A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera

A Two-part Study Top Assess the Safety and Preliminary Efficacy of Givinostat in Patients With JAK2V617F Positive Polycythemia Vera

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01901432

Enrollment

Registered

2013-07-17

Start date

2013-10-31

Completion date

2017-09-25

Last updated

2019-07-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Polycythemia Vera

Keywords

chronic myeloproliferative neoplasms, Polycythemia Vera, Essential Thrombocythemia, Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis, Givinostat

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.

Interventions

DRUGGivinostat

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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 Polycythemia Vera according to the revised World Health Organization criteria; 4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease; 5. Patients must have an active/not controlled disease defined as 1. hematocrit ≥ 45% or hematocrit \<45% in need of phlebotomy, and 2. platelet count \> 400 x109/L, and 3. white blood cell count \> 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; 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 chronic myeloproliferative neoplasms. 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: 1. Essential Thrombocythemia patients: Platelet count \> 600 x109/L; 2. Myelofibrosis patients: no response according to European Myelofibrosis Network criteria.

Exclusion criteria

1. Active bacterial or mycotic infection requiring antimicrobial treatment; 2. Pregnancy or nursing; 3. A clinically significant corrected QT interval prolongation at baseline; 4. Use of concomitant medications known to prolong the corrected QT interval; 5. Clinically significant cardiovascular disease including: 1. Uncontrolled hypertension despite medical treatment, myocardial infarction, unstable angina within 6 months from study start; 2. New York Heart Association Grade II or greater congestive heart failure; 3. History of any cardiac arrhythmia requiring medication (irrespective of its severity); 4. A history of additional risk factors for torsade de pointes; 6. Known positivity for human immunodeficiency; 7. Known active hepatitis B virus and/or hepatitis C virus infection; 8. Platelet count \< 100 x109/L within 14 days before enrolment; 9. Absolute neutrophil count \< 1.2x109/L within 14 days before enrolment; 10. Serum creatinine \> 2 times the upper limit of normal; 11. Total serum bilirubin \> 1.5 times the upper limit of normal except in case of Gilbert's disease; 12. Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) \> 3 times the upper limit of normal; 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 Janus Kinase 2 or Histone Deacetylase inhibitor or participation in an interventional clinical trial for chronic myeloproliferative neoplasms; 15. Systemic treatment for chronic myeloproliferative neoplasms other than aspirin/cardio aspirin; 16. Hydroxyurea within 28 days before enrolment; 17. Interferon alpha within 14 days before enrolment; 18. Anagrelide within 7 days before enrolment; 19. Any other investigational drug or device within 28 days before enrolment; 20. Patient with known hypersensitivity to the components of study therapy.

Design outcomes

Primary

Measure	Time frame	Description
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	168 days (up to Cycle 6 Day 28 in Part A).	Evaluations were performed on the type, incidence and severity of TEAEs, graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03, following administration of givinostat for up to 6 cycles of treatment in Part A. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / treatment-emergent serious adverse event (TESAE) corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.
Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study	28 days (up to Cycle 1 Day 28 in Part A).	The MTD of givinostat was based only on Cycle 1 DLTs. A DLT was defined as the following drug-related toxicity: * Grade 4 hematological toxicity, or * Grade 3 febrile neutropenia, or * Grade ≥3 non-hematological toxicity (with the exception Grade 3 diarrhea without adequate supportive care lasting less than 3 days, and Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days), or * Any drug-related serious AE, or * Any toxicity clearly not related to disease progression or intercurrent illness requiring interruption of dosing for more than 3 days during first cycle. At end of Cycle 1, for the third patient in each DL, the safety of the 3 patients treated for 1 cycle was reviewed and it was decided if the dose should be escalated or not. Results are reported as the number of patients with DLT events for Cycle 1 in Part A.
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	84 days (up to Cycle 3 Day 28 in Part B).	Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 3 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.
Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study	84 days (up to cycle 3 Day 28 in Part B).	ORR, CR and PR following administration of givinostat at MTD for 3 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological European LeukemiaNet (ELN) response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. CR defined as: 1. Hematocrit (HCT) \<45% without phlebotomy, and 2. Platelets ≤400 x10\^9/litre (L), and 3. White Blood Cell count ≤10 x10\^9/L, and 4. Normal spleen size, and 5. No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances). PR defined as: Patients not fulfilling CR and 1. HCT \<45% without phlebotomy, or 2. Response in ≥3 other criteria.

Secondary

Measure	Time frame	Description
Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.
Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.
Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.
Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUC0-12 was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note:concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) across all dose groups and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.
ORR After 3 Cycles and After 6 Cycles in Part A of the Study	84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).	ORR following administration of givinostat after 3 cycles and after 6 cycles in Part A, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed using the dataset for all Part A patients combined.
Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.
Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.
Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.
Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2374 (Cycle 1 Day 28) across all dose groups and for ITF2375 in the 50 mg b.i.d. dose group was not available for PK analysis.
Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.
ORR After 6 Cycles in Part B of the Study	168 days (up to Cycle 6 Day 28 in Part B).	ORR following administration of givinostat at the MTD for 6 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis.
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	168 days (up to Cycle 6 Day 28 in Part B).	Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 6 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Results are reported as number of patients with TEAEs for each of the indicated categories.
Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.	Pharmacokinetic (PK) evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Countries

France, Germany, Italy, Poland, United Kingdom

Participant flow

Recruitment details

This was a 2-part, multisite, open-label, non-randomized study to assess givinostat in patients with JAK2\^V617F positive Polycythemia Vera. Part A assessed safety and was the dose escalation portion of study, while Part B assessed preliminary efficacy. Patients were enrolled in 5 countries (France, Germany, Italy, Poland and the United Kingdom).

Pre-assignment details

Patients were enrolled into either Part A or Part B, transition from 1 part to the other was not allowed. 48 patients were enrolled into the study overall: 12 patients in Part A to determine the maximum tolerated dose (MTD) and 36 patients in Part B.

Participants by arm

Arm	Count
Givinostat DL0 (50 mg b.i.d.) (Part A) In Part A, 3 patients were assigned to receive givinostat by oral administration at DL0 (50 mg twice daily \[b.i.d.\]). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 50 mg b.i.d. (DL0) was the third DL to be administered.	3
Givinostat DL1 (100 mg b.i.d.) (Part A) In Part A, 3 patients were assigned to receive givinostat by oral administration at DL1 (100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.	3
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A) Following initial assignment of 3 patients to DL1 in Part A, a further 3 patients were assigned to DL1 so this treatment group is referred to as DL1 expanded (patients received givinostat by oral administration at 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). There were 3 DLs used during Part A; 100 mg b.i.d. (DL1) was the initial DL to be administered.	3
Givinostat DL6 (100 mg + 50 mg) (Part A) In Part A, 3 patients were assigned to receive givinostat by oral administration at DL6 (100 mg in the morning and 50 mg in the evening, i.e. 12 hours after). Patients were treated for up to 6 cycles in (28 days in each cycle). There were 3 DLs used during Part A; 100 mg + 50 mg (DL6) was the second DL to be administered.	3
Givinostat at MTD (100 mg b.i.d.) (Part B) In Part B, patients were assigned to receive the starting dose of givinostat by oral administration at the MTD determined in Part A (i.e. 100 mg b.i.d.). Patients were treated for up to 6 cycles (28 days in each cycle). Based on evaluations performed as part of the visit procedures on Day 28 of each cycle up to Cycle 5 and/or in any necessary additional study visit, the givinostat dose was decreased if appropriate for any patients that met dose reduction criteria.	36
Total Title	48
Total	96

Withdrawals & dropouts

Period	Reason	FG001	FG002	FG004
Overall Study	Adverse Event	1	1	1
Overall Study	Patient decision to stop study drug	0	0	1
Overall Study	Physician Decision	0	0	2
Overall Study	Withdrawal by Subject	0	1	5

Baseline characteristics

Characteristic	Givinostat DL0 (50 mg b.i.d.) (Part A)	Givinostat DL1 (100 mg b.i.d.) (Part A)	Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Givinostat DL6 (100 mg + 50 mg) (Part A)	Givinostat at MTD (100 mg b.i.d.) (Part B)	Total Title
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	1 Participants	2 Participants	1 Participants	8 Participants	13 Participants
Age, Categorical Between 18 and 65 years	2 Participants	2 Participants	1 Participants	2 Participants	28 Participants	35 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	3 Participants	3 Participants	3 Participants	36 Participants	48 Participants
Sex: Female, Male Female	2 Participants	1 Participants	1 Participants	1 Participants	11 Participants	16 Participants
Sex: Female, Male Male	1 Participants	2 Participants	2 Participants	2 Participants	25 Participants	32 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 3	0 / 3	0 / 3	0 / 3	0 / 35
other Total, other adverse events	3 / 3	3 / 3	3 / 3	3 / 3	35 / 35
serious Total, serious adverse events	0 / 3	1 / 3	0 / 3	1 / 3	2 / 35

Outcome results

Primary

Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study

The MTD of givinostat was based only on Cycle 1 DLTs. A DLT was defined as the following drug-related toxicity: * Grade 4 hematological toxicity, or * Grade 3 febrile neutropenia, or * Grade ≥3 non-hematological toxicity (with the exception Grade 3 diarrhea without adequate supportive care lasting less than 3 days, and Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days), or * Any drug-related serious AE, or * Any toxicity clearly not related to disease progression or intercurrent illness requiring interruption of dosing for more than 3 days during first cycle. At end of Cycle 1, for the third patient in each DL, the safety of the 3 patients treated for 1 cycle was reviewed and it was decided if the dose should be escalated or not. Results are reported as the number of patients with DLT events for Cycle 1 in Part A.

Time frame: 28 days (up to Cycle 1 Day 28 in Part A).

Population: The MTD analysis set included all patients who experienced a DLT in Cycle 1 of Part A, or received ≥90% of study drug doses in Cycle 1 of Part A.

Arm	Measure	Value (NUMBER)
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study	0 participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study	1 participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study	0 participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study	0 participants

Primary

Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study

Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 3 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

Time frame: 84 days (up to Cycle 3 Day 28 in Part B).

Population: The SAF analysis set included all recruited patients who received ≥1 dose of study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	TEAE	35 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Drug-related TEAE	33 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	TESAE	2 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Drug-related TESAE	1 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Death due to any cause	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Grade 3 TEAE	10 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Grade 3 drug-related TEAE	7 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Grade 4 TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Grade 4 drug-related TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Grade 5 TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Discontinuation due to TEAE	2 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Discontinuation due to drug-related TEAE	2 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Discontinuation due to TESAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study	Discontinuation due to drug-related TESAE	0 Participants

Primary

Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study

Evaluations were performed on the type, incidence and severity of TEAEs, graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03, following administration of givinostat for up to 6 cycles of treatment in Part A. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / treatment-emergent serious adverse event (TESAE) corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

Time frame: 168 days (up to Cycle 6 Day 28 in Part A).

Population: The Safety (SAF) analysis set included all recruited patients who received ≥1 dose of study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TESAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 drug-related TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TESAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 5 TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TEAE	3 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TESAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TEAE	1 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TESAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Death due to any cause	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TEAE	0 Participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 drug-related TEAE	0 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TEAE	1 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TEAE	1 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TESAE	0 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 TEAE	0 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 drug-related TEAE	2 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 TEAE	2 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 drug-related TEAE	0 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TEAE	3 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 5 TEAE	0 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Death due to any cause	0 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TESAE	1 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TEAE	3 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TESAE	0 Participants
Givinostat DL1 (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TESAE	0 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 drug-related TEAE	1 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TEAE	3 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TEAE	3 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TESAE	0 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 TEAE	1 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TESAE	0 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Death due to any cause	0 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 TEAE	1 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 drug-related TEAE	1 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 5 TEAE	0 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TEAE	1 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TEAE	1 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TESAE	0 Participants
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TESAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TEAE	1 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TEAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 TEAE	1 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Death due to any cause	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TEAE	3 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TEAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Drug-related TESAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	TESAE	1 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to drug-related TESAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Discontinuation due to TESAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 drug-related TEAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 5 TEAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 4 TEAE	0 Participants
Givinostat DL6 (100 mg + 50 mg) (Part A)	Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study	Grade 3 drug-related TEAE	0 Participants

Primary

Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study

ORR, CR and PR following administration of givinostat at MTD for 3 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological European LeukemiaNet (ELN) response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. CR defined as: 1. Hematocrit (HCT) \<45% without phlebotomy, and 2. Platelets ≤400 x10\^9/litre (L), and 3. White Blood Cell count ≤10 x10\^9/L, and 4. Normal spleen size, and 5. No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances). PR defined as: Patients not fulfilling CR and 1. HCT \<45% without phlebotomy, or 2. Response in ≥3 other criteria.

Time frame: 84 days (up to cycle 3 Day 28 in Part B).

Population: The Intent-to-Treat (ITT) analysis set included all recruited patients who received ≥1 dose of study drug and from whom ≥1 post-baseline efficacy measurement was obtained.

Arm	Measure	Group	Value (NUMBER)
Givinostat DL0 (50 mg b.i.d.) (Part A)	Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study	ORR (CR + PR)	80.6 percentage of participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study	CR	9.7 percentage of participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study	PR	71.0 percentage of participants

Secondary

Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUC0-12 was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note:concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) across all dose groups and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Time frame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	235 ng*h/mL	Standard Deviation 146
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	161 ng*h/mL	Standard Deviation 51.8
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	863 ng*h/mL	—
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	2020 ng*h/mL	Standard Deviation 1000
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	533 ng*h/mL	Standard Deviation 223
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	289 ng*h/mL	Standard Deviation 68.9
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	598 ng*h/mL	Standard Deviation 259
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	508 ng*h/mL	Standard Deviation 107
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	870 ng*h/mL	Standard Deviation 182
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	1180 ng*h/mL	Standard Deviation 1050
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	2340 ng*h/mL	Standard Deviation 970

Secondary

Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Time frame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	263 ng*h/mL	Standard Deviation 192
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	132 ng*h/mL	Standard Deviation 45.1
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	208 ng*h/mL	Standard Deviation 136
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	14.4 ng*h/mL	Standard Deviation 19
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	238 ng*h/mL	Standard Deviation 55.6
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	416 ng*h/mL	Standard Deviation 153
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	359 ng*h/mL	Standard Deviation 203
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	102 ng*h/mL	Standard Deviation 11.7
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	1390 ng*h/mL	Standard Deviation 675
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	1100 ng*h/mL	Standard Deviation 1050
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	1780 ng*h/mL	Standard Deviation 1190
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	158 ng*h/mL	Standard Deviation 42.6
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	611 ng*h/mL	Standard Deviation 146
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	29.6 ng*h/mL	Standard Deviation 9.64
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	429 ng*h/mL	Standard Deviation 109

Secondary

Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2374 (Cycle 1 Day 28) across all dose groups and for ITF2375 in the 50 mg b.i.d. dose group was not available for PK analysis.

Time frame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	2460 ng*h/mL	Standard Deviation 2450
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 1 Day 1	1080 ng*h/mL	Standard Deviation 619
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	561 ng*h/mL	Standard Deviation 176
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 1 Day 1	372 ng*h/mL	Standard Deviation 137
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	410 ng*h/mL	Standard Deviation 129
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	1460 ng*h/mL	Standard Deviation 608
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	326 ng*h/mL	Standard Deviation 54

Secondary

Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Time frame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	216 ng*h/mL	Standard Deviation 127
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 1 Day 1	888 ng*h/mL	Standard Deviation 439
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	1830 ng*h/mL	Standard Deviation 1660
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	459 ng*h/mL	Standard Deviation 145
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 1 Day 1	28.5 ng*h/mL	Standard Deviation 14
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 1 Day 1	289 ng*h/mL	Standard Deviation 130
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	1210 ng*h/mL	Standard Deviation 585
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	323 ng*h/mL	Standard Deviation 107
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	161 ng*h/mL	Standard Deviation 83.5
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	145 ng*h/mL	Standard Deviation 20.9
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	269 ng*h/mL	Standard Deviation 78.5

Secondary

Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Time frame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	32.3 ng/mL	Standard Deviation 21
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 1 Day 1	161 ng/mL	Standard Deviation 72.9
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	320 ng/mL	Standard Deviation 238
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	90.8 ng/mL	Standard Deviation 33.5
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 1 Day 1	7.85 ng/mL	Standard Deviation 4.89
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 1 Day 1	71.5 ng/mL	Standard Deviation 34.4
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	203 ng/mL	Standard Deviation 78.7
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	64.0 ng/mL	Standard Deviation 22.6
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	22.6 ng/mL	Standard Deviation 11.2
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	21.4 ng/mL	Standard Deviation 0.424
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	62.6 ng/mL	Standard Deviation 21.8

Secondary

Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Pharmacokinetic (PK) evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Time frame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	60.2 nanograms per millilitre (ng/mL)	Standard Deviation 43.1
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	22.4 nanograms per millilitre (ng/mL)	Standard Deviation 8.92
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	110 nanograms per millilitre (ng/mL)	Standard Deviation 22.8
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	68.6 nanograms per millilitre (ng/mL)	Standard Deviation 21.2
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	19.7 nanograms per millilitre (ng/mL)	Standard Deviation 7.24
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	259 nanograms per millilitre (ng/mL)	Standard Deviation 75.9
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	73.3 nanograms per millilitre (ng/mL)	Standard Deviation 31.9
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	54.3 nanograms per millilitre (ng/mL)	Standard Deviation 17.2
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	3.74 nanograms per millilitre (ng/mL)	Standard Deviation 4.09
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	82.5 nanograms per millilitre (ng/mL)	Standard Deviation 24.4
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	5.69 nanograms per millilitre (ng/mL)	Standard Deviation 2.87
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	101 nanograms per millilitre (ng/mL)	Standard Deviation 24.5
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	290 nanograms per millilitre (ng/mL)	Standard Deviation 330
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	31.3 nanograms per millilitre (ng/mL)	Standard Deviation 4.95
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	376 nanograms per millilitre (ng/mL)	Standard Deviation 215

Secondary

Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Time frame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	7.97 hours	Standard Deviation 0.0462
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	8.05 hours	Standard Deviation 0.249
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	3.00 hours	Standard Deviation 1.41
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	8.00 hours	Standard Deviation 0
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	7.00 hours	Standard Deviation 2.01
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	7.00 hours	Standard Deviation 2.01
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	7.00 hours	Standard Deviation 2.01
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	8.00 hours	Standard Deviation 0
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	8.00 hours	Standard Deviation 0
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	8.00 hours	Standard Deviation 0
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	8.00 hours	Standard Deviation 0
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	8.00 hours	Standard Deviation 0
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	8.02 hours	Standard Deviation 0.0252
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	8.02 hours	Standard Deviation 0.0252
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	6.70 hours	Standard Deviation 2.3

Secondary

Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28. Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis.

Time frame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEDIAN)
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	2.00 hours
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	3.90 hours
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	2.00 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	3.00 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	8.00 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	1.99 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	1.50 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	2.00 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	8.00 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 1	3.00 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 1	8.00 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 1	2.50 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	Givinostat Cycle 1 Day 28	2.05 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2374 Cycle 1 Day 28	2.00 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study	ITF2375 Cycle 1 Day 28	4.00 hours

Secondary

Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Time frame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEAN)	Dispersion
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	8.00 hours	Standard Deviation 0.034
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 1 Day 1	8.00 hours	Standard Deviation 0.0505
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	7.75 hours	Standard Deviation 1
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	8.00 hours	Standard Deviation 0.034
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 1 Day 1	7.42 hours	Standard Deviation 1.61
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 1 Day 1	7.42 hours	Standard Deviation 1.61
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	8.00 hours	Standard Deviation 0
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	7.98 hours	Standard Deviation 0.0753
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	7.98 hours	Standard Deviation 0.0753
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	7.99 hours	Standard Deviation 0.0212
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	7.99 hours	Standard Deviation 0.0212

Secondary

Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B. Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis.

Time frame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.

Population: The PK analysis set included all SAF patients with at least 1 PK assessment. Only patients with data available for analysis at each time point are presented.

Arm	Measure	Group	Value (MEDIAN)
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	4.00 hours
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 1 Day 1	3.00 hours
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	2.00 hours
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	2.00 hours
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 1 Day 1	8.00 hours
Givinostat DL0 (50 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 1 Day 1	2.00 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2375 Cycle 2 Day 28	2.00 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	2.00 hours
Givinostat DL1 (100 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	3.04 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	ITF2374 Cycle 2 Day 28	5.99 hours
Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)	Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study	Givinostat Cycle 2 Day 28	0.985 hours

Secondary

Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study

Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 6 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Results are reported as number of patients with TEAEs for each of the indicated categories.

Time frame: 168 days (up to Cycle 6 Day 28 in Part B).

Population: The SAF analysis set included all recruited patients who received ≥1 dose of study drug.

Arm	Measure	Group	Value (NUMBER)
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	TEAE	35 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Drug-related TEAE	33 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	TESAE	2 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Drug-related TESAE	1 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Death due to any cause	0 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Grade 3 TEAE	12 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Grade 3 drug-related TEAE	10 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Grade 4 TEAE	0 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Grade 4 drug-related TEAE	0 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Grade 5 TEAE	0 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Discontinuation due to TEAE	2 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Discontinuation due to drug-related TEAE	2 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Discontinuation due to TESAE	0 participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study	Discontinuation due to drug-related TESAE	0 participants

Secondary

ORR After 3 Cycles and After 6 Cycles in Part A of the Study

ORR following administration of givinostat after 3 cycles and after 6 cycles in Part A, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed using the dataset for all Part A patients combined.

Time frame: 84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).

Population: The ITT analysis set included all recruited patients who received ≥1 dose of study drug and from whom ≥1 post-baseline efficacy measurement was obtained.

Arm	Measure	Group	Value (NUMBER)
Givinostat DL0 (50 mg b.i.d.) (Part A)	ORR After 3 Cycles and After 6 Cycles in Part A of the Study	Cycle 3 Day 28	72.7 percentage of participants
Givinostat DL0 (50 mg b.i.d.) (Part A)	ORR After 3 Cycles and After 6 Cycles in Part A of the Study	Cycle 6 Day 28	72.7 percentage of participants

Secondary

ORR After 6 Cycles in Part B of the Study

ORR following administration of givinostat at the MTD for 6 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis.

Time frame: 168 days (up to Cycle 6 Day 28 in Part B).

Population: The ITT analysis set included all recruited patients who received ≥1 dose of study drug and from whom ≥1 post-baseline efficacy measurement was obtained.

Arm	Measure	Value (NUMBER)
Givinostat DL0 (50 mg b.i.d.) (Part A)	ORR After 6 Cycles in Part B of the Study	80.6 percentage of participants

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera

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Study design

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Secondary

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Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study

Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study

Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study

Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study

Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study

Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study

ORR After 3 Cycles and After 6 Cycles in Part A of the Study

ORR After 6 Cycles in Part B of the Study