J. Haematol. 2010; 150 (4): 446-55. 
23. Rambaldi et al., A phase II study of the HDAC inhibitor Givinostat in combination with  
hydroxyurea in patients with Polycythemia Vera resistant to hydroxyurea monotherapy, 
Poster at ASH 2011, Session Name: 634.Myeloproliferative Syndromes, Publication N.: 
1748, Submission ID: 40637, ClinicalTrial.gov Identifier: NCT00928707. 
24. Scherber et al., The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-
SAF): International Prospective Validation and Reliability Trial in 402 patients, Blood, 
2011 July 14; 118(2): 401-408. 
25. Le Tourneau C, Lee JJ, Siu LL, Dose Escalation Methods in Phase I Cancer Clinical 
Trials, JNCI, 2009 May 20; 101(10): 708–720. 
26. Rubinstein LV and Simon RM, Phase I clinical trial design, In Budman, Calvert, 
Rowinsky, (eds.), Handbook of Anticancer Drug Development, Elsevier, Amsterdam, 
297-308, 2003.  
27. Omura GA, Modified Fibonacci Search, J. Clin. Oncol., 2003 August 15; 21(16): 3177 – 
3177. 
28. Oken M.M., Creech R.H., Tormey DC et al., Toxicity and response Criteria of the eastern 
cooperative oncology group, Am. J. Clin. Oncol. 1982; 5: 649-655. 


 ITALFARMACO S.p.A.
                                 Study N.:       DSC/12/2357/45
                                                                                              EudraCT N.:     2013-000860-27 
Amendment 1 
Version 1.0  – 23rd  July 2013 
SOP 2 final version 12.09 
 
Page 29of 29 
Confidential
29. Barosi G, Bordessoule D, Briere J et al., Response criteria for myelofibrosis with myeloid 
metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET), 
Blood 2005; 106: 2849-53. 
30. Simon R., Optimal two-stage designs for phase II clinical trials, Controlled Clinical 
Trials, 1989; 10: 1-10. 
31. Lippert E., Girodon F., Hammond E., et al.: Concordance of assays designed for the 
quantification of JAK2V617F: a multicenter study, Haematologica 2008; 94: 8-45. 
32. Emanuel R.M., Dueck A.C., Geyer H.L. et al.: Myeloproliferative neoplasm (MPN) 
symptom assessment form total symptom score: prospective international assessment of 
an abbreviated symptom burden scoring system among patients with MPNs, JCO 
November 20, 2012; 30 (33): 4098-4103. 
33. Barosi G., Mesa R., Finazzi G. et al.: Revised response criteria for polycythemia 
vera and essential thrombocythemia: a ELN and IWG-MRT consensus project, 
Blood, 2013 June 6; 121(23): 4778-81. 

SAP_000.pdf: 
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 1 of 101 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
STUDY N. : DSC/12/2357/45 
 
 
A TWO-PART STUDY TO ASSESS THE SAFETY AND PRELIMINARY EFFICACY OF 
GIVINOSTAT IN PATIENTS WITH JAK2V617F POSITIVE POLYCYTHEMIA VERA 
 
 
 
 
AUTHOR:  
 
VERSION NUMBER AND DATE: VERSION 2.2, 21TH  MARCH 2018 
 
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 2 of 101 
Statistical Analysis Plan Signature Page 
Statistical Analysis Plan V2.2 (addendum) (Dated 21th March 2018) for a two-part study to assess the 
safety and preliminary efficacy of Givinostat in patients with JAK2V617F positive Polycythemia Vera 
(Study N. DSC/12/2357/45; study protocol version 3.0, dated 29th July 2015). 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Biostatistician 2 
 
Company: 
Quintiles  
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this study. 
Name 
Signature 
Date 
Approved By: 
 
 
 
 
 
Position: 
 Senior Clinical Project Manager 
 
Company: 
 Quintiles  
 
Approved By: 
 
 
 
 
 
Position: Associate Clinical Lead Director 
 
Company: Quintiles  
 
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 3 of 101 
 
Approved By: 
 
  
 
 
 
Position: Manager Biostatistics 
 
Company: Quintiles 
 
Customer Representatives:  
Approved By: 
 
Paolo Bettica 
 
 
 
Position: Clinical R&D Director 
 
Company: Italfarmaco S.p.A. 
 
Approved By: 
 
 
 
 
 
Position: Clinical Scientist 
 
Company: Italfarmaco S.p.A. 
 
Approved By: 
 
 
 
 
 
Position: Clinical R&D Manager 
 
Company: Italfarmaco S.p.A. 
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 4 of 101 
OUTPUT TEMPLATES SIGNATURE PAGE 
Output Templates V2.2 (Addendum) (Dated 21th March 2018): 
 
Part A: Analyses to determine the Maximum Tolerated Dose (MTD); 
 
Part B (I): Stage I (Interim Analysis) of the Simon’s 2-stage design (Primary evaluation of Response Rate) 
 
Part B (II): Stage 2 (Overall Analysis) of the Simon’s 2-stage design (at the end of Part B). 
For a two-part study to assess the safety and preliminary efficacy of Givinostat in patients with 
JAK2V617F positive Polycythemia Vera (Study N.: DSC/12/2357/45; study protocol version 3.0, dated 29th 
July 2015). 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Biostatistician 2 
 
Company: 
Quintiles  
Upon review of this document, the undersigned approves this version of the Output Templates, 
authorizing that the content is acceptable for the reporting of this study. 
Name 
Signature 
Date 
Approved By: 
 
 
 
 
 
Position: 
 Senior Clinical Project Manager 
 
Company: 
 Quintiles  
 
Approved By: 
 
 
 
 
 
Position: Associate Clinical Lead Director 
 
Company: Quintiles  
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 5 of 101 
Approved By: 
 
  
 
 
 
Position: Manager Biostatistics 
 
Company: Quintiles S.p.A. 
 
Customer Representatives:  
Approved By: 
 
Paolo Bettica 
 
 
 
Position: Clinical R&D Director 
 
Company: Italfarmaco S.p.A. 
 
Approved By: 
 
 
 
 
 
Position: Clinical Scientist 
 
Company: Italfarmaco S.p.A. 
 
Approved By: 
 
 
 
 
 
Position: Clinical R&D Manager 
 
Company: Italfarmaco S.p.A. 
 
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Effective Date: 01May2012 
 
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reproduction is strictly prohibited. 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 6 of 101 
MODIFICATION HISTORY 
 
Unique Identifier for this 
Version 
Author 
Significant 
Changes 
from  
Previous Authorized Version 
V1 
 
Not Applicable – First Version 
V2 
 
Added the text “In all cases, the medical 
judgment of the Investigator’s is taken 
into account. In particular, if the 
Investigator‘s 
clinical 
response 
assessment – that takes into account the 
overall medical judgment of the specific 
patient’s case - is not in agreement with 
the exact application of the clinico-
haematological 
ELN 
or 
EUMNET 
response criteria , the Investigator’s 
assessment 
will 
supersede 
the 
“mathematical” application of these 
criteria and used for analysis into study 
report.” to the following sections:  
Section 16.3, Sections 17.2, 18.1  and 18.2. 
But 
section 
16.11: 
sub 
section 
“EVALUATION OF PRELIMINARY EFFICACY 
ACCORDING 
TO 
THE 
REVISED 
ELN 
CRITERIA” and Section 19.1 the word 
updated from “clinico-haematological ELN 
or EUMNET response criteria ” to “revised 
clinico-haematological 
ELN 
response 
criteria” 
V2 
 
Section 5.2: ITT population definition 
updated  
V2 
 
Section 15.1: Compliance derivation 
equation updated.  
V2 
 
Section 16.2. EFFICACY ASSESSMENT; 
the LOCF section removed because 
study is not using LOCF method to 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 7 of 101 
handle missing data.
V2 
 
All Listing numbers changed from 
16.1.x.x to 16.2.x.x to follow ICH E3 
listing number guideline.  
V2 
 
The 
word 
of 
“exact 
method 
(as 
applicable)” added to the section 6.5 
V2.1 
 
The SAP section 10 updated to include 
following information in the table.  
Overall treatment group analysis for Part 
A tables and Figures, patients age group 
(< 60 years /≥60 years), Patients 
requiring phlebotomy, Patients with 
previous thrombosis history, patients 
with age ≥ 60 years and/or previous 
thrombosis 
history, 
Controlled 
hypertension (i.e. Normal ranges for 
systolic blood pressure: less than 120 
mmHg, diastolic blood pressure: less 
than 80mmHg) and  Number of patients 
with Pruritus, Headache, Microvascular 
Symptoms. Corresponding tables are 
updated for Part A and Part B II.   
V2.1 
 
SAP section 19.1: Additional analysis of 
patients without the symptom of 
headache, pruritus and microvascular 
symptoms (i.e MPN SAF Score =0) and 
number and percentage of patient with 
symptom score from 0 to 3, from 4 to 6 
and more than 7 are added. Also 
patients rate with normalized WBCs 
(WBCs count ≤ 10 x 109/L), Patients rate 
with normalized platelets (platelets ≤ 
400 x 109/L) and Patients rate with 
normalized haematocrit (haematocrit 
<45% without phlebotomy) are added. 
The following tables/figures are added. 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 8 of 101 
Tables 
14.2.5.1, 
14.2.5.2, 
14.2.5.3, 
14.2.5.4 and figures 14.2.1.18, 14.2.1.19, 
14.2.1.20, 
14.2.1.21, 
14.2.1.22, 
14.2.1.23, and 14.2.1.24 are added for 
Part A. 
Tables 
14.2.6.3, 
14.2.6.4, 
14.2.6.5 
14.2.6.6 and figures 14.2.1.19, 14.2.1.20, 
14.2.1.21, 14.2.1.22, 14.2.1.23, 14.2.1.24 
and 14.2.1.25 are added for Part BII. 
V2.1 
 
Section 20.4: Additional information of 
‘The number (n) and percentage (%) at 
baseline, Cycle 3 Day 28 and Cycle 6 Day 
28 showed a Spleen Volume reduction ≥ 
35%’ is added. 
MedDRA 
dictionary 
(version 
19.0) 
changed to MedDRA dictionary (version 
20.1) and WHO-DRL Drug Dictionary 
(Version 01MAR2016) changed to WHO-
DRL 
Drug 
Dictionary 
(Version 
01SEP2017) 
Section 15.1: ‘+1’ removed from the Per 
visit” Compliance calculation formula.  
Added the text ‘Also for the last cycle 
compliance calculation this formula will 
be used as the last dose of study drug 
date considering from disposition page.’ 
V2.2 (Addendum) 
 
1. Analysis performed for mathematical 
application of ELN response criteria (not 
agreed by the medical site team) and 
following tables are added.  
Part A: 14.2.1.1.1, 14.2.1.4.1, 14.2.1.7.1, 
14.2.1.8.1, 14.2.1.9.1, 14.2.1.10.1 
Part B: 14.2.1.1.1, 14.2.1.3.1, 14.2.2.1.1, 
14.2.2.2.1, 
14.2.2.3.1, 
14.2.2.4.1, 
14.2.9.1,  14.2.9.3, 14.2.2.7, 14.2.2.8. 
2. The following tables/Figures are 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 9 of 101 
added:- Part A: T14.3.5.3, T14.3.5.4, 
T14.2.5.5, 
T14.2.5.6, 
F14.2.1.25, 
F14.2.1.26 and T14.1.21.2 modified.    
Part B: T14.3.5.3, T14.3.5.4, T14.2.6.7, 
14.2.9.2, F14.2.1.26, F14.2.1.27 and 
T14.1.22.2 modified.   
3.  The following suffix number are 
added to TFLs outputs to differentiate 
the study parts in CSR:   .a added for Part 
A, .bi added for Part B IA and .bii added 
for Part B II. 
 
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 10 of 101 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE  
 
Adverse Event 
ALP 
 
Alkaline phosphatase 
ALT 
 
Alanine aminotransferase 
AST  
 
Aspartate aminotransferase 
ATC 
 
Anatomical Therapeutic Chemical Classification 
AUC 
 
Area under concentration-time curve 
AUC(0-)    
Area under concentration-time curve over the dosing interval: from t=0 to t=12h 
AUClast     
Area under concentration-time curve over the dosing interval: from t= 0 up to the last 
detectable concentration timepoint 
b.i.d. 
 
Bis In Die (twice daily) 
BLQ 
 
Below the lower limit of quantitation   
BUN 
 
Blood Urea Nitrogen 
Ca 
 
Calcium 
CIs 
 
Confidence Intervals 
Cl 
 
Chloride  
Clast  
 
Last detectable plasma concentration  
Cmax  
Maximal plasma concentration 
cMPN   
chronic Myelo-Proliferative Neoplasms 
CMO 
 
Contract Manufacturing Organization 
CR 
 
Complete Response 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CT 
 
Computerized Tomography 
CTCAE  
Common Terminology Criteria for AE 
C 
 
trough concentration (Pre-dose levels on day 28 in the cycles of treatment) 
CV 
 
Coefficient of Variation 
DLT  
 
Dose Limiting Toxicity 
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Page 11 of 101 
ECG 
 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
ELN 
 
European LeukemiaNet 
ET  
 
Essential Thrombocythemia  
EU  
 
European Union 
EUMNET 
European Myelofibrosis Network  
Hb  
 
Haemoglobin 
HBV  
 
Hepatitis B Virus 
HCT 
 
Haematocrit 
HCV 
 
Hepatitis C Virus 
HDACs   
Histone deacetylases  
HDACi  
Histone deacetylases inhibitors 
HDPE  
High-density Polyethylene 
HIV  
 
Human Immunodeficiency Virus 
ICH  
 
International Conference on Harmonization 
ITT 
 
Intent-to-treat 
JAK2 
 
Janus Kinase 2 
JAK2V617F 
Janus Kinase 2 mutated at position 617 
K 
 
Potassium 
LCM 
 
Left Costal Margin 
LDH 
 
Lactate Dehydrogenase 
MCH 
 
Mean Corpuscular Haemoglobin 
MCHC  
Mean Corpuscular Haemoglobin Concentration 
MCV  
 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF  
 
Myelofibrosis 
mg 
 
Milligram 
Mg 
 
Magnesium 
MPN-SAF  
Myeloproliferative Neoplasm Symptom Assessment Form  
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Page 12 of 101 
MRI  
 
Magnetic Resonance Imaging 
msec 
 
Millisecond 
MTD 
 
Maximum Tolerated Dose 
Na 
 
Sodium 
NCI 
 
National Cancer Institute 
nM 
 
Nanomolar 
NR 
 
No Response 
NYHA  
New York Heart Association 
NQ 
 
Not quantifiable 
o.d. 
 
Once Daily 
PD 
 
Pharmacodynamic 
PLT  
 
Platelets count 
PMF  
 
Primary Myelofibrosis 
PP  
 
Per-protocol 
PR 
 
Partial Response 
PT 
 
Preferred Term  
PV  
 
Polycythemia Vera 
PK  
 
Pharmacokinetics 
QOL  
 
Quality Of Life 
qRT-PCR 
Quantitative Real Time Polymerase Chain Reaction 
QTc 
 
QT interval corrected 
RBC 
 
Red Blood Cell count 
RT-PCR  
Real Time Polymerase Chain Reaction 
RR 
 
Response Rate 
SAE  
 
Serious Adverse Event 
SAP  
 
Statistical Analysis Plan 
SAS  
 
Statistical Analysis System 
SOC  
 
System Organ Class 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
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Page 13 of 101 
STAT5   
Signal Transducers and Activators of Transcriptase 5 
TdP 
 
Torsades de Pointes  
TEAE 
 
Treatment-Emergent Adverse Event 
t.i.d. 
 
Ter In Die (three times daily) 
Tmax 
 
Time of the maximal concentration in plasma 
Tlast 
 
Time of the last detectable concentration in plasma 
ULN 
 
Upper Limit of Normal 
WBC 
 
White Blood Cell count 
WHO 
 
World Health Organization 
WHO-DRL 
World Health Organization-Drug Reference List 
 
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 14 of 101 
 
CONTENTS 
1. 
Introduction .................................................................................................................................................. 19 
2. 
Study Objectives ............................................................................................................................................ 19 
2.1. 
Primary Objective ...................................................................................................................................... 20 
2.2. 
Secondary Objectives ................................................................................................................................ 20 
2.3. 
Exploratory Objectives............................................................................................................................... 21 
3. 
Study Design .................................................................................................................................................. 21 
3.1. 
General Description ................................................................................................................................... 21 
3.2. 
PART A ....................................................................................................................................................... 22 
3.2.1. Definition of Dose Limiting Toxicity (DLT) .................................................................................................... 23 
3.2.2. Study team definition .................................................................................................................................. 23 
3.2.2.1. Dose Levels (DLs) and dose escalation scheme ......................................................................................... 23 
3.2.2.2. Dose Escalation Rules ............................................................................................................................... 24 
3.2.2.3. Definition of MTD ..................................................................................................................................... 25 
3.3. 
Part B ......................................................................................................................................................... 26 
3.4. 
Treatments ................................................................................................................................................ 26 
3.4.1. Treatments Administered............................................................................................................................ 26 
3.4.2. Method of Assigning Patients to Dose Level ................................................................................................ 28 
3.4.3. Blinding ....................................................................................................................................................... 29 
3.5. 
Determination of Sample Size.................................................................................................................... 29 
3.6. 
Schedule of Events ..................................................................................................................................... 30 
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Page 15 of 101 
3.7. 
Changes in the Conduct of the Study or Planned Analyses......................................................................... 30 
4. 
Planned Analyses .......................................................................................................................................... 33 
5. 
Analysis Sets .................................................................................................................................................. 34 
5.1. 
Safety analysis set (SAF) ............................................................................................................................ 34 
5.2. 
Intent-to-treat analysis set (ITT) ................................................................................................................ 34 
5.3. 
Per Protocol analysis set (PP) ..................................................................................................................... 35 
5.3.1. Protocol Deviations ..................................................................................................................................... 35 
5.4. 
Maximum tolerated dose Analysis SET (MTD) ........................................................................................... 39 
5.5. 
PK Analysis set (PK) ................................................................................................................................... 39 
6. 
General Considerations ................................................................................................................................. 39 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 39 
6.2. 
Baseline ..................................................................................................................................................... 40 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 41 
6.4. 
Windowing Conventions ............................................................................................................................ 41 
6.5. 
Statistical Tests .......................................................................................................................................... 41 
6.6. 
Common Calculations ................................................................................................................................ 42 
6.7. 
Software Version ....................................................................................................................................... 42 
7. 
Statistical Considerations .............................................................................................................................. 42 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 42 
7.2. 
Multicentre Studies ................................................................................................................................... 42 
7.3. 
Missing data .............................................................................................................................................. 42 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 42 
7.5. 
Examination of Subgroups ......................................................................................................................... 43 
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8. 
Output Presentations .................................................................................................................................... 43 
9. 
Disposition and Withdrawals ......................................................................................................................... 45 
10. 
Demographic and other Baseline Characteristics ....................................................................................... 46 
10.1. 
Derivations ............................................................................................................................................ 52 
11. 
Medical History ......................................................................................................................................... 52 
12. 
Prior and Concomitant Illnesses................................................................................................................. 53 
12.1. 
Post-Treatment Diseases ....................................................................................................................... 53 
13. 
Medications (i.e. DRUGS) ........................................................................................................................... 53 
13.1. 
Non-Drugs Therapies ............................................................................................................................. 54 
14. 
Study Medication Exposure ....................................................................................................................... 54 
14.1. 
Derivations ............................................................................................................................................ 55 
15. 
Study Medication Compliance ................................................................................................................... 56 
15.1. 
Derivations ............................................................................................................................................ 56 
16. 
Efficacy And Safety Variables ..................................................................................................................... 58 
16.1. 
Definition of end of the study ................................................................................................................ 58 
16.2. 
Efficacy Assessment ............................................................................................................................... 58 
16.3. 
Criteria for assessing clinico-haematological improvement ................................................................... 59 
16.4. 
Criteria for determination of MTD ......................................................................................................... 62 
16.5. 
Criteria for characterization of PK .......................................................................................................... 62 
16.6. 
The Efficacy Population .......................................................................................................................... 62 
16.7. 
Safety assessments ................................................................................................................................ 62 
16.8. 
Laboratory evaluations .......................................................................................................................... 63 
16.9. 
Clinical safety assessments .................................................................................................................... 63 
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16.10. 
Adverse events ...................................................................................................................................... 64 
16.11. 
Exploratory parameters ......................................................................................................................... 64 
17. 
Primary Outcomes ..................................................................................................................................... 68 
17.1. 
Part A ..................................................................................................................................................... 68 
17.2. 
Part B ..................................................................................................................................................... 72 
18. 
Secondary Outcomes ................................................................................................................................. 74 
18.1. 
Part A ..................................................................................................................................................... 74 
18.2. 
Part B ..................................................................................................................................................... 75 
18.3. 
PK Analysis............................................................................................................................................. 77 
19. 
Exploratory Outcomes ............................................................................................................................... 79 
19.1. 
Parts A and B ......................................................................................................................................... 79 
20. 
Other Safety Outcomes ............................................................................................................................. 80 
20.1. 
Laboratory Evaluations. ......................................................................................................................... 80 
20.2. 
Laboratory Specific Deviations ............................................................................................................... 81 
20.3. 
ECG Evaluations ..................................................................................................................................... 84 
20.4. 
Spleen Evaluations ................................................................................................................................. 85 
20.5. 
Vital Signs .............................................................................................................................................. 86 
20.6. 
Physical Examination ............................................................................................................................. 87 
20.7. 
Other Safety Assessments...................................................................................................................... 87 
21. 
Molecular Analysis..................................................................................................................................... 87 
22. 
Bone Marrow Analysis ............................................................................................................................... 89 
23. 
Dose Modification Analysis........................................................................................................................ 90 
24. 
Over-dosage  and other situations putting the patient at risk of adverse reaction .................................... 90 
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25. 
Pregnancy .................................................................................................................................................. 91 
26. 
Data Not Summarised or Presented........................................................................................................... 92 
27. 
References ................................................................................................................................................. 93 
APPENDIX 1. 
Programming Conventions for Outputs ...................................................................................... 94 
APPENDIX 2. 
Partial Date Conventions ............................................................................................................ 99 
 
 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis for the 
Study N.: DSC/12/2357/45 (hereinafter “Study”). 
 
It describes the data to be summarised and analyzed, including specifics of the statistical analyses to be 
performed. Deviations from methods described in the statistical analysis plan might appear. In case of 
such deviations the reason for the deviation will be stated in the final statistical report.  
 
This Statistical Analysis Plan (SAP) is based on the Study protocol (version 1.0, dated 01st March 2013), 
Amended Protocol (version 3.0, dated 29 July 2015) and on two Amendments (Amendment 1, dated 
23rd July 2013 and Amendment 2 dated 29th July 2015). 
 
Notably, for the purpose of this document the name “Givinostat” is used to indicate the whole Study 
drug name “Givinostat hydrochloride monohydrate” (also known as ITF2357, i.e. its Sponsor’s research 
code). Therefore, the dosages/concentrations of the Study drug are expressed as Givinostat 
hydrochloride monohydrate. 
 
2. STUDY OBJECTIVES 
In recent years several reports have documented that histone deacetylases inhibitors (HDACi) induce 
neoplastic cells to undergo growth arrest, differentiation and/or apoptotic cell death. Among these 
agents, Givinostat (Sponsor’s research code: ITF2357) has most recently demonstrated effects on 
haematological parameters as well as constitutional parameters in patients with Polycythemia Vera 
(PV).  
Preliminary signs of clinical activity in patients with JAK2 mutant cMPN, have been observed in two 
studies with Givinostat (Studies N.: DSC/07/2357/28 and DSC/08/2357/38). In these studies, the 
maximum administered dose of Givinostat was 150 mg per day which was generally well tolerated. 
Assuming a linear relationship between dose and efficacy, greater clinical efficacy could be expected 
with increased doses of Givinostat. 
Since the Maximum Tolerated Dose (MTD) of Givinostat has not been defined previously, the first aim 
of the current Study (Part A, Phase Ib) is, therefore, to determine the MTD of Givinostat in patients 
with PV. This Study will investigate the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) activity of Givinostat monotherapy. As such, the Study will characterize Dose 
Limiting Toxicities (DLTs) and MTD of Givinostat.   
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The second aim of the Study (Part B, Phase II) is to characterize the clinical efficacy of Givinostat at the 
MTD. 
2.1. PRIMARY OBJECTIVE 
This is a two-part, multicentre, open label, non-randomized, phase Ib/II study to assess the safety and 
tolerability, MTD and preliminary efficacy of Givinostat in patients with JAK2V617F positive PV.  
Part A is the dose escalation portion of the Study; and, once the MTD is established, Part B is 
commenced where the preliminary efficacy of Givinostat in PV patients is to be established. Patients 
are enrolled either in Part A or Part B and transition from one part to the other is not allowed.  
PART A 
 
To characterize the safety, tolerability and MTD of Givinostat in patients with PV.  
PART B 
 
To evaluate the preliminary efficacy of Givinostat at the MTD after 3 cycles according to the 
clinico-haematological European LeukemiaNet (ELN) response criteria [1]. 
 
To determine the safety and tolerability of Givinostat at the MTD after 3 cycles. 
 
2.2. SECONDARY OBJECTIVES 
PART A 
 
To evaluate the preliminary efficacy of Givinostat after 3 and 6 cycles of treatment according to 
the clinico-haematological ELN response criteria [1]. 
 
To characterize PK. 
PART B 
• 
To evaluate the preliminary efficacy of Givinostat at the MTD after 6 cycles according to the 
clinico-haematological ELN response criteria [1]. 
• 
To determine the safety and tolerability of Givinostat at the MTD after 6 cycles. 
 
To characterize PK. 
 
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2.3. EXPLORATORY OBJECTIVES 
PART A AND B 
 
To evaluate the effect of Givinostat on single parameters of the clinical-haematological ELN 
response criteria [1]. 
 
To evaluate the effects of Givinostat on PD markers. 
 
To evaluate the effects of Givinostat on spleen size (by MRI or CT scan) in patients with 
confirmed splenomegaly at baseline. 
 
To evaluate the effects of Givinostat on disease-related quality of life. 
 
To evaluate the effect of Givinostat on JAK2V617F allele burden. 
 
To evaluate the reduction of the symptomatic treatment of pruritus. 
 
PART B 
 
To evaluate the preliminary efficacy of Givinostat after 6 cycles of treatment according to the 
“new” ELN response criteria (i.e. the revised ELN response criteria). 
 
To evaluate the effect of Givinostat on single parameters of the “new” ELN response criteria (i.e. 
the revised ELN response criteria) [2]. 
 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a two-part, multicentre, open label, non-randomized, phase Ib/II study to assess the safety and 
tolerability, MTD and preliminary efficacy of Givinostat in patients with JAK2V617F positive PV.  
Part A is the dose escalation portion of the Study and, once the MTD has been established, Part B is 
commenced where the preliminary efficacy of Givinostat in PV patients will be established. Patients 
are enrolled either in Part A or Part B and transition from one part to the other is not allowed. Only PV 
patients from Part A assigned to the dose selected for Part B (MTD) can be counted towards the 
efficacy assessment in Part B.  
Eligible patients for this Study have a confirmed diagnosis of PV according to the revised WHO criteria 
and the JAK2V617F positivity. Only if the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 
months), eligibility for this part of the Study could be expanded to all patients with cMPN.  
After providing informed written consent before undertaking any protocol-related procedure, a unique 
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patient identification code (i.e. patient screening ID which is a combination of his/her site ID, Study 
part ID and patient screening number, e.g. IT01-A01) is assigned to each patient which will identify the 
patient within his/her enrolment confirmation by Italfarmaco S.p.A. (Sponsor) or its designee (CRO) 
and can never be reused in case of screening failure. After the enrolment confirmation and the 
assignation of the dose level before the first drug intake, an unique patient identification code (i.e. 
patient ID which is a combination of patient screening number ID and dose level ID, e.g. IT01-A01-DL1) 
is assigned to each patient which willidentify the patient throughout his/her participation in the Study 
and can never be reused in case of premature drop-out. 
Study therapy is administered in 28 day cycles. In fact, the “cycle” is defined as 4 weeks of treatment. 
Disease response is evaluated according to the clinico-haematological ELN criteria [1] after 3 and 6 
cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the Study. 
All phlebotomies performed in the first 3 weeks of treatment are not been counted to assess the 
clinico-haematological response. 
The Study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, 
all patients achieving clinical benefit are allowed to continue treatment with Givinostat (at the same 
dose and schedule) in a long-term study (Study N.: DSC/11/2357/44), providing that the long-term 
study has already received all necessary approvals in that specific country and site, and the study has 
already been initiated in that particular site. 
Safety is monitored at each visit throughout the entire duration of the Study. Treatment is 
administered on an outpatient basis and patients are followed regularly with physical and laboratory 
tests, as specified in the protocol (see Appendix A and paragraph 4.5.4 of the Study protocol version 
3.0); in case of hospitalization, the treatment is continued or interrupted according to the 
Investigators’ decision.  
 
3.2. PART A 
Part A is the dose escalation part of this Study, evaluating the safety, tolerability and MTD of Givinostat 
in patients with JAK2V617F positive PV.  
In this part of the Study the first cycle of treatment is used to assess the safety and tolerability of 
Givinostat as well as PK/PD.  
After the completion of the first cycle, the patients are treated for an additional 5 cycles.  
Only PV patients from Part A assigned to the dose selected for Part B (MTD) can be counted towards 
the efficacy assessment in Part B.  
 
The Dose Levels and the rules of escalation to the next dose are detailed in Sections 4.1.1.3 and 4.1.1.4 
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Page 23 of 101 
of the Study protocol version 3.0 (see pages 46 and 47). 
 
3.2.1. DEFINITION OF DOSE LIMITING TOXICITY (DLT)  
DLT is defined as the following drug-related toxicity: 
 
Grade 4 haematological toxicities, or 
 
Grade 3 febrile neutropenia, or 
 
Grade ≥ 3 non-haematological toxicities with exception of: 
a) 
Grade 3 diarrhoea without adequate supportive care lasting less than 3 days, and 
b) 
Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days, or 
 
Any drug-related SAE, or 
 
Any toxicity that is clearly not related to disease progression or intercurrent illness requiring 
interruption of dosing for more than 3 days during the first cycle.  
 
The severity of the above mentioned events is graded according to NCI Common Terminology Criteria for 
Adverse Events (CTCAE v. 4.03, 14th June 2010). 
Only DLTs experienced during the first cycle of treatment are considered for dose escalation decisions. 
DLTs included all Adverse Events that are clearly not related to disease progression or intercurrent 
illnesses. 
Patients who do not experience a DLT and miss more than 10% of the doses in Cycle 1 of Part A should 
be replaced (see paragraph 4.6.4 of the Study protocol version 3.0). 
 
3.2.2. STUDY TEAM DEFINITION 
The Study team included: selected Principal Investigator/s (i.e. Chairman and/or Principal Investigator/s 
who recruited the patients under discussion), the CRO’s Medical Monitor, Sponsor’s Medical Expert/s, 
Sponsor’s Clinical Scientist and any other additional personnel, if necessary. 
3.2.2.1. DOSE LEVELS (DLS) AND DOSE ESCALATION SCHEME 
Dose escalation is conducted according to a standard 3+3 design, adopting a modified Fibonacci 
escalation schema [3, 4, 5]. Patients are enrolled in cohorts of 3 new patients (up to a maximum of 6) in 
rising dose levels (Table 1). Dose escalation to the next higher Dose Level (DL) can only occur after the 
third patient in the DL is followed for a minimum of 1 cycle after the first administration of study agent, 
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and the current dose is determined to have an acceptable safety profile according to the following rules 
summarised in Table 2. 
 
Table 1 – Dose escalation scheme for Givinostat mono-therapy in Part A 
Givinostat daily dose  
Givinostat dose level (DL) 
DL used primarily to assess 
50 mg b.i.d. 
DL0 
Safety, PK, PD* 
100 mg b.i.d. 
DL1 
MTD, PK, PD 
150 mg b.i.d. 
DL2 
MTD, PK, PD 
200 mg b.i.d. 
DL3 
MTD, PK, PD 
150 mg t.i.d. 
DL4 
MTD, PK, PD 
200 mg t.i.d. 
DL5 
MTD, PK, PD 
* DL previously demonstrated as safe. 
 
The DL0 (i.e. 50 mg b.i.d.) was previously shown to be well tolerated in studies (see Section 6 “Effects in 
humans” of the Investigator Brochure Dossier related to ITF2357). Therefore, it is preferred to assign 
patients to the highest available dose level (i.e. DL1, DL2, DL3, DL4 and DL5) before assigning patients to 
DL0. 
Intermediate Dose Levels (IDLs) and, consequently, additional DLs can be introduced to more accurately 
define the MTD. 
Note that if a pregnancy occurs, the patient can be replaced and another patient in that DL should be 
recruited. 
 
3.2.2.2. DOSE ESCALATION RULES 
In Part A each patient will receive Study drug at a specific DL. Once the first 3 patients of the first DL (i.e. 
DL1) are treated for 1 cycle, tolerability data are evaluated and a decision to escalate to the next dose is 
made.  
 
Table 2 summarises the dose escalation rules for Givinostat in Part A. 
 
 
 
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Table 2 - Dose escalation rules for Part A 
Number of patients with 
DLT at a given dose level 
Action 
0 out of 3 
Enter 3 patients at the next DL. 
1 out of 3 
Enter at least 3 more patients at this DL and 
 
if 0 of these 3 new patients experiences DLT, proceed to the 
next DL; 
 
if ≥ 1 of this group suffer DLT (for a total of ≥ 2/6 patients 
with a DLT), this DL exceeds the MTD and dose escalation is 
stopped. To further assess tolerability, 3 additional patients 
can be entered at the next lowest DL if only 3 patients were 
treated previously at that dose. Upon determination of the 
MTD, the Study should proceed directly to Part B. 
≥ 2 
Dose escalation should be stopped. This DL exceeded the MTD. To 
further assess tolerability, 3 additional patients can be entered at the 
next lowest DL if only 3 patients were treated previously at that DL 
and the Study should proceed directly to Part B of the Study. 
 
At any time, if ≥ 2/3 or ≥ 2/6 patients at a given DL develop a DLT, it is acceptable to de-escalate to an 
intermediate, not previously studied dose (see Table 1), if evaluation of toxicity at such a dose is desired, 
in lieu of proceeding directly to Part B of the Study. If this approach is taken, 3 patients should be 
enrolled at the intermediate dose, and the aforementioned rules should be used to determine 
enrolment at this dose. If the decision is made to proceed directly to the efficacy portion of the Study 
(i.e. Part B), the efficacy part should be started at the next lower dose below where ≥ 2/3 or ≥ 2/6 DLTs 
are observed (i.e. the MTD dose level).  
 
3.2.2.3. DEFINITION OF MTD 
If 2 or more patients per DL experienced a DLT, dose escalation is terminated and the MTD is the next 
lower DL if no more than one out of 6 patients have a DLT at that level. Once all patients enrolled in 
Part A are treated for at least 1 cycle, the study team determine the MTD to be used in Part B based 
on the safety and tolerability profile of Givinostat observed as well as the PK and PD data, if applicable.  
No intra-patient dose escalation is permitted prior to determining the MTD.  
At that time, patients on treatment at lower DLs can be allowed to escalate their Givinostat dose up to 
the MTD for the remainder part of the study (Part A) at the discretion of the Investigator and, after the 
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Sponsor’s written authorization. Of note, patients initially dosed at lower DLs that are allowed to 
escalate their Givinostat dose up to the MTD for the remainder part of the study (Part A), are to  
follow the dose modification rules of Part B (see paragraph 4.3.3.2 of the Study protocol version 3.0). 
Total daily dose can never exceed the MTD defined in Part A (i.e. 100 mg b.i.d.). 
 
3.3. PART B 
Part B is a multicentre, open label, non-randomized, phase II, cohort expansion Study to assess the 
preliminary clinical efficacy of Givinostat at the MTD in patients with JAK2V617F positive PV. 
Patients enrolled in Part B started at the MTD defined in Part A (i.e. 100 mg b.i.d.), according to an 
optimized Simon’s 2-stage design [6]. 
The dose of Givinostat is modified for Study protocol specified toxicities (see paragraph 4.3.3.2 of the 
Study protocol version 3.0).  
 
3.4. TREATMENTS 
3.4.1. TREATMENTS ADMINISTERED 
 
Givinostat is supplied by the Sponsor or its designee as hard gelatine capsules for oral administration 
at the strength of 50 mg, and/or 75 mg, and/or 100 mg each.  
Each capsule contains a granulate (obtained by wet granulation) composed of ITF2357, sodium starch 
glycolate, hydroxypropyl methyl cellulose (HPMC), sodium lauryl sulphate, lactose, magnesium 
stearate and colloidal silica. 
The packaging consists of HDPE plastic bottles- closed with a PP screw cap, tamper evident -  
containing hard gelatine capsules of Givinostat. Each bottle contains: 
 
30 capsules of 50 mg of Givinostat, or 
 
30 capsules of 75 mg of Givinostat, or 
 
15 capsules of 100 mg of Givinostat.  
At each visit, patients receive a number of bottles sufficient to cover the period between two visits. 
In Part A patients can be treated in DLs at the following starting daily doses of Givinostat:  
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 
50 mg b.i.d.; 
 
100 mg b.i.d.; 
 
150 mg b.i.d.; 
 
200 mg b.i.d.; 
 
150 mg t.i.d.; 
 
200 mg t.i.d.. 
Intermediate Dose Levels (IDLs) and, consequently, additional DLs can be used to establish the MTD 
(for more details, see paragraph 4.1.1.3 of the Study protocol version 3.0). 
Notably, the tested DLs to be considered for the MTD statistical analysis, are resumed in the Table 1.1.  
 
Table 1.1 - Dose escalation of Givinostat performed in Part A 
Givinostat daily dose 
Givinostat dose level (DL) 
DL used primarily 
to asses 
Label for Tables, 
Listings and 
Figures (TLFs) 
100 mg b.i.d. 
DL1 (first three patients) 
MTD, PK, PD 
DL1 
DL1 (additional three patients) 
DL1 expanded 
2 capsules of 50 mg at the 
morning AND 1 capsule of 50 
mg at the evening (i.e. 12 
hours after) 
DL6 
MTD, PK, PD 
DL6 
50 mg b.i.d. 
DL0 
Safety, PK, PD* 
DL0 
* DL previously demonstrated as safe. 
 
No patient will be treated at the DL2, none at DL3, none at DL4, none at DL5 in Part A, as per dose 
escalation scheme describe in the Study protocol and also summarised in the section 3.2.2.1. of the 
present document. 
In Part B patients are treated at the MTD of Givinostat established in Part A (i.e. 100 mg b.i.d., DL1).  
Dose adjustments are permitted for patients who do not tolerate the protocol-specified dosing 
schedule, in order to allow these patients to continue the treatment with Givinostat (see paragraph 
4.3.3.1 and paragraph 4.3.3.2 of the Study protocol version 3.0). The objective of the Givinostat dose 
adjustment rules described below is to optimize the response for each individual patient, avoiding 
specific drug-related toxicities.  
Both in Part A and in Part B, patients self-administer daily Givinostat capsules at home as instructed by 
the Investigator (see paragraph 4.4.7.2 and paragraph 4.4.7.4 of the Study protocol version 3.0), 
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except for the first drug administration (i.e. Day 1 of the Cycle 1). Patients cannot take the morning 
dose of Givinostat on the day selected for their timed PK and PD assessments (see paragraph 4.5.3.2 
and paragraph 4.5.3.3 of the Study protocol version 3.0). Study drug is administered in the clinic for 
these specific visits, in order to obtain pre- and/or post-dose plasma levels of Givinostat. On all the 
other days corresponding to study visits, patients should take the morning dose of Study drug prior to 
the visit. 
In Part A, the lowest dosage of Givinostat that can be dispensed to the patients is 50 mg o.d.. In this 
case, the patient should take the Study drug each day in the morning with fluids and between meals 
(i.e. to take the study drug at least 2 two hours after the last meal, or no less than 1 hour before the 
meal). In all other possible dosages (i.e. 50 mg b.i.d, or 100 mg b.i.d., or 150 mg/die), patients should 
self-administer daily Givinostat capsules at home at morning and in the evening (i.e. after 12 hours) 
with fluids and between meals (i.e. to take the study drug at least 2 two hours after the last meal, or 
no less than 1 hour before the meal). 
In Part B, the lowest dosage of Givinostat that can be dispensed to the patients is 50 mg b.i.d., while 
the highest dosage of Givinostat that could be dispensed to the patients is 100 mg b.i.d. In all the 
possible dosages (i.e. 50 mg b.i.d., 75 mg b.i.d., 100 mg b.i.d.), patients should self-administer daily 
Givinostat capsules at home at morning and in the evening (i.e. after 12 hours) with fluids and 
between meals (i.e. to take the study drug at least 2 two hours after the last meal, or no less than 1 
hour before the meal).  
Dose adjustments are permitted for patients who do not tolerate the Study protocol-specified dosing 
schedule, in order to allow to these patients to continue the treatment with Givinostat. The guidelines 
described in the Study protocol (see paragraph 4.3.3.2.1 and paragraph 4.3.3.2.2 of the Study protocol 
version 3.0) need to be followed. The objective of the Givinostat dose adjustment rules are to optimize 
the response for each individual patient, avoiding specific drug-related toxicities. Therefore, dose 
reductions or interruptions are mandated for specific toxicities and dose increases after an initial dose 
reduction are allowed in the case of inadequate efficacy at the reduced dosage. 
Each dose modification is to be recorded on the Case Report Form (CRF). 
 
3.4.2. METHOD OF ASSIGNING PATIENTS TO DOSE LEVEL  
When a Study site has a patient ready to enroll, prior to dosing, the site have to compile a Request for 
Registration Form and send it to the Sponsor or CRO team, in order to obtain the patient ID.  
This request is located in a specific section of the electronic CRF,  which the site should complete only 
after having fully compiled all the previous screening sections, including medical history, patient’s 
characteristics, a checklist related to the inclusion and exclusion criteria to verify the eligibility of the 
patient, etc.    
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The request for patient’s registration contain the site ID (e.g. “IT01”), the Study part ID (i.e. “A” for Part 
A and “B” for Part B), the assigned patient screening number and the date of the request.  
If the patient is eligible, the Sponsor or CRO confirm the enrolment of the patient assigning the related 
DL and the patient ID (i.e. the patient code after the enrolment confirmation) which is a combination 
of patient screening ID and dose level ID (e.g. “IT01-A01-DL1). 
Once assigned, both the patient screening ID and the patient ID must not be reused for any other 
patient. 
3.4.3. BLINDING 
No blinding procedures are applicable as the Study is open label. 
 
3.5. DETERMINATION OF SAMPLE SIZE 
A standard 3+3 design adopting a modified Fibonacci escalation schema is used in Part A [3, 4, 5].  
 
Sample size for Part B is discussed for the primary endpoint defined as the Overall Response Rate after 
3 cycles. Simon’s 2-stage design is employed in Part B [6] with the aim of testing the “null hypothesis” 
that RR ≤ 0.50 versus the “alternative” that RR ≥ 0.75. Response rate was assessed as defined in 
paragraph 6.2.5.2 of the Study protocol version 3.0. Overall, up to 28 patients are to be recruited, 12 
patients being enrolled in Stage 1. PV patients enrolled at the MTD in Part A can be counted towards 
Stage 1.  
Under the “null hypothesis” (if RR = 0.50), the expected total sample size is 18.2 patients, the 
probability of early termination at the end of Stage-1 is 0.613 and the probability of rejecting the “null 
hypothesis” is 0.081 (the target for the type-I error being 0.100).  
Under the “alternative hypothesis” (if RR = 0.75), the probability of rejecting the “null hypothesis” in 
favor of the “alternative” is 0.902 (the type-II error being 0.098).  
After testing the treatment on 12 patients in Stage 1, if 6 or fewer patients responded to the 
treatment, the trial should be terminated rejecting the “alternative” that RR ≥ 0.75. Otherwise, the 
trial should go on to Stage 2 enrolling a further 16 patients to a total of 28 patients.  
If at the end of Stage-2, a total of 17 or fewer patients responded to the treatment, the “alternative 
hypothesis” that RR ≥ 0.75 should be rejected; alternatively, if 18 or more patients responded, the 
“null hypothesis” that RR ≤ 0.50 should be rejected.  
Estimations were obtained from CRO proprietary software (based on SAS® 9.2) according to the 
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algorithm proposed by R. Simon [6]. 
 
3.6. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 4.5.4 of the Study protocol version 3.0. 
Patient must be followed at the study centre according to the visit schedule and assessments outlined 
in the flow-charts presented in Appendix A of the Study protocol version 3.0. 
 
3.7. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
CHANGES IN THE CONDUCT OF THE STUDY 
 
Two amendments were implemented to the final protocol version 1.0, dated 01st March 2013. 
The following changes were made in Amendment 1, dated 23rd July September 2013, with no impact 
on the planned statistical analysis, with the exception of the last point: 
1. Clarification of the meaning of an “effective means of contraception for women of childbearing 
potential and men with partners of childbearing potential” (i.e. inclusion criterion n. 5) 
mentioning that the contraceptive methods will be used for up to 3 months after stopping the 
study treatment, as requested by the French Regulatory Authority. 
2. Update of the patient numbering sections as per electronic CRF. 
3. Correction of some typographic mistakes existing in the clinical Study protocol version 1.0 
(dated 01st March 2013). 
4. Addition of the exploratory endpoint of Part B the evaluation of the preliminary efficacy of 
Givinostat according to the “new” ELN response criteria (i.e. the revised ELN response criteria) 
[2]. 
The following changes were made in Amendment 2, dated 29th July 2015.  Points 11 and 13-22 affect 
the planned statistical analyses:  
1. Amendment of some wording in the preclinical rationale (paragraph 1.3 of the Study protocol) 
based on the most updated available information. 
2. Update of the approved drugs for the treatment of PV and MF. 
3. Addition of the neuromuscular disorders in the indications explored with Givinostat. 
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4. Clarification about the necessity to have received all necessary approvals in that specific 
country and site, performed the site initiation in that particular site, before starting the long-
term study (Study N.: DSC/11/2357/44), that allows patients achieving clinical benefit in the 
Study to continue treatment with Givinostat (at the same dose and schedule) after completion 
of the Study.  
5. Addition of the Contract Manufacturing Organization (CMO) as possible delegate for the 
management of the Study drug (e.g. secondary packaging, distribution to the sites). 
6. Clarification of the meaning of “any other investigational drug or device” (i.e. exclusion 
criterion n. 19).  
7. Specification of the instructions related to the Study drug administration and dispensing. 
8. Clarification of the fact that no spleen evaluation should be performed in splenectomised 
patients, while the spleen evaluation was requested in all other patients in Part B, since the 
presence of splenomegaly was one of the parameters to evaluate as per primary objectives of 
Part B (i.e. according to the ELN response criteria [1]). 
9. Explanation of the fact that, in case the patient completed the Study (i.e. performed all the 
evaluations requested to be done at  Day 28 of Cycle 6), the evaluations performed at Cycle 6 
Day 28 visit were also counted for the End of Study visit. 
10. Specification of the fact that, in case the patient completed the Study (i.e. performs all the 
evaluations requested to be done at the Day 28 of Cycle 6) and she/he was eligible to continue 
the Study drug treatment in the long-term study (i.e. Study DSC/11/2357/44), the evaluation 
performed at the Day 28 of Cycle 6 visit of this Study could be also counted for the pre-
treatment evaluations of the Study DSC/11/2357/44, provided that no difference in the 
evaluations was present between the two studies (e.g. haematological and biochemical 
evaluations).  
11. Clarification that all efficacy analyses were conducted on this population and were based on 
the effective DL/daily doses of Givinostat at which each patient was treated. 
12. Correction of typographic mistakes and better explanation of some sentences existing in the 
clinical study protocol version 2.0 (including Amendment 1, version 1.0, 23rd July 2013), in 
order to better detail the right procedures to be followed. 
13. Update of the safety sections according to the more updated notification of Serious Adverse 
Event (SAE) Form (i.e.by electronic CRF), Adverse Events definition and the details of the 
Sponsor’s Drug Safety Unit. 
14. Update of the sections related to Part B, based on the definition of the MTD of Givinostat as 
chronic treatment in PV patients. Notably, in July 2015 the tolerability data related to the 
patients enrolled in Part A – i.e. the six patients treated at the Dose Level 1 (i.e. 100 mg b.i.d., 
DL1) and 3 patients treated at the Intermediate Dose Level (i.e. 150 mg/die, also defined 
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“DL6”) - have been considered in order to define the MTD of Givinostat as chronic treatment in 
PV patients. Even if only one DLT was observed in the 6 patients treated at DL1 during the first 
cycle of treatment (i.e. a  “grade ≥ 3 non-haematological toxicity” (dyspepsia), judged “drug-
related” by the Investigator) and the escalation at higher DLs could be possible, the Study team 
agreed unanimously to consider the DL1 (i.e. 100 mg b.i.d.) as MTD of Givinostat to be used in 
Part B as chronic treatment in PV patients, considering the following points: 
- Givinostat was a chronic treatment for PV patients in the current schedule; 
- The observed PLT decrease; 
- The knowledge of the safety profile of HDACi and, in particular, of Givinostat (i.e. 
thrombocytopenia was a side-effect); 
- It could be preferable/ethical to avoid exposing 3 patients to the higher dosage (i.e. 150 
mg b.i.d., DL2) that, as above reported, will be reasonably untollerated by the patients. 
Therefore, the dosage to use in Part B as established in Part A by the Study team, i.e. 100 mg 
b.i.d., was defined as the MTD of Givinostat taking into account the chronic schedule of the 
study drug as prescribed in this current study.   
15. Update of the dose modification rules to be applied in Part B and in Part A for patients who 
may be allowed to escalate their Givinostat dose up to the MTD for the remainder of the Study 
(Part A) at the discretion of the Investigator and Sponsor. 
The dose modifications rules to be applied in Part B have been updated based on the data 
related to the patients enrolled in Part A of this Study and to the results obtained in previous 
studies with Givinostat on cMPN. The objective of the updated Givinostat dose adjustments 
rules are to optimize the response for each individual patient, avoiding specific drug-related 
toxicities. Therefore, dose reductions or interruptions are mandated for specific toxicities and 
dose increases after an initial dose reduction are allowed in case of inadequate efficacy at the 
reduced dosage in absence of specific toxicities.  
Notably, the same dose modification criteria could be followed by patients initially dosed at 
lower dose levels in Part A that, after the definition of MTD, could be allowed to escalate their 
Givinostat dose at MTD for the remainder part of the study (Part A) at the discretion of the 
Investigator and Sponsor.    
16. Addition of the strength of 75 mg.   
17. Addition of PD evaluations, performed using an aliquot of the PK samples. 
18. Clarification of the calculation of eGFR (i.e. a derived biochemical parameter) in accordance 
with the Mayo Clinic Quadratic Equation, as agreed with the German Regulatory Authority. 
19. To allow the evaluation of Urea (in spite of BUN) in accordance with the site-specific clinical 
practice. 
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20. Addition of the recommendation to perform two additional ECG evaluations over a brief 
period (i.e. 5 minutes between each recording), if the first ECG evaluation demonstrates a 
prolonged QTc interval (i.e. a QTc interval ≥ 450 msec). 
21. Clarification of the fact that in Part B it is recommended that patients should be told to arrive 
after an overnight fast of at least 8 hours at all Study visits that requested a blood test. 
22. Addition of the collection of a blood sample for the quantitative RT-PCR evaluation of JAK2V617F 
mutational status on peripheral blood granulocyte at the following Study visits of Part B: Day 
28 of Cycles 1, 2, 4 and 5. 
 
CHANGES IN THE PLANNED ANALYSIS 
 
No changes to analysis from the Final version of the Protocol (version 3.0, dated 29 July 2015) are 
planned with the exception of the use of the SAS software, version 9.2 or higher, (instead of the 
StatXact-4 software) to compute Exact/Nonparametric 95% CIs.  
4. PLANNED ANALYSES 
The following analyses are planned: 
A. 
Part A: Analyses to determine the Maximum Tolerated Dose (MTD); 
B. 
Part B (I): Stage I (Interim Analysis) of the Simon’s 2-stage design (Primary evaluation of 
Response Rate)  
Interim analysis will be performed on the 12 patients of the first stage of part B. If seven or more 
responses will be observed in the first stage of part B, further 16 patients will be enrolled in the second 
stage of part B.  If six or fewer responses will be observed during the first stage then the study will be 
stopped. Futility will be assessed in 12 patients after 3 cycles. 
The Interim analysis will evaluate preliminary efficacy and safety and tolerability of Givinostat at the 
MTD after 3 cycles in 12 patients. Exploratory endpoints analysis will also be included with available 
data after 3 cycles.  
C. 
Part B (II): Stage 2 (Overall Analysis) of the Simon’s 2-stage design (at the end of Part B). 
Final analysis will be performed in all 28 patients enrolled in two stages of part B after 6 cycles. 
No formal DB lock is planned neither for the 1st Cycle of Part A not for Stage 1 (Simon’s 2-Stage design) 
of Part B of the study. 
 
Three different Output Templates will be presented for the 3 sets of analyses. 
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5. ANALYSIS SETS 
Agreement and authorization of patients included/excluded from each analysis set will be conducted 
prior to the database lock of the study during the Data Review Meeting.  
 
The analysis sets are defined distinctly for each of the 3 planned analyses. 
 
The number and percentage of the patients included in the analysis populations will be reported in a 
table showing the reason of exclusion for all patients enrolled into study. A listing of reasons of 
exclusion from analysis population will be provided. 
 
Patients who sign an informed consent form but who do not start Study treatment for any reason, will 
be considered as “Screening Failures”.  For these patients, a separate Table will be produced including 
the primary reason for screen failure and patient’s demographic information as per electronic CRF. 
5.1. SAFETY ANALYSIS SET (SAF) 
The Safety analysis set will include all enrolled patients who receive at least one dose of study 
medication. All safety analyses will be conducted on this population. 
5.2. INTENT-TO-TREAT ANALYSIS SET (ITT) 
The Intent-to-treat analysis set will include all recruited patients who receive at least one dose of study 
medication and from whom at least one post-baseline efficacy measurement is obtained.  
Of note, patients who dropped the study due to drug-related TEAE(s) before that the post-baseline 
efficacy measurement is obtained (i.e. at C3D28 and/or at C6D28), will be considered in the ITT 
analysis set; in these cases, the post-baseline efficacy measurements (i.e. at C3D28 and/or at C6D28) 
will be considered as “No Response”, even if these assessments were not performed.    
In addition, patients who have performed the visit when the post-baseline efficacy measurements (i.e. 
at C3D28 and/or at C6D28) had to be performed, but for which the following conditions will happen, 
will be excluded from the ITT analysis set: 
 
HCT > 45% or HCT ≤ 45% with phlebotomy(ies), AND  
 
at least 2 out of 4 assessments of the following will be not performed: 
a) WBC count; 
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b) PLT count; 
c) Spleen evaluation by CT scan or MRI; 
d) Disease-related assessment by MPN-SAF.  
This is due to the fact that is not possible to define a clinico-haematological response as per ELN 
response criteria in these cases.  
All efficacy analyses will be conducted on this population and will be based on the effective/actual 
DL/daily doses of Givinostat at which each patient has been treated. 
5.3. PER PROTOCOL ANALYSIS SET (PP) 
In order to assess the robustness of the efficacy analysis, the analysis of the efficacy end-point will be 
repeated on the Per Protocol (PP) analysis set. The Per-protocol analysis set will include all ITT patients 
who receive at least 14 daily doses without interruptions, and without any major deviation from the 
protocol procedures. 
5.3.1. PROTOCOL DEVIATIONS 
Protocol deviations to be reviewed will include, but will not be limited to, patients who: 
 
Did not meet inclusion/exclusion criteria or eligibility not adequately verified. 
 
Received disallowed concomitant medications pre- and/or post-treatment. 
 
Developed withdrawal criteria but were not withdrawn. 
 
According to Quintiles SOPs the PDs are classified as Minor, Major and Critical. Starting from 1st March 
2016, the categorization changed into Minor, Important (for Major) and Priority (for Critical). 
In order to comply with the Protocol requirements, the categorization of ‘Critical’, ‘Important’ and 
‘Priority’ will fall into the ‘Major’ one. 
 
A. Major protocol deviations to be reviewed will include, but will not be limited to, the following 
groups: 
1. Entry criteria: 
 
Any "no" response to inclusion criteria and/or any "yes" response to exclusion criteria and 
patient was subsequently enrolled. 
NOTE: only in case of previous written Sponsor authorization this type of deviation can be considered 
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as ‘Minor’.  
 
2. Investigational Medicinal Product: 
 
Investigational Product dosing error: in case the patient takes a dose of IP that is different 
from the assigned dose (example: dose level, DL0, DL1, DL6 or MTD as defined at the end 
of study Part A). 
 
Enrolled out of DL - NOTE: only in the case of previous written Sponsor authorization to 
have the patient enrolled on cohort DL0 this is not considered as a protocol deviation. 
 
Part A (between C2D1 and C6D28) and Part B: Non-compliant with IMP usage (under 80%). 
According to the protocol “A patient will be considered sufficiently compliant with 
Givinostat treatment if he/she has taken at least 80% of the prescribed dose over the total 
duration of study drug dosing”. 
 
The site dispensed the used IMP stored out of the following storage conditions described 
in the IMP handling manual, to the patient without the Sponsor’s written authorization: (i) 
IMP storage temperature ≥ 30°C and ≤ 40°C for ≥ 30 days, or (ii) IMP storage temperature 
> 40°C 
 
Incorrect IMP dispensation to a patient: (i) in case the site incorrectly assign a dosage 
different from the one approved by the Sponsor at the time of enrollment (example: dose 
level, DL0, DL1, DL6 or MTD as defined at the end of study Part A), or (ii) in case the site 
performed a dose escalation not predicted by the study protocol. 
 
3. Informed Consent: 
 
Patient did not sign Main ICF.  
 
ICF is signed after study procedure was done, except for invasive procedures performed 
before the ICF signature as clinical practice AND, anyway, only after the Sponsor’s  written 
authorization to be obtained before the first drug intake. 
 
4. Concomitant Medications:   
 
Patient used prohibited medication(s) during the study course. 
 
5. Study Procedures: 
 
SAEs not reported in according to the correct timelines. 
 
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B. Minor protocol deviations to be reviewed will include, but will not be limited to, the following 
groups: 
 
1. Entry criteria: 
 
Patient enrolled without all data and results available to evaluate the inclusion and 
exclusion criteria, or not following the correct enrollment protocol procedures. 
 
Enrollment of the patient with the local laboratory report for confirming the JAK2V617F 
positivity before receiving the confirmation from the central laboratory and without 
the Sponsor’s written authorization.  
 
2. Investigational Medicinal Product: 
 
The patient has assumed the IMP out of the procedures described in the IMP Handling 
manual. 
 
IMP accountability not done or not fully completed by the site. 
 
Missed IMP dose that does not affect the 80% of IMP compliance.  
 
3. Visit Schedule: 
 
Screening visit performed outside approved protocol window (28 days +/- 7 days). In 
fact, patient must be medically stable on the basis of physical examination, medical 
history, and vital signs performed at screening [within 28 days before randomization 
to Day 1]. If there are abnormalities, they must be consistent with the underlying 
illness in the study population. 
 
End of Study Visit (EOS) not performed or performed more than 7 days after last drug 
intake, except for completers patients.  
 
Patient visits performed outside approved window, except in case of the Sponsor’s 
written authorization (for example, the patient is in vacation and the study visit should 
be performed 2 days before his/her coming back). 
 
Patient visits not fully performed as per study protocol. 
 
Patient(s) miss an entire visit. 
 
4. Informed Consent: 
 
Incorrect version of ICFs signed. 
 
In case of pregnancy, the patient – if female – or the patient partner – if the patient is 
a male - has not signed the Pregnancy ICF and the pregnancy data have been collected. 
 
Missing date of ICFs. 
 
Site personnel who signed ICFs is not on Site Personnel Signature Delegation Log 
and/or not authorized by PI to sign ICFs. 
 
Bone Marrow (BM) consent not provided, but BM histological evaluation done. 
 
Pregnant Partner ICF obtained although the partner of the patient IS not pregnant. 
 
Latest version of non-substantial ICFs not signed by the patient at the first study visit 
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once the ICFs is available at site. 
 
IEC/IRB contact details or site's contact details not included on ICFs. 
 
Patient did not directly add his/her name on the ICFs space near to the signature. 
 
 
5. Study Procedures: 
 
Lack of adherence to delegation requirements. 
 
Bone Marrow consent provided, but sample not collected by the site.  
 
SAEs not appropriately reported Systemic lack of Principle Investigator oversight of 
safety data. 
 
Not collecting samples related to primary efficacy variables: haematology samples not 
collected at cycle 3. 
 
Study procedures needed for the primary objectives and primary endpoints not done: 
haematology samples not collected, spleen evaluation not done, MPN-SAF QOL and 
Questionnaire not completed at all at cycle 3, ECG including QTc determination not 
completed at cycle 3. Study procedures needed for the secondary objectives and 
secondary endpoints not done: haematology samples not collected, spleen evaluation 
not done, MPN-SAF QOL Questionnaire not completed at all, PK sample not collected 
at cycles 3 and 6 and Bone Marrow histological evaluation not done at cycle 6. 
 
Study procedures needed for the exploratory objectives and endpoints not done: 
haematology samples not collected, PD samples not collected, spleen evaluation not 
done, MPN-SAF QOL Questionnaire not completed at all, JAK2V617F not collected 
according to the protocol and Bone Marrow histological evaluation not done. 
 
A negative urine B-human chorionic gonadotropin (B-hCG) pregnancy test not 
collected at screening visit for patient, if women of childbearing potential. 
 
Delegation log not up to date prior to study procedures being performed. 
 
Study procedures that do not affect the patient’s safety, eligibility confirmation and 
response assessment not done.   
 
Patient did not answer to all the questions of the MPN-SAF QOL Questionnaire. 
Information partially collected. 
 
6. Laboratory: 
 
Back-up sample of JAK2V617F, PK and PD not collected. 
 
Primary and back-up samples of JAK2V617F, PK and PD of the same patient and collected 
at the same visit, shipped to the Central Laboratory with the same shipment. 
 
PK and/or PD samples not collected at pre-dose at visit Day1 Cycle 1 and at the 
subsequent time points as predicted by the protocol. 
 
Blood samples drawn by staff not listed on study delegation log or site staff not 
certified. 
 
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All potential protocol deviations will be discussed and reviewed on a case-by-case basis before the 
database lock. 
Individual protocol deviations will be presented in a data listing. The number and percentage of 
patients with protocol deviations will be summarized by deviation. Additional Major and Minor 
protocol deviations may be identified during data review and will be reflected in the table and listing 
as appropriate. 
5.4. MAXIMUM TOLERATED DOSE ANALYSIS SET (MTD) 
The MTD analysis set will include all patients who experienced DLTs in Cycle 1 of Part A, or who 
received at least 90% of the doses of study medication in Cycle 1 of Part A. The data regarding the 
Cycle 1 of Part A will be used to determine MTD from this analysis set. 
5.5. PK ANALYSIS SET (PK) 
The PK Analysis Set will consist of all SAF patients with at least 1 PK assessment. 
This analysis set will be used for PK analysis. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day of 
assessments and events.  
For both Part A and Part B, reference start date is defined as the day of the first dose of study 
medication (C1D1 is the day of the first dose of study medication) and is referred to as “Day 1” for the 
definition of the Baseline value. Day - 1 is the day that precedes Day 1. Day 0 is not defined. 
The date and the time of the first investigational study drug of each patient will be taken from the “On-
site Dosing (DOSING)” raw data panel.  
 
• If the date of the event is on or after the reference date then: 
Study Day = (date of start of the event – reference date) + 1. 
 
• If the date of the event is prior to the reference date then: 
Study Day = (date of start event – reference date). 
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In the situation where the event date is partial or missing, the date will appear partial or missing in the 
listings, and Study Day, and any corresponding durations will be presented based on the imputations 
specified in Appendix 2; Partial Date Conventions. 
 
The duration of an event will be presented in days, rounded to one decimal place and will be 
calculated as follows: 
 
Duration of event= (date of end of event – date of start of event) + 1.  
 
In the case of a retest (same visit number assigned) of a non laboratory data (i.e. 3 ECG repeated as 
per QTc prolongation), the average of all measurements will be used for by-visit summaries.  
Early termination data will be summarised in the specific visit where occurred. 
 
Listings will include all scheduled, unscheduled and early discontinuation data. 
6.2. BASELINE 
The Screening/Baseline Period is defined as the period from informed consent signature to the first 
investigational study drug administration (i.e. C1D1 in Parts A and B). In the case where the last non-
missing measurement and the reference start date coincide, that measurement will be considered pre-
baseline (i.e. C1D1), but Adverse Events (AEs) and medications commencing on the reference start date 
will be considered post-baseline.  
 
Baseline, is defined as the last scheduled non-missing measurement taken prior to dosing and will 
correspond to Day 1 (i.e. C1D1 in Parts A and B) for clinical laboratory evaluations and physical 
examinations and to Day 1, predose for PK concentrations, PD assessments vital signs and ECGs.  
However, if a patient is missing the planned baseline collection, the previous non-missing evaluation 
will become the baseline value.  
 
The Baseline descriptive analysis will be based on the SAF set. 
 
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6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
 
Unscheduled safety measurements (Laboratory, Vital signs, ECG) of all patients, within each dose level 
for Part A and within MTD, for Part B, will be evaluated as following: 
 
if a planned visit was not performed, the nearest (±3 days) unscheduled visit will be considered 
as the correspondent planned one. 
 
if unscheduled visits were performed in addition of the planned one, each unscheduled visit 
between two planned ones will be summarized and ordered by date. 
 
In the case of a retest (same visit number assigned) of a non laboratory data (i.e. 3 ECG repeated as 
per QTc prolongation), the average of all measurements will be used for by-visit summaries.  
Early termination data will be summarised in the specific visit where occurred. 
 
Listings will include all scheduled, unscheduled and early discontinuation data. 
 
6.4. WINDOWING CONVENTIONS  
No visit windowing will be performed for this study at this time. 
6.5. STATISTICAL TESTS 
The main purpose of this phase Ib/II study consists in providing accurate estimates of clinically relevant 
variables and measures.  
The two tailed 95% confidence intervals of the primary endpoint will be computed using the Normal 
Approximation or exact method (as applicable) for proportions.  Confidence intervals for model 
parameters will be based on either the profile likelihood function. All tests will be two-sided, unless 
otherwise specified in the description of the analyses. 
 
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6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline (absolute and percentage) will be calculated as: 
 
• 
Test Value at Visit X – Baseline Value 
• 
(Test Value at Visit X – Baseline Value)/ Baseline Value*100 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.2 (or higher).  
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES 
No adjustment for covariates will be performed for this study. 
7.2. MULTICENTRE STUDIES 
This study will be conducted by multiple investigators at multiple centres internationally.   
No statistical adjustment will be made for geographic region. Geographic Region or Site related 
differences will not be evaluated.  
7.3. MISSING DATA 
Missing data will not be imputed.  
Notably, both in Part A and in Part B, in case the patient completes the study (i.e. performs all the 
evaluations requested to be done at the Day 28 of Cycle 6), the evaluation performed at C6D28 visit 
can be counted for the End of Study visit. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No adjustments for type I error inflation due to multiplicity of the tests will be considered. 
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7.5. EXAMINATION OF SUBGROUPS 
Sub-group analyses will be performed for exploratory purposes and are related to the evaluation of: 
each single parameter of the clinical-haematological ELN response criteria [1] and the “new” ELN 
response criteria (for Part B only) [2]; spleen size (by MRI or CT scan) in patients with confirmed 
splenomegaly at baseline; disease-related quality of life; JAK2V617F allele burden and reduction of the 
symptomatic treatment of pruritus. 
 
Since these analyses will be used to promote hypotheses rather than confirm them, no adjustments 
for type I error inflation due to multiplicity of the tests will be considered. Moreover post-hoc and 
data-driven analyses will be carefully considered and ranked according to their biological plausibility. 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the data presentations for this study and therefore the 
format and content of the summary tables, figures and listings to be provided by Quintiles 
Biostatistics. 
Both continuous and categorical data will be summarised and tabulated in 2-way tables (i.e. variable-
by-DL, variable-by-visit, visit-DL, etc). 
Statistical tables will be presented by treatment DL and the treatment labels to be used in the Tables, 
Listings and Figures (TLFs) are defined in Table 1.1.  
 
The DL will be sorted, so that DL1 appears as first. 
All data will be listed sorted by site, patient ID and within patient by visit (where appropriate). 
The visit names/labels to be used in the analysis data sets and in the TLFs are defined in Table 3. 
 
Table 3 – Study Visits performed in Parts A and B 
Study Part  
Visit  
Visit label for Tables, Listings and Figures 
(TLFs)1 
Part A 
Screening Visit 
A - Baseline  
Cycle 1 Day 1 Visit – PRE-DOSE 
A - C1D1 – PRE 
Cycle 1 Day 1 Visit – POST-DOSE 
A - C1D1 - POST 
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Cycle 1 Day 2 Visit 
A - C1D2 
Cycle 1 Day 3 Visit 
A - C1D3  
Cycle 1 Day 4 Visit 
A - C1D4 
Cycle 1 Day 8 Visit 
A - C1D8  
Cycle 1 Day 10 Visit 
A - C1D10 
Cycle 1 Day 15 Visit 
A - C1D15 
Cycle 1 Day 22 Visit 
A - C1D22 
Cycle 1 Day 28 Visit 
A - C1D28 
Cycle 2 Day 28 Visit 
A - C2D28 
Cycle 3 Day 28 Visit 
A - C3D28 
Cycle 4 Day 28 Visit 
A - C4D28 
Cycle 5 Day 28 Visit 
A - C5D28 
Cycle 6 Day 28 Visit 
A - C6D28 
End of Study Visit for completers 
patients 
A – EOS  
Unscheduled Visit n. 1 – PRE-DOSE 
A - UNSCHEDULED 1 – PRE* 
Unscheduled Visit n. 2 – PRE-DOSE 
A - UNSCHEDULED 1 – PRE* 
… 
… 
Unscheduled Visit n. N – PRE-DOSE 
A - UNSCHEDULED N – PRE* 
Unscheduled Visit n. 1 – POST- DOSE 
A - UNSCHEDULED 1 – POST*  
Unscheduled Visit n. 2 – POST- DOSE 
A - UNSCHEDULED 2 – POST*  
… 
… 
Unscheduled Visit n. N – POST-DOSE 
A - UNSCHEDULED N – POST* 
Part B 
Screening Visit 
B - Baseline 
Cycle 1 Day 1 Visit – PRE-DOSE 
B - C1D1 – PRE 
Cycle 1 Day 1 Visit – POST-DOSE 
B - C1D1 – POST 
Cycle 1 Day 28 Visit 
B - C1D28 
Cycle 2 Day 28 Visit 
B - C2D28 
Cycle 3 Day 28 Visit 
B - C3D28 
Cycle 4 Day 28 Visit 
B - C4D28 
Cycle 5 Day 28 Visit 
B - C5D28 
Cycle 6 Day 28 Visit 
B - C6D28 
End of Study Visit 
B - EOS 
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Unscheduled Visit n. 1 – PRE-DOSE 
B - UNSCHEDULED 1 – PRE* 
Unscheduled Visit n. 2 – PRE-DOSE 
B - UNSCHEDULED 1 – PRE* 
… 
… 
Unscheduled Visit n. N – PRE-DOSE 
B - UNSCHEDULED N – PRE* 
Unscheduled Visit n. 1 – POST- DOSE 
B - UNSCHEDULED 1 – POST*  
Unscheduled Visit n. 2 – POST- DOSE 
B - UNSCHEDULED 2 – POST*  
… 
… 
Unscheduled Visit n. N – POST-DOSE 
B - UNSCHEDULED N – POST* 
1 In all cases, the day of the visit should be reported.* To be ordered on the basis of the date of the 
visit.  
 
EOS visit refers to the endpoint value (last non-missing value) for all patients. Notably, both in Part A 
and in Part B, in case the patient completes the study (i.e. performs all the evaluations requested to be 
done at the Day 28 of Cycle 6), the evaluation performed at C6D28 visit can be counted for the End of 
Study visit. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be counted for this Study. Therefore, the number of 
consented patients by site will be displayed. 
Patient disposition and withdrawals, and protocol violations (including inclusion and exclusion criteria), 
will be presented for the SAF set. Therefore, the number of patients who were recruited, treated and 
completed the study, as well as the reasons for all discontinuations, grouped by DL, will be presented.  
A patient disposition listing with reasons for discontinuation will also be provided. 
 
Drop-out visit refers to patients who prematurely discontinued the treatment showing data recorded 
during their last assessment visit. 
 
Screening failures will be handled in the analysis for the pertinent data (i.e. screening visit), but they 
will be reported separately from the treated patients. 
 
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10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the SAF analysis set. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
Default summary statistics will be produced by treatment group and overall - i.e. for each DL in Part A 
as per Table 1.1, for the 12 patients of Part B – Stage 1 and for the 28 patients of Part B – Stage 2 -  for 
the following demographic and other baseline characteristics reported for this Study: 
 
 Visit date (to be reported only in the patient’s data listings).  
 Fasting Conditions: Fasting Conditions for at least 8 hours before the time of the visit (Yes/No/Not 
Applicable).   
 Informed Consent Form (ICF): date of ICF signature (to be reported only in the patient’s data listings), 
Yes/No. 
 Bone Marrow Histology ICF: date of bone marrow histology ICF signature (to be reported only in the 
patient’s data listings and only for Part B), Yes/No/Not Applicable. 
 Demography: Date of birth (to be reported only in the patient’s data listings), Age (years), Age Group 
(<60 years/≥60 years), Sex (Female/Male) and Race (White, Asian, Asian Indian, Black, American 
Indian or Alaska native, Pacific Islander, Other). 
 Inclusion and Exclusion Criteria (to be reported only in the patient’s data listings). 
 Disease History: Date of Initial Diagnosis (years), Time form Diagnosis (months), Type of disease (PV, 
ET, MF). 
 Disease Treatment – Medications: description (to be reported only in the patient’s data listings) of 
previous drug treatments, including medication name (e.g. hydroxyurea, cardioaspirin, etc etc), 
dose, unit (e.g. mg, g, L, etc etc), frequency (e.g. o.d., b.i.d., t.i.d., q.i.d., other), route of 
administration (e.g. oral, infusion), treatment start date (years), treatment end date (years), best 
response to the therapy as per ELN Response criteria (i.e. Complete Response, Partial Response, No 
Response, Other) [1], reason for discontinuation (Therapy ineffective, Adverse reaction, Other).  
Prior disease medications are defined as those starting and ending prior to the first administration of 
investigational study drug. Prior medications will be classified according to active drug substance 
using the WHO-DRL Drug Dictionary (Version 01SEP2017). Frequency tabulations will be presented 
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Page 47 of 101 
for prior medication by primary therapeutic subgroup (3rd level ATC code), generic name, active 
principle and treatment group. 
 Disease Treatment non-drug therapies: description (to be reported only in the patient’s data listings) 
of procedures (i.e. phlebotomy, transfusion, other), Start Date (years), End Date (years), best 
response to therapy as per ELN Response criteria (i.e. Complete Response, Partial Response, No 
Response, Other) [1], reason for discontinuation (Therapy ineffective, Adverse reaction, Other). 
Patients requiring phlebotomy will be produced additionally.  
 Medical History: description (to be reported only in the patient’s data listings) of Medical History 
Diagnosis (i.e. disease), Start Date (years), End Date (years), Current Medication (Yes/No).  
Any condition entered on the Relevant medical history / current medical conditions CRF will be coded 
using the MedDRA dictionary (version 20.1). They will be summarised in tables by system organ class 
(SOC) and preferred term (PT) of the MedDRA dictionary using Safety analysis set. A data listing will 
be produced for all the patients’ medical history. Patients with previous thrombosis history and age 
≥60 years and previous thrombosis history will be produced. 
 
Physical Examination: Physical Examination Performed (Yes/No), Any Clinically Significant 
Abnormalities Found (Yes/No).  
 
Vital Signs: date of evaluation (to be reported only in the patient’s data listings), Systolic Blood 
Pressure (mmHg), Diastolic Blood Pressure (mmHg), Heart Rate (bpm), Respiratory Rate (resp/min), 
Body Temperature (C), Height (cm), Weight (kg). Controlled hypertension (i.e. Normal ranges for 
systolic blood pressure: less than 120 mmHg, diastolic blood pressure: less than 80mmHg) at 
baseline will be produced.  
 
ECOG: date of evaluation (to be reported only in the patient’s data listings), value (i.e. 0, 1, 2, 3, 4, 5). 
 
Contraception Method:  
o Female of childbearing potential:  
- True abstinence (absence of any sexual intercourse);  
- Double barrier contraception such as diaphragm or a barrier method of contraception in 
conjunction with spermicidal jelly;  
- Intra-uterine device (non-hormone-releasing) in place for at least 90 days previously and the 
male partner must use a condom with spermicide;  
- Tubal ligation at least 6 months previously and 1 additional acceptable contraception 
method;  
- Vasectomy of the male partner (with negative sperm post-vasectomy semen analysis) at least 
6 months previously and 1 additional acceptable contraception method; 
o Female of non-childbearing potential: 
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- Postmenopausal; 
- Documented hysterectomy and/or oophorectomy; 
o Male : 
- True abstinence (absence of any sexual intercourse); 
- Condom with spermicide and female partner must use an acceptable method of 
contraception; 
- Vasectomy of the male partner (with negative sperm post-vasectomy semen analysis) at least 
6 months previously and 1 additional acceptable contraception method; 
-  No participation in sperm donation. 
 
Pregnancy: Date of test, Result (Positive/Negative), Sample taken (Urine/Serum), Reason to not 
done (to be reported only in the patient’s data listings). 
Notably, the pregnancy test (if indicated) are performed within 72 hours before the first Givinostat 
dose. The test can be performed by urine or serum pregnancy test. In case of a borderline-positive 
urine pregnancy test, this is confirmed with a serum pregnancy test and the result recorded in the 
electronic CRF. These data will presented. 
 
Blood Chemistry: Sample Date (to be reported only in the patient’s data listings), Laboratory ID (to 
be reported only in the patient’s data listings), value, unit (as per International Units), interpretation 
(Normal/Abnormal and Not clinically significant/Abnormal and Clinically Significant) of the following 
parameters: 
o Sodium;  
o Potassium;  
o Calcium;  
o Chloride;  
o Magnesium;  
o Albumin;  
o Glucose;  
o Blood Urea Nitrogen (BUN);  
o Urea;  
o Creatinine; 
o Alanine Aminotransferase (ALT);  
o Aspartate Aminotransferase (AST);  
o Alkaline Phosphatase;  
o Total Bilirubin;  
o Lactate Dehydrogenase;  
o eGFR (as per Mayo Clinic Quadratic Equation).  
 
Urinalysis: Sample Date (to be reported only in the patient’s data listings), Laboratory ID (to be 
reported only in the patient’s data listings), value, unit (as per International Units), interpretation 
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(Normal/Abnormal and Not clinically significant/Abnormal and Clinically Significant) of the following 
parameters: 
o pH;  
o Specific Gravity; 
o Glucose; 
o Protein. 
 
Haematology: Sample Date (to be reported only in the patient’s data listings), Laboratory ID (to be 
reported only in the patient’s data listings), value, unit (as per International Units), interpretation 
(Normal/Abnormal and Not clinically significant/Abnormal and Clinically Significant) of the following 
parameters: 
o Haematocrit (HCT); 
o Haemoglobin (Hb); 
o RBC; 
o PLT; 
o WBC; 
o Basophils; 
o Eosinophils; 
o Lymphocytes; 
o Monocytes; 
o Neutrophils; 
o Mean Corpuscular Volume (MCV); 
o Mean Corpuscular Haemoglobin (MCH); 
o Mean Corpuscular Haemoglobin Concentration (MCHC). 
 
ECG: Evaluation Date (to be reported only in the patient’s data listings), value of the following 
parameters: 
o RR Interval (sec); 
o QT interval (msec); 
o QTc interval as per Bazzet’s correction formula (msec).  
Results Interpretation (Normal/Abnormal and Not clinically significant/Abnormal and Clinically 
Significant), Findings detected in the ECG evaluation – that will be presented by primary SOC and 
Preferred Term using the MedDRA dictionary (version 20.1) – and related Interpretation 
(Normal/Abnormal and Not clinically significant/Abnormal and Clinically Significant). 
If the first ECG evaluation demonstrated a prolonged QTc interval (i.e. a QTc interval ≥ 450 msec), 
two additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) 
are performed. The averaged value of these three ECG evaluations is used for the evaluation of the 
QTc interval requested by the exclusion criterion n. 3. In the electronic CRF all the performed ECG 
evaluations have to be entered as well as the average value of multiple ECG evaluation, if necessary. 
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In the patient listings all the additional ECG data have to be presented as soon as the first one.  
 
Spleen: Evaluation Date (to be reported only in the patient’s data listings), Imaging Technique (i.e. 
MRI, CT scan), Results Interpretation (Normal/Abnormal and Not clinically significant/Abnormal and 
Clinically Significant) and value of the following parameters: 
o Longitudinal Diameter (cm); 
o Antero-Posterior Diameter (cm); 
o Transversal Diameter (cm); 
o Splenic Volume Index (SVI, in cm3). 
Notably, patients with splenomegaly performed the spleen evaluation as per site-specific clinical 
practice. Therefore, patients with splenomegaly before the treatment start are followed according 
to institutional guidelines (i.e. MRI, CT scan). The same imaging technique and the same instrument 
is used on a patient throughout the Study, when possible. No spleen evaluation is performed in 
splenectomised patients. 
 
Molecular Examination: Sample Collection Date (to be reported only in the patient’s data listings), 
Sample Accession Number (to be reported only in the patient’s data listings), Back-Up Sample 
Collection Date (to be reported only in the patient’s data listings), Back-Up Sample Accession 
Number (to be reported only in the patient’s data listings) and value of the following parameters: 
o Positivity (Yes/No); 
o Qualitative Evaluation (Homozygous/Heterozygous); 
o Quantitative Evaluation (%). 
 
MPN-SAF Quality of Life Questionnaire: Completion Date (to be reported only in the patient’s data 
listings) and value (from a score 0 to a score 10) of the following parameters: 
o Level of fatigue right NOW (i.e. at the completion of the MPN-SAF questionnaire); 
o USUAL level of fatigue during past 24 hours (i.e. 24 hours before the completion of the MPN-SAF 
questionnaire); 
o WORST level of fatigue during past 24 hours (i.e. 24 hours before the completion of the MPN-SAF 
questionnaire); 
o Fatigue has interfered with General Activity during the past 24 hours (i.e. 24 hours before the 
completion of the MPN-SAF questionnaire); 
o Fatigue has interfered with Mood during the past 24 hours (i.e. 24 hours before the completion 
of the MPN-SAF questionnaire); 
o Fatigue has interfered with Walking Ability during the past 24 hours (i.e. 24 hours before the 
completion of the MPN-SAF questionnaire); 
o Fatigue has interfered with Normal Work (includes work both outside the home and daily 
chores) during the past 24 hours (i.e. 24 hours before the completion of the MPN-SAF 
questionnaire); 
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Page 51 of 101 
o Fatigue has interfered with Relations with other people (includes work both outside the home 
and daily chores) during the past 24 hours (i.e. 24 hours before the completion of the MPN-SAF 
questionnaire); 
o Fatigue has interfered with Enjoyment of life (includes work both outside the home and daily 
chores) during the past 24 hours (i.e. 24 hours before the completion of the MPN-SAF 
questionnaire); 
o Patient’s difficulty with Filling up quickly when eats (early satiety) during the past week (i.e. one 
week before the completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Abdominal pain during the past week (i.e. one week before the 
completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Abdominal discomfort during the past week (i.e. one week before the 
completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Inactivity during the past week (i.e. one week before the completion of 
the MPN-SAF questionnaire); 
o Patient’s difficulty with Problems with Headaches during the past week (i.e. one week before the 
completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Problems with Concentration during the past week (i.e. one week before 
the completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Dizziness/ Vertigo/ Light-headedness during the past week (i.e. one week 
before the completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Numbness/ Tingling (in hands and feet) during the past week (i.e. one 
week before the completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Difficulty sleeping during the past week (i.e. one week before the 
completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Depression or sad mood during the past week (i.e. one week before the 
completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Problems with Sexual Desire or Function during the past week (i.e. one 
week before the completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Cough during the past week (i.e. one week before the completion of the 
MPN-SAF questionnaire); 
o Patient’s difficulty with Night Sweats during the past week (i.e. one week before the completion 
of the MPN-SAF questionnaire); 
o Patient’s difficulty with Itching (pruritus) during the past week (i.e. one week before the 
completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Bone Pain (diffuse not joint pain or arthritis) during the past week (i.e. 
one week before the completion of the MPN-SAF questionnaire); 
o Patient’s difficulty with Fever during the past week (i.e. one week before the completion of the 
MPN-SAF questionnaire); 
o Unintentional weight loss last 6 months (i.e. six months before the completion of the MPN-SAF 
questionnaire); 
o Overall Quality of Life statement; 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 52 of 101 
o MPN-SAF Total Symptom Score (TSS) (only for Part B).   
o Number of patients with Pruritus, Headache, Microvascular Symptoms  
 
Bone Marrow (only for Part B): Evaluation Date (to be reported only in the patient’s data listings) 
and the following parameters: 
o Is age-adjusted normocellularity present? (Yes/No); 
o Is trilinear hyperplasia absent? (Yes/No); 
o Is there an absence of grade >1 reticulin fibrosis? (Yes/No). 
 
ENROLL: Date of Enrolment Request (to be reported only in the patient’s data listings), Study Part 
(Part A/Part B), Enrolment Confirmation Date (to be reported only in the patient’s data listings), 
Dose Level (DL1, DL1 – expanded, DL6, DL0), Patient ID. 
Listings of patient’s baseline characteristics will be produced on all consented patients. 
10.1. DERIVATIONS 
 Age (years) = Date of Signature of Informed Consent – Date of Birth  
Notably, due to privacy law applicable in some countries included in this Study (e.g. Italy), in the 
electronic CRF only the months and the year of birth were collected. Therefore, since the day of birth 
was not collected on electronic CRF, this will be defined as the first day of the month of birth. 
 
 Time form Diagnosis (months) = Date of Signature of Informed Consent - Date of Initial 
Diagnosis 
11. MEDICAL HISTORY 
   Medical History information will be presented for the SAF analysis set.  
 
Medical History will be coded using version 20.1 of Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. 
 
Medical History conditions are defined as those conditions recorded on eCRF form “MH”. 
 
Presented by System Organ Class (SOC) and Preferred term (PT).  
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 53 of 101 
12. PRIOR AND CONCOMITANT ILLNESSES 
Prior and Concomitant Illnesses will be presented for the SAF analysis set. 
 
Prior and Concomitant Illnesses will be coded using the version 20.1 of MedDRA dictionary. 
 
Prior disease medications are defined as those starting and ending prior to the first 
administration of investigational study drug. 
 
Concomitant Illnesses are conditions recorded on eCRF form “MH” and which started prior to or 
at Screening and are ongoing at the date of Screening.  
 
Presented by SOC and PT. 
12.1. POST-TREATMENT DISEASES  
Post-treatment disease will be presented for the SAF analysis set. 
 
Post-treatment diseases will be coded using the version 20.1 of MedDRA Dictionary. 
 
Post-treatment diseases are conditions recorded on electronic CRF in the Form “AE” and which 
started after the last Study drug intake. 
 
Presented by SOC and PT. 
13. MEDICATIONS (I.E. DRUGS) 
Prior medications to treat PV will include regimens discontinued up to 24 weeks prior to enrolment. 
The information captured in electronic CRF included drug name, start and stop dates, best response to 
therapy (where applicable) and reason for discontinuations.  
Medications will be presented for the SAF analysis set and coded using the 01SEP2017 version of 
WHO-DRL Dictionary. Frequency tabulations will be presented for prior and concomitant medication 
by primary therapeutic subgroup (3rd level ATC code), generic name and active principle. 
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to 
define a medication as prior, concomitant, or post treatment, the medication will be classified by the 
worst case (i.e. concomitant medication):  
 
‘Prior’ drug medications are defined as those starting and ending prior to the first administration 
of investigational Study drug (i.e. C1D1). 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 54 of 101 
 
‘Concomitant’ drug medications are defined as those started at or after first administration of 
Study drug (i.e. C1D1) and include those started prior to the first administration of 
investigational Study drug (i.e. C1D1) but continued during the Study. 
 
‘Post’ drug medications are defined as drug medications which started after the last Study drug 
intake.  
13.1. NON-DRUGS THERAPIES  
Prior and significant non-drug therapies (e.g. phlebotomies, transfusions) to treat PV will include 
regimens discontinued up to 24 weeks prior to enrolment. Non-drug-therapies will be summarised by 
type of procedure (i.e. transfusion, phlebotomy, other), date of procedure, reason for procedure. Non-
drug therapies (e.g. transfusion, phlebotomy) will be presented for the SAF analysis set.  
See Appendix 2 for handling of partial dates for non-drugs therapies, in the case where it is not 
possible to define a non-drug therapy as prior, concomitant, or post treatment, the non-drug therapy 
will be classified by the worst case (i.e. concomitant non-drug therapy):  
 
‘Prior’ non-drug therapies are defined as those starting and ending prior to the first 
administration of investigational Study drug (i.e. C1D1). 
 
‘Concomitant’ non-drug therapies are defined as those started at or after first administration of 
Study drug (i.e. C1D1) and include those started prior to the first administration of 
investigational Study drug (i.e. C1D1) but continued during the Study. 
 
‘Post’ non-drug therapies are non-drug therapies which started after the last Study drug intake.  
Frequency tabulations will be also presented for significant non-drug therapies. 
Notably, all phlebotomies performed in the first 3 weeks of treatment will be not counted to assess 
the clinico-haematological response according to the clinico-haematological ELN response criteria [1] 
at C3D28 and at C3D28 in Parts A and B. 
 
14. STUDY MEDICATION EXPOSURE 
Exposure to study medication in days will be presented for the SAF analysis set. 
 
The date of the first investigational study drug of each patient will be taken from the 
“On-site Dosing (DOSING)” raw data panel. This date of first investigational study drug administration 
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Page 55 of 101 
(Day 1) is the key variable RFSTDTN and used in the calculation of relative days. 
The date of first study medication administration will be taken from the eCRF “Dosing” Form (C1D1). 
 
The date of the last investigational study drug of each patient will be taken from the “Patient 
Disposition” form of eCRF. If the date is missing, the date of the last visit will be imputed, if 
appropriate. This date of last investigational study drug is the key variable RFENDTN. 
 
The duration (days) of exposure and the daily dosage (mg) of Givinostat will be calculated for each 
patient, and will be summarized descriptively including the mean, standard deviation, median, 
minimum and maximum. 
A listing of treatment exposure data, including the first and last dates of Study drug administration will 
be presented by-subject and within-subject by available interval and overall exposure. 
 
Interruptions, compliance, and dose changes are not taken into account for duration of exposure.  
Reason for treatment discontinuation and number of patients treated beyond protocol-specified 
discontinuation criteria will also be summarised. Analysis will be based on safety population. 
 
In general, In the case of missing data on the eCRF, the cycle C1D1 visit date and the last visit cycle 
performed date will be used in order to determine the first and last date of study medication. 
14.1. DERIVATIONS 
The duration of investigational study drug or exposure to treatment is equal to the day number of 
the last day of drug administration (LDA) and is derived as follows from the previous two dates 
(RFSTDTN and RFENDTN): 
 
LDA (days) = (Date of Last Drug Administration [RFENDTN] – Date of First Drug Administration 
[RFSTDTN]) + 1 
 
LDA then indicates the relative day that the last dose of investigational study drug is administered per 
patient, as calculated relative to the first day of dosing. 
 
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Page 56 of 101 
15. STUDY MEDICATION COMPLIANCE  
The Investigator recorded in the electronic CRF the assigned dose of Givinostat and any dose reduction 
(if applicable) to allow the evaluation of compliance to treatment. At each visit, patients brought back 
to the Study site all drug bottles previously received (i.e. used, partially used and unused) and receive a 
new Study drug supply. The number of residual capsules in the dispensed bottles were counted by the 
Investigator and reported in the electronic CRF.  
Compliance with Givinostat treatment will be calculated based on the Study drug accountability 
documented by the site staff and monitored by Italfarmaco S.p.A. or its designee (i.e. capsule counts).  
A patient will be considered sufficiently compliant with Givinostat treatment if he/she has taken at 
least 80% of the prescribed dose over the total duration of Study drug dosing. In addition, patients 
who didn’t experience a DLT and missed more than 10% of the doses in Cycle 1 of Part A will be 
considered not sufficiently compliant. 
 
Treatment compliance to Study drug will be presented for the SAF analysis set, ITT analysis set, PP 
analysis set, MTD analysis set and PK analysis set, during all six Cycles of treatment (i.e. from C1D1 to 
C6D28). Treatment compliance will be calculated for C1D1 – C1D28 in Part A, and C1D1 – C6D28 in 
Parts A and B (both Stages).  
 
Treatment compliance per interval is defined as the number of capsules that were actually taken 
within a given interval relative to the number of capsules that should have been taken by the patient 
for the duration of actual treatment exposure for that interval. 
 
Summary statistics for the Actual Total Dose delivered (mg), Givinostat Dose Intensity (mg/day) will be 
presented. 
 
Summaries showing Givinostat dose modification during the Study will be presented by treatment 
group. 
15.1. DERIVATIONS 
In general, the percentage compliance (%), assessed by capsule count, will be calculated as follows: 
 
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 “Per visit” Compliance to study medication will be calculated as follows: 
 
  
{([୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ ୚୧ୱ୧୲ (௡)] – [୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ ୚୧ୱ୧୲ (௡ାଵ)])
ൣ[ୈୟ୲ୣ ୭୤ ୚୧ୱ୧୲ (௡ାଵ)] ି [ୈୟ୲ୣ ୭୤ ୚୧ୱ୧୲ (௡)]൧୶ ୒୳୫ୠୣ୰ ୭୤ ୡୟ୮ୱ୳୪ୣୱ ୮୰ୣୱୡ୰୧ୠୣୢ ୠ୷ ୢୟ୷ 
x 100 
 
 Overall Compliance to study medication will be calculated as follows: 
 
{([୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ େ୷ୡ୪ୣ ଵ] – [୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ େ୷ୡ୪ୣ ଶ])
ା⋯ା
([୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୟ୲ େ୷ୡ୪ୣ(୬ିଵ)] – [୒ ୭୤ େୟ୮ୱ୳୪ୣୱ ୰ୣ୲୳୰୬ୣୢ ୟ୲ େ୷ୡ୪ୣ(୬)])} 
ൣ[ୈୟ୲ୣ ୭୤ େ୷ୡ୪ୣ(୬)] ି [ୈୟ୲ୣ ୭୤ ୈ୧ୱ୮ୣ୬ୱ୧୬୥ ୟ୲ େ୷ୡ୪ୣ ଵ]ାଵ ൧୶ ୒୳୫ୠୣ୰ ୭୤ ୡୟ୮ୱ୳୪ୣୱ ୮୰ୣୱୡ୰୧ୠୣୢ ୠ୷ ୢୟ୷ 
x 100 
 
Also for the last cycle compliance calculation this formula will be used as the last dose of study drug 
date considering from disposition page. 
For patients who permanently stop the study medication, the “Date of visit (n)” will be replaced by the 
date of study withdrawal.  
 
A patient will be considered sufficiently compliant with Givinostat treatment if he/she has taken at 
least 80% of the prescribed dose over the total duration of study drug dosing. 
 
The calculated percentage compliance per interval will be categorized as: 
A) Part A – Cycle 1: 
- 
Too Low:  ≤ 90% compliance. 
- 
Adequate:  > 90% to ≤ 100% compliance. 
- 
Too High:  > 100% compliance. 
B) Part A (all Cycles) and Part B:  
- 
Too Low:  < 80% compliance. 
- 
Adequate:  ≥ 80% to ≤ 100% compliance. 
- 
Too High:  > 100% compliance. 
 
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Page 58 of 101 
Categories of overall compliance will be presented by treatment group using default summary 
statistics. Calculated compliance (%) per applicable interval and overall will be also presented. 
All drug accountability data will be presented, that is, the number of capsules dispensed and returned 
at each applicable interval. The total number of capsules taken per applicable interval and overall (%), 
as well as the calculated compliance (%) per applicable interval and overall will be presented, if 
applicable. 
 
The Givinostat summary statistics for the Actual Total Dose delivered (mg) and Dose Intensity 
Givinostat: DI (mg/day) will be presented and calculated as follow: 
 
Actual Total Dose delivered (mg) = sum over all days of actual dose received (mg). 
 
Dose Intensity Givinostat: DI (mg/day) = [Actual Total Dose Level of Givinostat (mg)/Duration of 
exposure (days)]. 
16. EFFICACY AND SAFETY VARIABLES 
16.1. DEFINITION OF END OF THE STUDY 
The end of the Study (last patient last visit) will occur after all patients in whole Study (Part B) have 
completed their last assessment as per Study protocol. Note that the analysis of the biological samples 
could be performed after the end of Study due to scientific (i.e. after evaluation of preliminary results 
and data exploration, some additional analyses could be performed to identify and quantify other 
molecular parameters of interest in term of improving of the knowledge of cMPN and the activity of 
the drug in these disorders) or technical reason. 
In any case, after the completion of the analysis all data should be formally reported in a Clinical Study 
Report and/or in a specific technical report.     
 
16.2. EFFICACY ASSESSMENT  
Timing information are summarised in the Study flow-chart (Appendix A of the Study protocol) and 
detailed in the paragraph 4.5.4 of the Study protocol. 
 
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16.3. CRITERIA FOR ASSESSING CLINICO-HAEMATOLOGICAL IMPROVEMENT 
Disease response will be evaluated according to the following clinico-haematological ELN criteria [1] 
after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat both in Part A 
(exploratory endpoints) and in Part B (primary and secondary endpoints, respectively).  
 
Complete response:  
1. HCT < 45% without phlebotomy, and 
2. Platelets ≤ 400 x 109/L, and 
3. WBC ≤ 10 x109/L, and 
4. Normal spleen size, and 
5. No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances). 
 
 
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1. HCT < 45% without phlebotomy, or  
2. Response in 3 or more of the other criteria. 
 
 
No response: any response that does not satisfy partial response. 
 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months) and the eligibility for 
this part of the study may be expanded to all patients with cMPN, disease response for this part of the 
study can be evaluated according to the clinico-haematological ELN and EUMNET criteria [7] after 3 and 
6 cycles of treatment with Givinostat, in ET and MF patients, respectively. 
 
For ET (from the clinico-haematological ELN response criteria): 
 
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 
Complete response:  
1. Platelets ≤ 400 x109/L, and 
2. No disease related systemic symptoms (i.e. pruritus, headache, microvascular disturbances), 
and 
3. Normal spleen size, and 
4. WBC ≤10 x109/L. 
 
 
Partial response:  
Patients who do not fulfil the criteria for complete response and 
1. Platelet count < 600 x 109/L, or  
2. Platelet count decrease > 50% from baseline. 
 
 
No response: any response that does not satisfy partial response. 
 
Both for PV and ET patients, all phlebotomies performed in the first 3 weeks of treatment are not 
counted to assess the clinico-haematological response. 
 
 
For MF (from EUMNET response criteria)  
 
 
Complete response: complete response in anemia, splenomegaly, constitutional symptoms, 
platelet and leukocyte count. 
1. Complete response in anaemia: Haemoglobin ≥ 12 g/dL for transfusion-independent patients 
or ≥ 11 g/dL for transfusion-dependent patients (applicable only for patients with baseline 
haemoglobin level of  10 g/dL); 
2. Complete response in splenomegaly: Spleen not palpable; 
3. Complete response in constitutional symptoms: Absence of constitutional symptoms (fever, 
drenching night sweats, or ≥ 10% weight loss); 
4. Complete response in platelet count: Platelet count 150-400 x109/L; 
5. Complete response in leukocyte count: Leukocyte count 4-10 x109/L. 
 
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 
Major response: Any response in both anaemia and splenomegaly without progression in 
constitutional symptoms or complete response in anaemia without progression in splenomegaly 
or partial response in anaemia in a baseline transfusion-dependent patient combined with 
response in constitutional symptoms without progression in splenomegaly or any response in 
splenomegaly combined with response in constitutional symptoms without progression in 
anaemia. 
1. Partial response in splenomegaly: Either ≥ 50% decrease in spleen size if baseline ≤ 10 cm 
from left costal margin (LCM) or ≥ 30% decrease if baseline > 10 cm from LCM. 
2. Partial response in platelet count: A ≥ 50% decrease in platelet count if baseline > 800 x109/L 
or platelet count increase by  ≥ 50% x 109/L if baseline < 100 x109/L. 
 
3. Partial response in leukocyte count: A ≥ 50% decrease in leukocyte count of baseline >  20 
x109/L or leukocyte count increase by ≥ 1 x109/L if baseline < 4 x109/L 
4. Progression in anaemia: A haemoglobin decrease of ≥ 2 g/dL  or  a 50% increase in 
transfusion requirement or becoming transfusion dependent 
5. Progression in splenomegaly: A ≥ 50% increase in spleen size if baseline ≤ 10 cm from LCM or 
a ≥ 30% increase if baseline > 10 cm from LCM. 
6. Progression in constitutional symptoms: Appearance of constitutional symptoms. 
 
 
Moderate response: Complete response in anaemia with progression in splenomegaly or partial 
response in anaemia without progression in splenomegaly or any response in splenomegaly 
without progression in   anaemia and constitutional symptoms.  
 
 
Minor response: Any leukocyte- or platelet-based response without progression in anaemia, 
splenomegaly, or constitutional symptoms. 
 
 
No response: Any response that does not qualify at least as minor response. 
 
In all cases (PV, ET and MF patients), the disease-related systemic symptoms are evaluated directly by 
patients according to MPN-SAF QOL questionnaire [8, 9]. 
In all cases, the response status of the patient can be reviewed by a panel of independent Investigators, 
if necessary. 
In all cases, the medical judgment of the Investigator’s is taken into account. In particular, if the 
Investigator‘s clinical response assessment – that takes into account the overall medical judgment of the 
specific patient’s case - is not in agreement with the exact application of the clinico-haematological ELN 
or EUMNET  response criteria , the Investigator’s assessment will supersede the “mathematical” 
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application of these criteria and used for analysis into study report. Also mathematical application of ELN 
response criteria (not agreed by the medical site team) will be analyzed. 
 
16.4. CRITERIA FOR DETERMINATION OF MTD 
Once all patients enrolled in Part A are treated for at least 1 cycle, the study team (see paragraph 
3.2.2.1) determined the MTD to be used in Part B based on the safety and tolerability profile of 
Givinostat observed as well as the PK and PD data, if applicable. 
 
16.5. CRITERIA FOR CHARACTERIZATION OF PK 
Plasma concentrations from Parts A and B are evaluated by dose and time point for all patients and 
time points with at least one PK assessment. 
 
16.6. THE EFFICACY POPULATION 
The analysis sets are defined in the section 5. 
Patients with a disease-related global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported in the 
electronic CRF as disease progression clinically assessed. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
The response status of the patient may be reviewed by a panel of independent investigators, if 
necessary. 
 
16.7. SAFETY ASSESSMENTS 
Safety and tolerability are evaluated by monitoring haematology and blood chemistry, urinalysis (only 
in the first cycle of Part A), by measurement of physical examination, vital signs, weight, body 
temperature, ECOG performance status, ECG assessment and evaluation, QTc determination and 
adverse events recording at scheduled times as described above. Timing information are summarised 
in the Study flow-chart (Appendix A of the Study protocol) and detailed in the paragraph 4.5.4 of the 
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Study protocol. 
All significant findings already present during the screening visit before drug administration are  
reported in the appropriate section of electronic CRF, i.e. Medical History section or Current Medical 
Conditions section. Significant findings occurring after patient enrolment - identified as AEs - are 
recorded in Adverse Event section of electronic CRF.  
 
The following criteria are used to assess the safety and tolerability both in Part A (primary endpoint) 
and after 3 and 6 cycles (primary and secondary endpoints, respectively) in Part B: 
 
Number of patients experiencing AEs.  
 
Type, incidence, and severity of treatment-related adverse events, graded according to Common 
Terminology Criteria for Adverse Events (CTCAE v. 4.03, 14th June 2010). 
 
16.8. LABORATORY EVALUATIONS  
The following laboratory examinations (haematology, blood chemistry and urinalysis) are performed at 
each investigational unit by a local laboratory co-operating with the Investigator following its own 
procedures:  
 
Haematology: RBC count, HCT, Hb, MCV, MCH, MCHC, WBC count (full and differential), PLT 
count;  
 
Blood chemistry: ALT/SGPT, AST/SGOT, ALP, total bilirubin, LDH, creatinine, BUN or Urea (as per 
site-specific clinical practice), glucose, Na, K, Ca, Cl, Mg, albumin, eGFR determination (according 
to the Mayo Clinic Quadratic Equation); 
 
 Urinalysis: pH, specific gravity, protein, glucose. 
 
The required amount of blood and urine are collected at each visit as scheduled above. Timing 
information are summarised in the Study flow-chart (Appendix A of the Study protocol) and detailed in 
the paragraph 4.5.4 of the Study protocol.  
All results of laboratory examinations are entered into the appropriate electronic CRF sections.  
 
16.9. CLINICAL SAFETY ASSESSMENTS 
Clinical safety assessments include a thorough physical examination, vital signs assessment 
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(respiratory rate, pulse rate and sitting blood pressure are measured after 5 minutes of rest), weight, 
body temperature, ECOG performance status, ECG assessment and evaluation, QTc determination 
(according to Bazett’s correction formula, Appendix D of the Study protocol).  
Of note, if the ECG evaluation demonstrate a prolonged QTc interval (i.e. a QTc interval ≥ 450 msec), 
two additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) are 
performed. The averaged value of these three ECG evaluations are used for the evaluation of the QTc 
interval of the related visit. In the electronic CRF all the performed ECG evaluations are entered as well 
as the average value of multiple ECG evaluation, if necessary. 
 
16.10. 
 ADVERSE EVENTS 
All AEs either observed by the Investigator, or reported by the patient spontaneously or in a response 
to a direct question are evaluated by the Investigator and are recorded on the AE section of the 
electronic CRF.  
If the patient discontinues for any reason (including discontinuation for pregnancy), with drug related 
adverse event ongoing at Study end, he/she will be followed until resolution or stabilization of the 
event or until it will be reasonable to consider the event not drug related any more or until the start of 
a new treatment, whichever occurs first.  
In case of multiple reasons (e.g. patient withdraws the consent for toxicity), “adverse event” is 
indicated as the primary reason whenever applicable. All relevant information related to the reason for 
treatment discontinuation including contributory factors are included on the electronic CRF. 
A complete end of Study visit must be performed by 7 days after the last drug intake for any patient 
permanently discontinuing Study treatment. All drug-related AEs that are still ongoing beyond the last 
scheduled visit, are followed at subsequent follow-up visits until recovery. If a patient does not return 
for a scheduled visit, every effort will be made to contact the patient. In any circumstance every effort 
will be made to complete and report the observations as thoroughly as possible. All relevant 
information related to the reason for treatment discontinuation including contributory factors are 
included on the electronic CRF. 
For AEs definitions, coding and reporting procedures see paragraph 5 of the Study protocol. 
 
16.11. 
EXPLORATORY PARAMETERS 
EVALUATION OF THE EFFECTS OF GIVINOSTAT ON EACH SINGLE PARAMETER OF THE CLINICO-
HAEMATOLOGICAL ELN RESPONSE CRITERIA 
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Each single parameter of the clinico-haematological ELN response criteria [1] (see paragraph 16.3) is 
used to evaluate the effect of Givinostat in PV patients. 
Only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months) and the eligibility 
for this part of the study may be expanded to all patients with cMPN, in this part of the study each 
single parameter of the ELN and EUMNET criteria can be used to evaluate the effect of Givinostat in ET 
and MF patients, respectively. 
 
EVALUATION OF THE EFFECTS OF GIVINOSTAT ON PD MARKERS 
 
To evaluate the effects of Givinostat on PD markers, the analysis on mRNA is used.  
After evaluation of preliminary results and data exploration, some additional analyses can be performed 
to identify and quantify other molecular parameters of interest in terms of improving of knowledge of 
cMPN and the activity of the drug in these disorders.    
 
SPLEEN SIZE ASSESSMENT 
 
The spleen evaluation is performed at the study centre according to the visit schedule outlined in the 
flow-chart (Appendix A of the Study protocol). 
To evaluate the effects of Givinostat on spleen size, MRI or CT scan is used.  
The spleen evaluation is performed during the study according to institutional guidelines and site-
specific clinical practice (i.e. MRI or CT scan). For this reason, it is strictly recommended to the sites to 
provide the Sponsor or their designee with the local normal spleen values of the imaging performed for 
each patient according to institutional guidelines and site-specific clinical practice (i.e. MRI or CT scan). 
The same imaging technique and the same instrument to assess spleen dimension (i.e. MRI or CT scan) is 
used on a patient throughout the study, if possible.  
If possible, the spleen dimensions are evaluated as longitudinal diameter (A), antero-posterior diameter 
(B), transversal diameter (C) and Splenic Volumetric Index (SVI): 
 
 
SVI = (A x B x C) / 27 
 
IMPROVEMENT OF CONSTITUTIONAL SYMPTOMS 
 
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To evaluate the improvement of disease-related constitutional symptoms, the Myeloproliferative 
Neoplasm Symptom Assessment Form (MPN-SAF) questionnaire (about 20 items) is used in Parts A and 
B, in order to assess the most important clinical symptoms among patients with MPNs [8].  
In addition, starting from MPN-SAF questionnaire, in Part B also the MPN-SAF Total Symptom Score [9] is 
assessed as requested by the “new” ELN criteria (i.e. revised ELN response criteria) [2].  
 
REDUCTION OF THE JAK2V617F ALLELE BURDEN 
 
To evaluate the reduction of the JAK2V617F allele burden, the qRT-PCR is used. This molecular examination 
is performed in a central laboratory (Appendix E of the Study protocol).  
After evaluation of preliminary results and data exploration, some additional analyses can be performed 
to identify and quantify other molecular parameters of interest in terms of improving of knowledge of 
cMPN and the activity of the drug in these disorders. 
 
REDUCTION OF THE SYMPTOMATIC TREATMENT OF PRURITUS IN TERM OF 
DOSAGE AND/OR DAYS OF TREATMENT 
To evaluate the reduction of the symptomatic treatment of pruritus, the dosage and/or the days of 
treatment of each concomitant medication taken by the patient to treat this symptom is used. This 
assessment is performed using the data entered by Investigators in the specific section of the electronic 
CRF. 
 
EVALUATION OF PRELIMINARY EFFICACY ACCORDING TO THE REVISED ELN 
CRITERIA 
 
Disease response is evaluated also according to the following “new” ELN criteria (i.e. the revised ELN 
response criteria) after 6 cycles of treatment with Givinostat in Part B [2].  
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 
Complete remission:  
1. Durable resolution of disease-related signs including palpable hepato-splenomegaly 
improvement, and large symptoms improvement, and 
2. Durable peripheral blood count remission, defined as HCT < 45% without phlebotomies, and 
PLT count ≤ 400 x109/L, and WBC count < 10 x109/L, and 
3. No progressive disease, and absence of any haemorrhagic or thrombotic event, and 
4. Bone marrow histological remission defined as the presence of age-adjusted normo-
cellularity, and disappearance of tri-linear hyperplasia, and absence of grade > 1 reticulin 
fibrosis. 
 
Partial remission:  
1. Durable resolution of disease-related signs including palpable hepato-splenomegaly, and 
large symptoms improvement, and 
2. Durable peripheral blood count remission, defined as HCT < 45% without phlebotomies, and 
PLT count ≤ 400 x109/L, and WBC count < 10 x109/L, and 
3. No progressive disease, and absence of any haemorrhagic or thrombotic event, and 
4. No bone marrow histological remission defined as persistence of tri-linear hyperplasia. 
 
No response: any response that does not satisfy partial remission. 
 
Progressive Disease: transformation into post-PV myelofibrosis, myelodysplastic syndrome or 
acute leukemia (according to the IWG-MRT criteria for the diagnosis of post-PV myelofibrosis and 
according to WHO criteria for the diagnosis of myelodysplastic syndrome and acute leukemia). 
 
Please note that according to the “new” ELN criteria (i.e. revised ELN response criteria) [2]: 
 
1) Molecular response is not required for assignment as Complete Remission or Partial Remission. 
Molecular response evaluation requires analysis in peripheral blood granulocytes. Complete 
response is defined as eradication of a pre-existing abnormality. Partial response applies only to 
patients with at least 20% mutant allele burden at baseline. Partial response is defined as  ≥ 50% 
decrease in allele burden. 
2) “Durable” is defined as lasting at least 12 weeks. 
3) “Large symptom improvement” is defined as ≥ 10 points of decrease in MPN-SAF Total Symptom 
Score [9]. 
 
In all cases, the medical judgment of the Investigator’s is taken into account. In particular, if the 
Investigator‘s clinical response assessment – that takes into account the overall medical judgment of the 
specific patient’s case - is not in agreement with the exact application of the revised clinico-
haematological ELN response criteria , the Investigator’s assessment will supersede the “mathematical” 
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application of these criteria and used for analysis into study report. Also mathematical application of ELN 
response criteria (not agreed by the medical site team) will be analyzed. 
 
EVALUATION OF THE EFFECTS OF GIVINOSTAT ON EACH SINGLE PARAMETER OF 
THE REVISED ELN RESPONSE CRITERIA 
 
Each single parameter of the “new” ELN criteria (i.e. revised ELN response criteria) [2] (see section 
16.11.7.) is used to evaluate the effect of Givinostat in PV patients in Part B. 
 
17. PRIMARY OUTCOMES  
17.1. PART A 
The Primary objective of the Part A is to characterize the safety, tolerability and MTD of Givinostat in 
patients with PV. The determination of the MTD of Givinostat will be based on C1 DLTs. 
The following primary safety parameters will be evaluated in Part A based on SAF analysis set: 
 
Number of patients experiencing adverse events. 
 
Type, incidence, and severity of treatment-related adverse events, graded according to Common 
Terminology Criteria for Adverse Events (CTCAE v. 4.03, 14th June 2010). 
 
AEs will be coded using MedDRA dictionary (using the 20.1 version). AEs will be reported on a per 
patient basis. If a patient has more than one AE for a treatment that coded to the same PT, the patient 
will be counted only once for that PT. Similarly, if a patient has more than one AE for a treatment 
within a SOC category, the patient will be counted only once in that SOC category. A patient with 
multiple CTCAE grades for an AE will be summarised under the maximum CTCAE grade recorded for 
the event.  
Any AE which started at or after the first administration of Study treatment (i.e. C1D1) will be 
considered a Treatment Emergent Adverse Event (TEAE). If the start date is missing for an AE, the AE 
will be considered to be a TEAE. 
An overview of AEs including the number of patients with at least one AE, at least one TEAE, at least 
one drug-related TEAE, at least one Serious TEAE (TESAE), any SAE, any AE leading to death, any TEAE 
leading to death, any TEAE leading to drug discontinuation, at least one grade ≥ 3 TEAE, will be 
presented. The following AE frequency tables will be also provided:  
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• 
Incidence of TEAEs by primary SOC and PT; 
• 
Incidence of drug-related TEAEs by primary SOC and PT; 
• 
Incidence of TEAEs by maximum severity, primary SOC and PT; 
• 
Incidence of TEAEs by strongest relationship, maximum severity, primary SOC and PT; 
• 
Incidence of TESAEs by primary SOC and PT; 
• 
Incidence of TEAEs leading to study drug discontinuation by primary SOC and PT; 
• 
Incidence of TEAEs leading to dose modification by primary SOC and PT. 
 
In addition, the following primary parameter will be evaluated in Part A based on MTD analysis set 
population: 
• 
MTD of Givinostat. 
 
All outputs for safety outcomes will be based on the SAF analysis set, and presented by DLs (Part A 
only). There will be no planned statistical comparisons among treatment groups for safety data. 
 
ADVERSE EVENTS 
 
AE Investigator terms will be assigned to a PT and will be classified by primary SOC. AEs will be coded 
using the 20.1 version of MedDRA dictionary. TEAEs are defined as adverse events started at or after 
the first administration of study treatment.  
See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to define an AE 
as treatment emergent or not, the AE will be classified by the worst case (i.e. TEAE).  
An overall summary of number of patients within each of the categories described in the sub-section 
below, will be provided as specified in the templates. Listings will include AEs and TEAEs. 
A case narrative for each AE leading to treatment discontinuation (the “Action Taken with Study Drug” 
in section “AE” of the electronic CRF is “Definitively withdrawn”), and/or leading to death (see below), 
and/or ongoing at the end of treatment (the “Outcome” in the section “AE” of the electronic CRF is 
“Ongoing” at the time of database look) will be reported in the Clinical Study Report. 
 
ALL TEAEs 
 
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Incidence of TEAEs will be presented by primary SOC and PT and also broken down further by 
maximum severity and relationship to Study medication. 
 
SEVERITY AND COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
 
AEs will be graded by the Investigators according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03, dated 14th June 2010. The grade assigned by the Investigator will be used 
for this analysis. 
TEAEs starting after the first dose of Study medication (i.e. C1D1) with a missing severity will be 
classified as “severe*” (i.e. “grade 3*”), in order to distinguish them from the TEAEs graded as severe 
that will be reported without “*” (i.e. “severe”).  
If a patient reports a TEAE more than once within that SOC/PT, the AE with the worst severity will be 
used in the corresponding severity summaries. 
 
RELATIONSHIP TO STUDY MEDICATION 
In electronic CRF the relationship of an AE with the Study drug is classed as “Not Related”, “Related” or 
“Unknown”, based on Investigator’s judgment. 
A “Related” TEAE is defined as a TEAE with a relationship to the Study medication; in this case, the 
Investigator ticked “Related” in the field “Relationship with Study Drug” of the section “AE” of the 
electronic CRF.  
A “Not Related” TEAE is defined as a TEAE without a reasonable relationship to the Study medication; 
in this case, the Investigator ticked “Not Related” in the field “Relationship with Study Drug” of the 
section “AE” of the electronic CRF. 
If a TEAE is reported as “Unknown” in the field “Relationship with Study Drug” of the section “AE” of 
the electronic CRF even after the database lock, the worst relationship will be considered (i.e. 
“Related*). TEAEs with a missing relationship to Study medication even after the database look, the 
worst relationship will be considered (i.e. “Related*”). In both cases, the “*” will allow to distinguish 
them from the TEAEs considered by the Investigators as “Related” and reported without “*” (i.e. 
“Related”). 
If a patient reports the same TEAEs more than once within that SOC and/or PT, the TEAE with the 
worst case relationship to Study medication will be used in the corresponding relationship summaries.  
 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of Study medication will be identified by using the 
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response on “Action taken with Study Drug” ticked as “Definitively withdrawn” from the section “AE” 
of the electronic CRF. 
For TEAEs leading to discontinuation of Study drug, summaries of incidence rates (i.e. frequencies and 
percentages) by SOC and PT will be presented. 
 
ADVERSE EVENTS LEADING TO DEATH 
If any patients died during the Study, as recorded on the sections “EOS” and/or “AE” of the electronic 
CRF, the information will be presented in a summary table and a data listing. 
TEAEs leading to death will be identified by using the following responses on the section “AE” of the 
electronic CRF: 
 
“Yes” at the question “Is this a serious event?” (death details); 
 
“Fatal” on the field “Outcome”; 
 
“Death related to AE” on the field “Severity”. 
A summary of TEAEs leading to death by SOC and PT will be prepared. 
All details of TEAEs leading to Death (date of death, autopsy performed and date of autopsy, if 
applicable, and death due to of Progression of the disease), recorded on “Death report” page on eCRF, 
will be listed only.  
A case narrative for each death will be reported in the Clinical Study Report. 
 
DOSE LIMITING TOXICITIES 
 
A DLT is defined as one of the following drug-related toxicity: 
 
Grade 4 haematological toxicities, or 
 
Grade 3 febrile neutropenia, or 
 
Grade ≥ 3 non-haematological toxicities with exception of: 
a) Grade 3 diarrhoea without adequate supportive care lasting  less than 3 days, and 
b) Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days, or 
 
Any drug-related SAE, or 
 
Any toxicity that is clearly not related to disease progression or intercurrent illness requiring 
interruption of dosing for more than 3 days during the first cycle.  
The severity of the above mentioned events is graded by the Investigators according to CTCAE v. 4.03, 
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dated 14th June 2010. 
Only DLTs experienced during the first cycle of treatment (i.e. up to C1D28) of Part A are considered 
for dose escalation decisions. DLTs include all AEs that are clearly not related to disease progression or 
intercurrent illnesses. Patients who didn’t experience a DLT and missed more than 10% of the doses in 
Cycle 1 of Part A are replaced. 
 
DLTs will be identified by using the response “Yes” at the question “Was this a Dose Limiting Toxicity 
Event?” on the section “AE” of the electronic CRF.  
A summary of DLT by SOC and PT will be prepared.  
A case narrative for each DLT will be reported in the Clinical Study Report. 
 
SERIOUS ADVERSE EVENTS 
 
SAEs will be identified by using the response on “Is this a serious event?” ticked as “Yes” on the “AE” 
section of the electronic CRF. A summary of SAE and Treatment Emergent SAEs (TESAEs) by SOC and 
PT will be prepared. 
A case narrative for each SAE will be reported in the Clinical Study Report. 
 
17.2. PART B 
The following primary efficacy parameters will be evaluated in Part B after 3 cycles of treatment (i.e. at 
the end of Cycle 3) based on ITT analysis set and PP analysis set: 
 For PV and ET (if any): Complete response (CR) and partial response (PR) rate according to clinico-
haematological ELN response criteria [1]; 
 For MF (if any): CR, major response, moderate response and minor response rate according to the 
EUMNET response criteria [7]. 
Note that only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months, the 
eligibility for this part of the study could be expanded to all patients with cMPN.  
The clinico-haematological ELN response criteria [1] and EUMNET response criteria will be used to assess 
the preliminary efficacy of Givinostat (primary endpoint) after 3 cycles of treatment in Part B for PV/ET 
and MF patients, respectively.  
In all cases, the medical judgment of the Investigator’s is taken into account. In particular, if the 
Investigator‘s clinical response assessment – that takes into account the overall medical judgment of the 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 73 of 101 
specific patient’s case - is not in agreement with the exact application of the clinico-haematological ELN 
or EUMNET response criteria , the Investigator’s assessment will supersede the “mathematical” 
application of these criteria and used for analysis into study report. Also mathematical application of ELN 
response criteria (not agreed by the medical site team) will be analyzed. 
 
Frequency and percentage of patients in each response category (CR, PR, no response (NR) for PV and 
ET; CR, major response, moderate response, minor response and NR rate for MF) will be presented at 
Cycle 3 Day 28 (C3D28). Of note, patients who dropped the study due to drug-related TEAE(s) before 
that the post-baseline efficacy measurement is obtained (i.e. at C3D28 and/or at C6D28), the post-
baseline efficacy measurements (i.e. at C3D28 and/or at C6D28) will be considered as “No Response*”, 
even if these assessments were not performed. “*” will allow to distinguish them from them from the 
therapeutic response evaluation result of “No Response”, that will be reported without “*” (i.e. “No 
Response”). Other missing data will not be replaced, if not otherwise specified.  
 
For Part B – Stage 1, Simon’s design hypothesis will be evaluated by calculating the frequency and 95% CI 
of patients with a CR and/or PR at C3D28. 
For Part B – Stage 2, the efficacy of Givinostat will be evaluated by means of a generalized linear model 
(logit link function and binomial distribution) adjusting for age, sex and disease type (PV, ET, MF). The 
therapeutic response will be collapsed in two categories in order to improve the model performance: 
- 
For PV and ET:  
a) “Responders” (i.e. CR and PR), and  
b) “Not Responders” (i.e. NR);  
- 
For MF: 
a) “Responders” (i.e. CR, major response, moderate response and minor response), and 
b) “Not Responders” (i.e. NR for MF).  
 
In addition, the following primary safety parameters will be evaluated in Part B after 3 cycles of 
treatment (i.e. at the end of Cycles 3, or including data related to Cycles 1, 2 and 3) based on SAF 
analysis set: 
 Number of patients experiencing AEs. 
 Type, incidence, and severity of treatment-related AEs, graded according to CTCAE v. 4.03 (14th June 
2010). 
AEs will be coded using MedDRA dictionary (using the 20.1 version). AEs will be reported on a per patient 
basis. If a patient has more than one AE for a treatment that is coded to the same PT, the patient will be 
counted only once for that PT. Similarly, if a patient has more than one AE for a treatment within a SOC 
category, the patient will be counted only once in that SOC category. A patient with multiple CTCAE 
grades for an AE will be summarised under the maximum CTCAE grade recorded for the event.  
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 74 of 101 
Any AE which started at or after the first administration of Study treatment will be considered a TEAE. If 
the start date is missing for an AE, the AE will be considered to be treatment emergent.  
An overview of AEs including the number of patients with at least one AE, at least one TEAE, at least one 
drug-related TEAE, at least one TESAE, any SAE, any AE leading to death, any TEAE leading to death, any 
TEAE leading to drug discontinuation, at least one grade ≥ 3 TEAE, will be presented. The following AE 
frequency tables will be also provided:  
 Incidence of TEAEs by primary SOC and PT; 
 Incidence of drug-related TEAEs by primary SOC and PT; 
 Incidence of TEAEs by maximum severity, primary SOC and PT; 
 Incidence of TEAEs by strongest relationship, maximum severity, primary SOC and PT; 
 Incidence of TESAEs by primary SOC and PT; 
 Incidence of TEAEs leading to study drug discontinuation by primary SOC and PT; 
 Incidence of TEAEs leading to dose modification by primary SOC and PT. 
The primary safety parameters will be evaluated in Part B after 3 cycles of treatment (i.e. at the end of 
Cycles 3, or including data related to Cycles 1, 2 and 3) based on SAF analysis set and taking into account 
the same rules describes in the paragraphs 17.1. 
 
18. SECONDARY OUTCOMES 
18.1. PART A 
The following secondary efficacy parameters will be evaluated in Part A after 3 and 6 cycles of 
treatment (i.e. at the end of Cycles 3 and 6, respectively) based on ITT analysis set and PP analysis set: 
 Preliminary efficacy of Givinostat (secondary endpoint) for PV/ET and MF patients, respectively: 
- For PV and ET (if any): CR and PR rate according to the clinico-haematological ELN response 
criteria [1];  
- For MF (if any): CR, major response, moderate response and minor response rate according to the 
EUMNET response criteria [7].  
In all cases, the medical judgment of the Investigator’s is taken into account. In particular, if the 
Investigator‘s clinical response assessment – that takes into account the overall medical judgment of the 
specific patient’s case - is not in agreement with the exact application of the clinico-haematological ELN 
or EUMNET response criteria , the Investigator’s assessment will supersede the “mathematical” 
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reproduction is strictly prohibited. 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 75 of 101 
application of these criteria and used for analysis into study report. Also mathematical application of ELN 
response criteria (not agreed by the medical site team) will be analyzed. 
Note that only in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months, the 
eligibility for this part of the study can be expanded to all patients with cMPN.  
Frequency and percentage of patients in each response category (CR, PR, NR rate for PV and ET; CR, 
major response, moderate response, minor response and NR rate for MF) will be presented at C3D28 
and at Cycle 6 Day 28 (C6D28).  
 Of note, patients who dropped the study due to drug-related TEAE(s) before that the post-baseline 
efficacy measurement is obtained (i.e. at C3D28 and/or at C6D28), the post-baseline efficacy 
measurements (i.e. at C3D28 and/or at C6D28) will be considered as “No Response*”, even if these 
assessments were not performed. “*” will allow to distinguish them from them from the therapeutic 
response evaluation result of “No Response”, that will be reported without “*” (i.e. “No Response”). 
Other missing data will not be replaced, if not otherwise specified. 
 
The following secondary parameter will be evaluated in Part A based on PK analysis set: 
– Individual Givinostat concentrations tabulated by DL along with descriptive statistics.  
Plasma concentrations from Part A will be listed and tabulated by dose and time point for all patients 
and time points with at least 1 PK assessment.  
Descriptive statistics for all PK parameters for Part A will be calculated. 
 
18.2. PART B 
The following secondary efficacy parameter will be evaluated in Part B after 6 cycles of treatment (i.e. at 
C6D28) based on ITT analysis set and PP analysis set: 
 Preliminary effectiveness of Givinostat (secondary endpoint) after 6 cycles of treatment in Part B for 
PV/ET and MF patients, respectively: 
- 
For PV and ET (if any): CR and PR rate according to the clinico-haematological ELN response 
criteria [1]; 
- 
For MF (if any): CR, major response, moderate response and minor response rate according to 
the EUMNET response criteria [7]. 
In all cases, the medical judgment of the Investigator’s is taken into account. In particular, if the 
Investigator‘s clinical response assessment – that takes into account the overall medical judgment of the 
specific patient’s case - is not in agreement with the exact application of the clinico-haematological ELN 
or EUMNET response criteria , the Investigator’s assessment will supersede the “mathematical” 
application of these criteria and used for analysis into study report. Also mathematical application of ELN 
response criteria (not agreed by the medical site team) will be analyzed. Note that only in case the 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 76 of 101 
enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months), the eligibility for this part of the study 
can be expanded to all patients with cMPN.  
Frequency and percentage of patients in each response category (CR, PR and NR rate for PV and ET; CCR, 
major response, moderate response, minor response and NR rate for MF) will be presented at C6D28. Of 
note, patients who dropped the study due to drug-related TEAE(s) before that the post-baseline efficacy 
measurement is obtained (i.e. at C3D28 and/or at C6D28), the post-baseline efficacy measurements (i.e. 
at C3D28 and/or at C6D28) will be considered as “No Response*”, even if these assessments were not 
performed. “*” will allow to distinguish them from them from the therapeutic response evaluation result 
of “No Response”, that will be reported without “*” (i.e. “No Response”). Other missing data will not be 
replaced, if not otherwise specified. 
 
The following secondary safety parameter will be evaluated in Part B after 6 cycles of treatment (i.e. at 
C6D28, or including data related to Cycle 4 Day 28 (C4D28), Cycle 5 Day 28 (C5D28) and any unscheduled 
visit included in that interval period) based on SAF analysis set: 
 Number of patients experiencing AEs. 
 Type, incidence, and severity of treatment-related AEs, graded according to CTCAE v. 4.03 (14th June 
2010). 
AEs will be coded using MedDRA dictionary (using the 20.1 version). AEs will be reported on a per patient 
basis. If a patient has more than one AE for a treatment that coded to the same PT, the patient will be 
counted only once for that PT. Similarly, if a patient has more than one AE for a treatment within a SOC 
category, the patient will be counted only once in that SOC category. A patient with multiple CTCAE 
grades for an AE will be summarised under the maximum CTCAE grade recorded for the event.  
Any AE which started at or after the first administration of study treatment will be considered a TEAE. If 
the start date is missing for an AE, the AE will be considered to be a TEAE. 
TEAE included in this analysis are defined as those starting after the date of the first administration of 
Cycle 4. 
An overview of AEs including the number of patients with at least one AE, at least one TEAE, at least one 
drug-related TEAE, at least one TESAE, any SAE, any AE leading to death, any TEAE leading to death, any 
TEAE leading to drug discontinuation, at least one grade ≥ 3 TEAE, will be presented. The following AE 
frequency tables will be also provided:  
 Incidence of TEAEs by primary SOC and PT; 
 Incidence of drug-related TEAEs by primary SOC and PT; 
 Incidence of TEAEs by maximum severity, primary SOC and PT; 
 Incidence of TEAEs by strongest relationship,  maximum severity, primary SOC and PT; 
 Incidence of TESAEs by primary SOC and PT; 
 Incidence of TEAEs leading to study drug discontinuation by primary SOC and PT; 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
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 Incidence of TEAEs leading to dose modification by primary SOC and PT. 
These secondary safety parameters will be evaluated in Part B after 6 cycles of treatment (i.e. at C6D28, 
or including data related to C4D28, C5D28 and any unscheduled visit included in that interval period) 
based on SAF analysis set and taking into account the same rules describes in the paragraphs 17.1. 
 
The following secondary parameters will be evaluated in Part B based on PK analysis set: 
 Individual Givinostat concentrations tabulated with descriptive statistics: plasma concentrations from 
Part B will be listed and tabulated by time point for all patients and time points with at least 1 PK 
assessment; descriptive statistics for all PK parameters for Part B will also be calculated; these tables 
will include number of observations, mean, standard deviation, median, minimum and maximum and 
additionally the geometric mean and Coefficient of Variation (CV), not for time to maximum plasma 
concentration. 
 
18.3. PK ANALYSIS 
PK analyses will be carried-out by Accelera using Phoenix WinNonlin 6.3 (Certara Company).  
 
For both Part A and B, PK parameters of Givinostat and its metabolites (ITF-2374 and ITF-2375) will be:  
Cmax, Clast, CTmax, AUClast and if data permit and only for Givinostat AUC(0- τ), Ro (observed 
accumulation ratio on Cmax, AUClast and if data permit AUC(0-τ)) and Ratio ITF-2374 parent or ITF-
2375/parent Cmax and AUClast.   
 
The actual plasma sampling times will be used in the analysis.  
For the PK calculation, plasma concentrations below the lower limit of quantification (BLQ) will be 
treated as follows: 
 
All  BLQ values before the first detectable concentration will be set equal to zero.  
 
All BLQ values after the last detectable plasma concentration will be excluded .  
 
BLQ value between two detectable plasma concentrations will be excluded.  
For the descriptive statistic calculation on plasma concentration data, the BLQ values will be treated as 
follows: 
 
BLQ values will be set equal to zero.  
 
BLQ values between two detectable plasma concentrations will be excluded.  
Individual values considered to be anomalous will be excluded from the pharmacokinetic analysis and 
descriptive statistics.  Justification for exclusion will be provided in the pharmacokinetic report. 
 
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STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 78 of 101 
 
The following PK plasma parameters will be calculated for both part A and B:  
 
Tmax,  
 
Tlast, 
 
Cmax,  
 
Clast,  
 
Cτ,  
 
AUClast  
and if data permit AUC(0- τ) and Ro (observed accumulation ratio on Cmax and AUClast and if data 
permit AUC(0- τ)) between the individual parameter obtained on Day 28 to the corresponding one 
on Day 1. 
 
Pharmacokinetic parameters will be calculated as follows:  
 
Tmax,  
 
Tlast,  
 
Cmax,  
 
Clast  
and Cτ will be taken directly from the raw data.  
 
Areas under the plasma concentration vs. time curve (AUClast, AUC(0-τ)) will be calculated using linear 
trapezoidal rule.  
Accumulation ratios Ro on Cmax, AUClast and if data permit on AUC(0- τ) will be calculated as the ratio 
between the individual parameter obtained on Day 28 to the corresponding one on Day 1. Ratios 
between metabolites (ITF-2374 and ITF-2375) to parent drug will be performed on Cmax and AUClast on 
day 1 and day 28. 
Descriptive statistics of plasma concentrations and pharmacokinetic parameters of Givinostat will 
include N, Mean, SD, Coefficient of Variation (CV) Median, Minimum, and Maximum.  
 
The following units will be used for individual and mean parameters of the compound: 
 
Cmax, Clast, C τ:  ng/mL, 
 
Tmax, Tlast: hr, 
 
AUCs: nghr/mL. 
 
Descriptive statistics of plasma concentrations and pharmacokinetic parameters of Givinostat will 
include N, Arithmetic Mean, SD, Geometric Mean, Coefficient of Variation (%), Min, Median and Max. 
 
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Page 79 of 101 
Appropriate statistical methods will be applied to analyze accumulation ratio (R0) and dose 
proportionality. 
In particular, to estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio will be determined using Cmax and AUClast and if data permit AUC(0- τ) log-transformed values.  
A mixed effect model will be implemented with day as fixed effect and patient as a random effect.  Day 
28 will be compared vs Day 1 for each dose level. Again, the 90% CIs for the differences will be calculated 
and back-transformed.  
  
Due to the scheme in dose escalation and the study design (parallel groups), the dose proportionality 
evaluation will be approached with a pure explorative intent. AUClast, Cmax and if the data permit 
AUC(0- τ) following repeat doses will be used for a preliminary assessment being aware the results 
should be interpreted with caution. The method foresees to apply the power model approach where the 
slope of the line obtained by regressing log(PK parameter) on log(dose) will be estimated and presented 
together with its 90% CI. Dose-proportionality implies a CI of regression coefficient (b as below) including 
1 in the following model: 
log(PK parameter) = a + (b · log(dose)) + ε 
 
where a is the intercept, b the slope and ε the random error term. 
19. EXPLORATORY OUTCOMES  
19.1. PARTS A AND B 
The following exploratory parameters will be evaluated using ad-hoc descriptive analysis in Parts A and B 
based on ITT analysis set and PP analysis set: 
• 
The effect of Givinostat on each single response parameter according to the clinico-
haematological ELN (for PV and ET) [1] and EUMNET response criteria (for MF) [7]; note that only 
in case the enrolment in Part A is slow (i.e. < 5 patients enrolled in 3 months), the eligibility for 
this part of the study could be expanded to all patients with cMPN.  
• 
Effects of Givinostat on PD markers. 
• 
Effects of Givinostat on spleen size in patients with confirmed splenomegaly at baseline. 
• 
Improvement of constitutional symptoms evaluated according to MPN-SAF QOL questionnaire 
[8, 9] including patients without the symptom of headache, pruritus and microvascular 
symptoms (i.e MPN SAF Score =0) and number and percentage of patient with symptom score 
from 0 to 3; from 4 to 6 and more than 7. 
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Page 80 of 101 
• 
Reduction of the JAK2V617F allele burden, tested by quantitative RT-PCR. 
• 
Reduction of the symptomatic treatment of pruritus in term of dosage and/or days of treatment. 
The following exploratory parameters will be evaluated using ad-hoc descriptive analysis in Part B based 
on ITT analysis set and PP analysis set: 
• 
The preliminary efficacy of Givinostat after 6 cycles of treatment according to the “new” ELN 
criteria (i.e. revised ELN response criteria) [2]. In all cases, the medical judgment of the 
Investigator’s is taken into account. In particular, if the Investigator‘s clinical response 
assessment – that takes into account the overall medical judgment of the specific patient’s case - 
is not in agreement with the exact application of the revised clinico-haematological ELN 
response criteria , the Investigator’s assessment will supersede the “mathematical” application 
of these criteria and used for analysis into study report. Also mathematical application of ELN 
response criteria (not agreed by the medical site team) will be analyzed. 
• 
The effect of Givinostat on single parameters of the “new” ELN response criteria (i.e. revised ELN 
response criteria) [2]. 
 
The “new” ELN response criteria [2] are detailed in the paragraph 4.8.7 of the Study protocol.  
Explorative endpoints will be summarised by descriptive methods based on ITT analysis set and PP 
analysis set. Default summary statistics and changes from baseline (where applicable) to each time point 
for all parameters will be produced. 
20. OTHER SAFETY OUTCOMES 
All patients who receive at least one dose will be included in the safety evaluation.  
Safety data including laboratory evaluations, physical exams, ECG monitoring and vital signs assessments 
will be summarised at each time point.  
Descriptive statistics (arithmetic mean, standard deviation, median, minimum and maximum) will be 
calculated for quantitative safety data as well as for the difference from baseline, if applicable. 
Frequency counts will be compiled for classification of qualitative safety data.  
In addition, a shift table describing out of normal range shifts (low/normal/high values) will be provided 
for clinical laboratory results.  
A normal-abnormal shift table will also be presented for physical exam and ECG results. 
20.1.  LABORATORY EVALUATIONS. 
Results from the local laboratories will be included in the reporting of this study for Haematology, 
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Blood Chemistry and Urinalysis.  
A list of laboratory assessments to be included in the outputs is included in the paragraph 4.7.1 of the 
Study protocol.  
Outputs will be based on the SAF analysis set, presented by DL (for Part A only), and will use the 
International System (SI) Units. 
The following summaries will be provided for Haematology, Blood Chemistry, Urinalysis laboratory 
data by DL (for Part A only): 
• 
Actual and change from baseline by visit (for quantitative measurements); 
• 
Shift from baseline according to normal range criteria (for categorical measurements); 
• 
Presence/absence, with number (n) and percentage (%), where applicable (i.e. Glucose and 
Protein, for Urinalysis test). 
• 
Listing of laboratory data by Study Part and patient ID; 
• 
Listing of patients with clinically significant abnormal values, as reported in electronic CRF 
based on Investigator’s judgment; 
• 
Listing of patients with markedly significant abnormal values (e.g. grade 3 thrombocytopenia 
as per CTCAE version 4.03). 
 
20.2. LABORATORY SPECIFIC DEVIATIONS 
To convert from each local laboratory conventional unit to the SI unit, values will be multiplied by the 
conversion factor: 
 
Component 
Conventional Unit 
Conversion 
Factor 
SI Unit 
Haematology 
Haematocrit 
%  
0.01 
Proportion of 1.0 
Haemoglobin  
g/dL 
10 
g/L 
RB count 
x 106/μL  
1  
x 1012/L 
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Page 82 of 101 
Platelets  
x 103/μL 
1 
x 109/L 
WB count 
x 103/μL 
1 
x 109/L 
Basophils 
x 103/μL 
1 
x 109/L 
Eosinophils 
x 103/μL 
1 
x 109/L 
Lymphocytes 
x 103/μL 
1 
x 109/L 
Monocytes 
x 103/μL 
1 
x 109/L 
Neutrophils  
x 103/μL 
1 
x 109/L 
Mean Corpuscular Volume 
fL 
1 
μm3 
Mean Corpuscular Haemoglobin 
Pg 
0.062 
fmol 
Mean Corpuscular Haemoglobin 
Concentration 
g/dL 
10 
g/L 
Blood Chemistry 
Sodium  
mEq/L  
1.0  
mmol/L 
Potassium 
mEq/L  
1.0  
mmol/L 
Calcium 
mg/dL  
mEq/L  
0.25 
0.50 
mmol/L 
Chloride 
mEq/L 
1 
mmol/L 
Magnesium 
mg/dL 
0.4114 
mmol/L 
Albumin 
g/dL 
10 
g/L 
Blood Glucose 
mg/dL 
0.0555 
mmol/L 
BUN 
mg/dL  
0.357 
mmol/L 
Urea 
mg/dL  
0.357 
mmol/L 
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Page 83 of 101 
Creatinine 
mg/dL 
88.4 
μmol/L 
Alanine aminotransferase (ALT) 
U/L 
1 
U/L 
Aspartate aminotransferase (AST) 
U/L 
1 
U/L 
Alkaline phosphatase 
U/L 
1 
U/L 
Total Bilirubin 
mg/dL 
17.104 
μmol/L 
Lactate Dehydrogenase 
U/L 
1  
U/L 
Urinalysis 
pH 
(unitless) 
 
 
Specific Gravity 
(unitless) 
 
 
Glucose 
mg/dL 
0.0555 
mmol/L 
Protein 
g/dL 
10.0 
g/L 
 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
 
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in local units and categorized as: 
 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
 
Potentially clinically significant laboratory values will be summarised by laboratory variable. Platelets 
values will be evaluated as a potentially clinically significant low value at any time during the study, 
and will be presented by visit.  
 
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The Platelets potentially clinically significant low value is defined as follows: 
 
• 
Platelets count < 150 x 109/L but > 75 x 109/L (i.e. grade 1 thrombocytopenia as per CTCAE 
version 4.03); 
• 
Platelets count < 75 x 109/L but > 50 x 109/L (i.e. grade 2 thrombocytopenia as per CTCAE 
version 4.03); 
• 
Platelets count < 50 x 109/L but > 20 x 109/L (i.e. grade 3 thrombocytopenia as per CTCAE 
version 4.03); 
• 
Platelets count < 25 x 109/L (i.e. grade 4 thrombocytopenia as per CTCAE version 4.03). 
 
20.3. ECG EVALUATIONS 
Results from the ECG will be based on the SAF analysis set, presented by DL (for Part A only) 
The following ECG variables will be reported for this study: 
Qualitative Evaluations: 
 Overall assessment of ECG (Investigator’s judgment Interpretation): 
 
Normal 
 
Abnormal - Not Clinically Significant; 
 
Abnormal - Clinically Significant. 
 
All the abnormalities – including the details of detected “Findings” as reported on electronic CRF - will 
be listed.  
 
 
RR Interval (msec); 
 
QT Interval (msec); 
 
QTc Interval (msec) – automatically calculated on electronic CRF using the Bazett’s correction 
formula. 
 
The following summaries will be provided for ECG data: 
 
The number (n) and percentage (%) from baseline by visit for qualitative interpretation; 
 
Actual and change from baseline by visit for quantitative measurements; 
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 
Shift from baseline according to markedly abnormal criteria for quantitative measurements; 
 
Listing of patients meeting markedly abnormal criteria for quantitative measurements; 
 
ECG SPECIFIC DERIVATIONS 
 
Bazett’s Correction (msec) is derived directly from eCRF and it is calculated as follows: 
o 
𝑄𝑇𝑐 (msec) =
ொ் (௠௦௘௖)
ඥோோ(௦௘௖)  
 
Where, RR Interval, imputed directly on the eCRF by the investigator, is calculated as follows: 
o 
𝑅𝑅 (sec) = 
଺଴
ுோ (௕௣௠) 
 
ECG MARKEDLY ABNORMAL CRITERIA 
 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the following 
predefined markedly abnormal criteria: 
• 
Absolute values for QTc interval > 450 msec  
• 
Change from Baseline for QTc interval >30 msec increase from baseline 
20.4. SPLEEN EVALUATIONS 
Results from the Spleen evaluation will be based on the SAF analysis set and presented by Cohort (Part 
A only). 
 
The following spleen variables will be reported for this study: 
 Imaging Technique of Spleen: 
 MRI; 
 CT Scan. 
 Qualitative Evaluation: Overall assessment of Spleen (Investigator’s judgment Interpretation): 
 Normal; 
 Abnormal, Not Clinically Significant; 
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 Abnormal, Clinically Significant. 
The Abnormalities will be listed.  
 
 Quantitative Evaluations: 
  Longitudinal Diameter (cm);  
  Antero/Posterior Diameter (cm); 
  Transversal Diameter (cm); 
  Splenic Volumetric Index (cm3) - automatically field on eCRF.  
  
The following summaries will be provided for Spleen data: 
• 
The number (n) and percentage (%) at baseline for Technique of Imaging; 
• 
The number (n) and percentage (%) at baseline for qualitative interpretation; 
 
The number (n) and percentage (%) at baseline, Cycle 3 Day 28 and Cycle 6 Day 28 showed a 
Spleen Volume reduction ≥ 35%. 
Spleen Specific Derivations: Splenic Volumetric Index (cm3) is automatically calculated by electronic 
CRF as following: 
 
SVI (cm3)=
(௅௢௡௚௜௧௨ௗ௜௡௔௟∗୅୬୲ୣ୰୭/୔୭ୱ୲ୣ୰୧୭୰∗୘୰ୟ୬ୱ୴ୣ୰ୱୟ୪) ୈ୧ୟ୫ୣ୲ୣ୰ୱ 
ଶ଻
 
 
20.5. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
 
• 
Systolic Blood Pressure (mmHg); 
• 
Diastolic Blood Pressure (mmHg); 
• 
Heart Rate (bpm); 
• 
Respiratory Rate (breaths/min); 
• 
Body Temperature (⁰C); 
• 
Height (cm), only for Baseline; 
• 
Weight (kg); 
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The following summaries will be provided for vital signs data: 
• 
Actual and change from baseline by visit; 
• 
Listings of all measurements by DL (for Part A only) and patient ID. 
20.6. PHYSICAL EXAMINATION 
The following summaries will be provided for physical examination data: 
• 
Incidence of abnormalities at screening; 
• 
Incidence of abnormalities post baseline. 
20.7. OTHER SAFETY ASSESSMENTS 
No other safety assessment will be collected for this study. 
 
21. MOLECULAR ANALYSIS 
Results from the molecular analysis performed during the Study will be listed, including results from 
pharmacodynamic (PD) markers.  
 
The following information will be provided for JAK2V617F allele burden evaluations: 
 
•   JAK2V617F positivity (Yes/No); 
 
Qualitative evaluation of JAK2V617F allele burden 
 Heterozygous 
 Homozygous 
 Quantitative evaluation of JAK2V617F allele burden (%); 
 Actual and change from baseline by visit; 
 Number (n) and percentage (%) of patients with: 
 a reduction of any specific molecular abnormality to undetectable levels; 
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 a reduction of ≥ 50% from baseline value in patients with < 50% mutant allele burden at baseline;  
 a reduction of ≥ 25% from baseline value in patients with > 50% mutant allele burden at baseline. 
 Descriptive statistics of quantitative evaluation of JAK2V617F allele burden. 
 
Notably, approximately 4.0 mL of blood for PD markers is collected before the first Givinostat dose 
(pre-dose) and 12 hours after the first Givinostat dose (post-dose) at C1D1 both in Part A and in Part B 
for measurement of levels of molecular markers, to evaluate the PD effect of Givinostat and to identify 
markers predictive of clinical benefit of Givinostat (see Appendix A of the Study protocol). In addition, 
PD evaluations are performed also using an aliquot of the PK samples collected at time points 
described in the paragraph 4.5.3.2 of the Study protocol. The molecular markers to be measured may 
include mRNA levels of JAK2, STAT5A, BclXL, PIM1, NFE2, LMO2, cMyc as well as HDAC3, STAT4, 
MYBL1, MEGF9, GLRX, FAM49A. The final list of PD markers to be measured will depend on ongoing 
scientific developments as well as availability of assays and other business considerations. For all time 
points an additional PD blood sample is collected as back-up sample. 
This assessment is mandatory and is performed by a central laboratory. The exact date and time of the 
PD blood draws is recorded along with the date and time of the last dose of study drug preceding the 
blood draw.  
 
All molecular examinations (e.g. JAK2V617F allele burden evaluated by quantitative RT-PCR, mRNA 
isolation, gene expression) are performed in a central laboratory.  
The results are transcribed into the electronic CRF by the central laboratory team or its designee and 
the original signed and dated laboratory print-out/tracings are monitored and stored at the central 
laboratory.  
 
After evaluation of preliminary results and data exploration, some additional analyses may be 
performed to identify and quantify other molecular parameters of interest in term of improving of the 
knowledge of cMPN and the activity of the drug in these disorders. 
 
JAK2V617F allele burden (%) and changes (reductions) from baseline will be summarised using 
descriptive statistics (n, mean, SD, arithmetic CV (%), median, minimum and maximum) by dose level 
and time point. 
A patient listing of all the relevant molecular examinations data (JAK2V617F allele burden, mRNA 
isolation, gene expression) will be presented by DL (for Part A only) and time point. 
 
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22. BONE MARROW ANALYSIS 
A bone marrow histological evaluation is performed to all patients recruited that provided the specific 
consent in Part B in order to assess the presence of age adjusted normocellularity and/or trilinear 
hyperplasia as requested by the “new” ELN response criteria (i.e. the revised ELN response criteria) [2].  
 
This examination is performed in the local laboratory of each site. The results of this test are 
transcribed into the electronic CRF and the original signed and dated laboratory print-out/tracings, 
including the assessment of the presence of age adjusted normocellularity and/or trilinear hyperplasia, 
is monitored and stored at the study site. 
Notably, in case the patient performs the bone marrow histological evaluation as requested by the 
“new” ELN criteria (i.e. the revised ELN response criteria) [2] – i.e. bone marrow evolution including 
the assessment of the presence of age adjusted normocellularity and/or trilinear hyperplasia - 1 month 
before the study start (i.e. the signature of the “primary” ICF), this examination has not to be repeated 
for this Study in order to limit the discomfort for the patient. In any case, the results of this test are 
transcribed into the electronic CRF and the original signed and dated laboratory print-out/tracings, 
including the assessment of the presence of age adjusted normocellularity and/or trilinear hyperplasia, 
is monitored and stored at the study site. 
 
In case the patient drops-out the Study during the first 3 Cycles (i.e. before the C3D28), this evaluation 
has not to be performed at EOS visit. 
 
Finally, in case the patient refused to provide this written consent to perform the bone marrow 
evaluation, this patient can still be recruited in Part B. However, this patient will not be counted to 
assess the related exploratory endpoints (i.e. overall response rate of Givinostat at the MTD after 6 
cycles according to the revised ELN response criteria [2], and the evaluation of the effect of Givinostat 
on each single response parameter according to the revised ELN response criteria [2]).   
 
The following information will be provided for the bone marrow histological evaluation: 
 Number (n) and percentage (%) of patient with marrow histological evaluation; 
 Number (n) and percentage (%) of presence of age-adjusted normocellularity; 
 Number (n) and percentage (%) of trilinear hyperplasia absence; 
 Number (n) and percentage (%) of grade >1 reticulin fibrosis absence; 
 Listing of reason of not performed evaluation. 
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23. DOSE MODIFICATION ANALYSIS  
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patients to continue the treatment with the study drug. 
The objective of the Givinostat dose adjustment rules is to optimize the response for each individual 
patient, avoiding specific drug-related toxicities. Therefore, dose reductions or interruptions will be 
mandatory for specific toxicities and dose increases after an initial dose reduction will be allowed in 
the case of inadequate efficacy at the reduced dosage in absence of specific toxicities. 
In the Cycle 1 of Part A dose modifications will not be allowed. Patients receiving subsequent cycles of 
treatment in Part A may have up to two dose modifications for drug related DLT’s. 
Each dose modification has to be recorded on the CRF and the severity of the above mentioned events 
will be graded according to NCI Common Terminology Criteria for AE (CTCAE v. 4.03, 14th June 2010).  
 
Reason for treatment discontinuation and number of patients treated beyond protocol-specified 
discontinuation criteria will also be summarised for the safety population. 
 
The following information will be provided for the Dosage Change, by DL (for Part A only) and time 
point: 
• 
Number (n) and percentage (%) of patient with dose temporarily stopped; dose restarted at 
previous dose; dose restarted and actual dose reduced; dose reduced; dose restarted and actual dose 
increased; 
• 
Listing of start/end date, type of dose change, single dose (mg) and reason for 
Change/Interruption. 
The calculation of the compliance, in percentage and collapsed in class (Too low, Adequate, Too high), 
as per Section 15.1 will be capture, for each patient, the deviation from the dose administration plan. 
 
24. OVER-DOSAGE  AND OTHER SITUATIONS PUTTING THE PATIENT AT RISK OF 
ADVERSE REACTION 
In general, a drug overdose in a clinical trial is defined as the accidental or intentional use of a drug or 
medicine in an amount exceeding the protocol defined dose(s). In this Study, if an AE is associated with 
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(“results from”) the overdose of Givinostat, the AE is reported as an SAE, even if no other criteria for 
seriousness is met. 
If a dose of Givinostat meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse 
effect.” Any instance of overdose (suspected or confirmed, with and without an AE) has to be reported 
to the Sponsor within 24 hours and, only in case of AEs, it has to be fully documented as a SAE. Details 
of any signs or symptoms and their management should be recorded in the SAE Form including details 
of any antidote(s) or systematic treatment administered. Any signs or symptoms of over-dosage are 
treated symptomatically.  
Any other situations putting the patient at risk of adverse reaction, such as misuse and abuse, 
medication errors, suspect of transmission of infective agents must be reported to the Sponsor within 
24 hours and must be fully documented as a SAE. 
Listing of patients with overdose reported as a non-serious Even will be provided. 
25. PREGNANCY 
Female patients who have a positive pregnancy test during the pre-treatment evaluations assessment 
are not eligible for Study participation. If a patient becomes pregnant while on Study, the treatment is 
immediately stopped.  
Patients are instructed to notify the Investigator if, after completion of the study, it is determined that 
they became pregnant during the treatment phase or through 3 months after the last dose of study 
drug. 
Whenever possible, a pregnancy with an onset within the above defined time frame is followed until 
termination, any premature termination is reported, and the status of the mother and child is reported 
as well after delivery. 
If the Investigator is made aware that the partner of a male patient who is participating in the Study 
become pregnant, he/she is required to report the pregnancy.  
Whenever possible, such pregnancy is followed until termination, any premature termination is 
reported, and the status of the mother and child is reported as well after delivery. 
 
Listing of pregnant patients will be provided. 
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26. DATA NOT SUMMARISED OR PRESENTED 
These variables and/or domains will not be summarised, but they will be listed: 
• 
Comments, with the expection for ECI (if any); 
• 
Investigator signature page*; 
• 
Participation Status* (i.e. Is the patient continuing to the next visit?). 
*These variables will not be listed, but will be available in the clinical study database. 
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27. REFERENCES  
ICH E9 Statistical Principles of Clinical Trials (CPMP/ICH/363/96) 
 
Study protocol (Study N.: DSC/12/2357/45; EudraCT N.: 2013-000860-27), version 1.0, dated 01st  
March 2013 and amendments (Amendment 1, dated 23rd July 2013, and Amendment 2, dated 29th July 
2015). 
 
1. Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Kiladjian JJ, 
Lengfelder E, McMullin MF, Passamonti F, Reilly JT, Vannucchi AM, Barbui T, Response criteria for 
essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus 
conference, Blood. 2009 May 14; 113(20): 4829-33. 
2. Barosi G., Mesa R., Finazzi G. et al., Revised response criteria for polycythemia vera and essential 
thrombocythemia: a ELN and IWG-MRT consensus project, Blood, 2013 June 6; 121(23): 4778-81. 
3. Le Tourneau C, Lee JJ, Siu LL, Dose Escalation Methods in Phase I Cancer Clinical Trials, JNCI, 2009 
May 20; 101(10): 708–720. 
4. Rubinstein LV and Simon RM, Phase I clinical trial design, In Budman, Calvert, Rowinsky, (eds.), 
Handbook of Anticancer Drug Development, Elsevier, Amsterdam, 297-308, 2003.  
5. Omura GA, Modified Fibonacci Search, J. Clin. Oncol., 2003 August 15; 21(16): 3177 – 3177. 
6. Simon R., Optimal two-stage designs for phase II clinical trials, Controlled Clinical Trials, 1989; 10: 1-
10. 
7. Barosi G, Bordessoule D, Briere J et al., Response criteria for myelofibrosis with myeloid metaplasia: 
results of an initiative of the European Myelofibrosis Network (EUMNET), Blood 2005; 106: 2849-53. 
8. Scherber et al., The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): 
International Prospective Validation and Reliability Trial in 402 patients, Blood, 2011 July 14; 118(2): 
401-408. 
9. Emanuel R.M., Dueck A.C., Geyer H.L. et al.: Myeloproliferative neoplasm (MPN) symptom 
assessment form total symptom score: prospective international assessment of an abbreviated 
symptom burden scoring system among patients with MPNs, JCO November 20, 2012; 30 (33): 4098-
4103. 
 
 
 
 
 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
DATES & TIMES 
 
Depending on data available, dates and times will take the form respectively 
 
 
yyyy-mm-dd or dd-mmm-yyy; 
 
 
hh:mm:ss. 
SPELLING FORMAT 
 
English UK.  
 
PRESENTATION OF TREATMENT DOSE LEVELS 
 
For MTD analysis set, DLs will be represented as follows and in that order: 
 
Givinostat daily dose 
Givinostat dose level (DL) 
DL used primarily 
to asses 
Label for Tables, 
Listings and 
Figures (TLFs) 
100 mg b.i.d. 
DL1 (first three patients) 
MTD, PK, PD 
DL1 
DL1 (additional three patients) 
DL1 expanded 
2 capsules of 50 mg at the 
morning AND 1 capsule of 50 
mg at the evening (1.e. 12 
hours after) 
DL6 
MTD, PK, PD 
DL6 
50 mg b.i.d. 
DL0 
Safety, PK, PD* 
DL0 
 
FOR PRESENTATION OF VISITS 
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For outputs, visits will be represented, if applicable, as follows and in that order: 
 
Study Part  
Visit  
Visit label for Tables, Listings and Figures 
(TLFs)1 
Part A 
Screening Visit 
A - Baseline  
Cycle 1 Day 1 Visit – PRE-DOSE 
A - C1D1 – PRE 
Cycle 1 Day 1 Visit – POST-DOSE 
A - C1D1 - POST 
Cycle 1 Day 2 Visit 
A - C1D2 
Cycle 1 Day 3 Visit 
A - C1D3  
Cycle 1 Day 4 Visit 
A - C1D4 
Cycle 1 Day 8 Visit 
A - C1D8  
Cycle 1 Day 10 Visit 
A - C1D10 
Cycle 1 Day 15 Visit 
A - C1D15 
Cycle 1 Day 22 Visit 
A - C1D22 
Cycle 1 Day 28 Visit 
A - C1D28 
Cycle 2 Day 28 Visit 
A - C2D28 
Cycle 3 Day 28 Visit 
A - C3D28 
Cycle 4 Day 28 Visit 
A - C4D28 
Cycle 5 Day 28 Visit 
A - C5D28 
Cycle 6 Day 28 Visit 
A - C6D28 
End of Study Visit for completers 
patients 
A – EOS  
Unscheduled Visit n. 1 – PRE-DOSE 
A - UNSCHEDULED 1 – PRE* 
Unscheduled Visit n. 2 – PRE-DOSE 
A - UNSCHEDULED 1 – PRE* 
… 
… 
Unscheduled Visit n. N – PRE-DOSE 
A - UNSCHEDULED N – PRE* 
Unscheduled Visit n. 1 – POST- DOSE 
A - UNSCHEDULED 1 – POST*  
Unscheduled Visit n. 2 – POST- DOSE 
A - UNSCHEDULED 2 – POST*  
… 
… 
Unscheduled Visit n. N – POST-DOSE 
A - UNSCHEDULED N – POST* 
Part B 
Screening Visit 
B - Baseline 
Cycle 1 Day 1 Visit – PRE-DOSE 
B - C1D1 – PRE 
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Cycle 1 Day 1 Visit – POST-DOSE 
B - C1D1 – POST 
Cycle 1 Day 28 Visit 
B - C1D28 
Cycle 2 Day 28 Visit 
B - C2D28 
Cycle 3 Day 28 Visit 
B - C3D28 
Cycle 4 Day 28 Visit 
B - C4D28 
Cycle 5 Day 28 Visit 
B - C5D28 
Cycle 6 Day 28 Visit 
B - C6D28 
End of Study Visit 
B - EOS 
Unscheduled Visit n. 1 – PRE-DOSE 
B - UNSCHEDULED 1 – PRE* 
Unscheduled Visit n. 2 – PRE-DOSE 
B - UNSCHEDULED 1 – PRE* 
… 
… 
Unscheduled Visit n. N – PRE-DOSE 
B - UNSCHEDULED N – PRE* 
Unscheduled Visit n. 1 – POST- DOSE 
B - UNSCHEDULED 1 – POST*  
Unscheduled Visit n. 2 – POST- DOSE 
B - UNSCHEDULED 2 – POST*  
… 
… 
Unscheduled Visit n. N – POST-DOSE 
B - UNSCHEDULED N – POST* 
1 In all cases, the day of the visit should be reported.* To be ordered on the basis of the date of the 
visit. 
 
 
*Drop-out visit refers to patients who prematurely discontinued the treatment showing data 
recorded during their last assessment visit. 
 
SCREENING FAILURES 
 
Patients who sign an ICF but who do not start Study treatment for any reason, will be considered as 
“Screening Failures”.  
For screening failure patients, a separate Table will be produced including the primary reason for 
screen failure and patient’s demographic information as per electronic CRF.  
 
LISTINGS 
 
PPD
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Document:
Author: 
Version Number:
V2.2 
 
Version Date:
21 March 2018 
Template No:  CS_TP_BS016 – Revision 3 
Reference:  CS_WI_BS005 
Effective Date: 01May2012 
 
Copyright © 2012 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Italfarmaco S.p.A. 
STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 97 of 101 
All listings will be ordered by the following: 
• 
Part A  
- 
DL group; 
- 
Patient ID; 
- 
Date (where applicable). 
• 
Part B  
Patient ID; 
- 
Date (where applicable). 
 
 
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Document:
Author: 
Version Number:
V2.2 
 
Version Date:
21 March 2018 
Template No:  CS_TP_BS016 – Revision 3 
Reference:  CS_WI_BS005 
Effective Date: 01May2012 
 
Copyright © 2012 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Italfarmaco S.p.A. 
STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 98 of 101 
TEXT CASE 
• 
For titles and column labels, capitalize important words, i.e. nouns, pronouns, verbs, adverbs 
and adjectives but not articles, conjunctions or prepositions. 
• 
All Footnotes will be in sentence case format. 
• 
All symbols used in body of outputs will be footnoted. 
• 
Continuous Variables: 
- 
Number (“n”), 
- 
Mean,  
- 
Standard Deviation (“SD”),  
- 
Median,  
- 
Minimum (“min”),  
- 
Maximum (“max”) 
will be presented for all variables on the original scale. 
 
• 
Categorical Variables: 
- 
Number (“n”),  
- 
Percentage (%)  
in each category will be the default summary presentation. 
•  The percentage of patients in each category relative to the total number of patients in the relevant 
analysis population will be the default. Percentages relative to the total number of patients in the 
relevant analysis population with a non-missing assessment will be specified in a programming note on 
the shell if required. 
•  Where percentages are presented, a footnote will be added to explain what the denominator of the 
percentage is, in the form “Percentages are calculated relative to the total number of patients in the 
SAF” as the first footnote. 
• All computed percentages will be presented using one decimal place except for where the 
percentage is 100 where no decimal places are presented. 
• The percentage will be also presented if the count is zero. 
 
 
 
 
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Document:
Author: 
Version Number:
V2.2 
 
Version Date:
21 March 2018 
Template No:  CS_TP_BS016 – Revision 3 
Reference:  CS_WI_BS005 
Effective Date: 01May2012 
 
Copyright © 2012 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Italfarmaco S.p.A. 
STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 99 of 101 
 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, 
but 
known 
components show that it 
cannot be on or after 
study med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start 
date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
PPD
PPD


 
Document:
Author: 
Version Number:
V2.2 
 
Version Date:
21 March 2018 
Template No:  CS_TP_BS016 – Revision 3 
Reference:  CS_WI_BS005 
Effective Date: 01May2012 
 
Copyright © 2012 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Italfarmaco S.p.A. 
STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 100 of 101 
START DATE 
STOP DATE 
ACTION 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
ALGORITHM FOR PRIOR/CONCOMITANT MEDICATIONS AND 
PRIOR/CONCOMITANT NON-DRUG THERAPIES: 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant  
If stop date >= study med start date and start date > end of 
treatment, assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
PPD
PPD


 
Document
Author: 
Version Number:
V2.2 
 
Version Date:
21 March 2018 
Template No:  CS_TP_BS016 – Revision 3 
Reference:  CS_WI_BS005 
Effective Date: 01May2012 
 
Copyright © 2012 Quintiles Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Italfarmaco S.p.A. 
STATISTICAL ANALYSIS PLAN: Study N.: DSC/12/2357/45 
Page 101 of 101 
START DATE 
STOP DATE 
ACTION 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown) and 
impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 
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