Trial Outcomes & Findings for A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera (NCT NCT01901432)

NCT ID: NCT01901432

Last Updated: 2019-07-30

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 48 participants
• Primary outcome timeframe: 168 days (up to Cycle 6 Day 28 in Part A).
• Results posted on: 2019-07-30

Participant Flow

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).

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.

Participant milestones

Measure	Givinostat DL0 (50 mg b.i.d.) (Part A) In Part A, 3 patients were assigned to receive givinostat by oral administration at Dose Level 0 (DL0) (50 milligrams \[mg\] 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.	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.	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.	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.	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.
Overall Study STARTED	3	3	3	3	36
Overall Study Received Study Drug	3	3	3	3	35
Overall Study COMPLETED	3	2	1	3	27
Overall Study NOT COMPLETED	0	1	2	0	9

Reasons for withdrawal

Measure	Givinostat DL0 (50 mg b.i.d.) (Part A) In Part A, 3 patients were assigned to receive givinostat by oral administration at Dose Level 0 (DL0) (50 milligrams \[mg\] 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.	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.	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.	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.	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.
Overall Study Adverse Event	0	1	1	0	1
Overall Study Withdrawal by Subject	0	0	1	0	5
Overall Study Physician Decision	0	0	0	0	2
Overall Study Patient decision to stop study drug	0	0	0	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Givinostat DL0 (50 mg b.i.d.) (Part A) n=3 Participants 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.	Givinostat DL1 (100 mg b.i.d.) (Part A) n=3 Participants 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.	Givinostat DL1 Expanded (100 mg b.i.d.) (Part A) n=3 Participants 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.	Givinostat DL6 (100 mg + 50 mg) (Part A) n=3 Participants 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.	Givinostat at MTD (100 mg b.i.d.) (Part B) n=36 Participants 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.	Total Title n=48 Participants
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	28 Participants n=21 Participants	35 Participants n=8 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	8 Participants n=21 Participants	13 Participants n=8 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	11 Participants n=21 Participants	16 Participants n=8 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	25 Participants n=21 Participants	32 Participants n=8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	36 Participants n=21 Participants	48 Participants n=8 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	Givinostat DL6 (100 mg + 50 mg) (Part A) n=3 Participants 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.
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study TEAE	3 Participants	3 Participants	3 Participants	3 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Drug-related TEAE	3 Participants	3 Participants	1 Participants	1 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study TESAE	1 Participants	0 Participants	0 Participants	1 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Drug-related TESAE	0 Participants	0 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Death due to any cause	0 Participants	0 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Grade 3 TEAE	2 Participants	1 Participants	0 Participants	1 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Grade 3 drug-related TEAE	2 Participants	1 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Grade 4 TEAE	0 Participants	1 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Grade 4 drug-related TEAE	0 Participants	1 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Grade 5 TEAE	0 Participants	0 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Discontinuation due to TEAE	1 Participants	1 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Discontinuation due to drug-related TEAE	1 Participants	1 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Discontinuation due to TESAE	0 Participants	0 Participants	0 Participants	0 Participants
Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study Discontinuation due to drug-related TESAE	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	Givinostat DL6 (100 mg + 50 mg) (Part A) n=3 Participants 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.
Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study	1 participants	0 participants	0 participants	0 participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=35 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study TEAE	—	—	35 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Drug-related TEAE	—	—	33 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study TESAE	—	—	2 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Drug-related TESAE	—	—	1 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Death due to any cause	—	—	0 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Grade 3 TEAE	—	—	10 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Grade 3 drug-related TEAE	—	—	7 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Grade 4 TEAE	—	—	0 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Grade 4 drug-related TEAE	—	—	0 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Grade 5 TEAE	—	—	0 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Discontinuation due to TEAE	—	—	2 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Discontinuation due to drug-related TEAE	—	—	2 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Discontinuation due to TESAE	—	—	0 Participants	—
Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study Discontinuation due to drug-related TESAE	—	—	0 Participants	—

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=31 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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 Interval 62.53 to 92.55	—
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 Interval 2.04 to 25.75	—
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 Interval 51.96 to 85.78	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=11 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
ORR After 3 Cycles and After 6 Cycles in Part A of the Study Cycle 3 Day 28	—	—	72.7 percentage of participants Interval 39.03 to 93.98	—
ORR After 3 Cycles and After 6 Cycles in Part A of the Study Cycle 6 Day 28	—	—	72.7 percentage of participants Interval 39.03 to 93.98	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=31 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
ORR After 6 Cycles in Part B of the Study	—	—	80.6 percentage of participants Interval 62.53 to 92.55	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=35 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study TEAE	—	—	35 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Drug-related TEAE	—	—	33 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study TESAE	—	—	2 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Drug-related TESAE	—	—	1 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Death due to any cause	—	—	0 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Grade 3 TEAE	—	—	12 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Grade 3 drug-related TEAE	—	—	10 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Grade 4 TEAE	—	—	0 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Grade 4 drug-related TEAE	—	—	0 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Grade 5 TEAE	—	—	0 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Discontinuation due to TEAE	—	—	2 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Discontinuation due to drug-related TEAE	—	—	2 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Discontinuation due to TESAE	—	—	0 participants	—
Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study Discontinuation due to drug-related TESAE	—	—	0 participants	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=6 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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	82.5 nanograms per millilitre (ng/mL) Standard Deviation 24.4	60.2 nanograms per millilitre (ng/mL) Standard Deviation 43.1	—
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	5.69 nanograms per millilitre (ng/mL) Standard Deviation 2.87	—	—
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	101 nanograms per millilitre (ng/mL) Standard Deviation 24.5	—	—
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	290 nanograms per millilitre (ng/mL) Standard Deviation 330	22.4 nanograms per millilitre (ng/mL) Standard Deviation 8.92	—
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	31.3 nanograms per millilitre (ng/mL) Standard Deviation 4.95	—	—
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	376 nanograms per millilitre (ng/mL) Standard Deviation 215	110 nanograms per millilitre (ng/mL) Standard Deviation 22.8	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=6 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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 Interval 2.0 to 2.0	3.00 hours Interval 2.0 to 3.0	2.00 hours Interval 1.92 to 3.0	—
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 Interval 8.0 to 8.0	8.00 hours Interval 3.0 to 8.0	—	—
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 Interval 2.0 to 3.0	2.50 hours Interval 2.0 to 3.0	—	—
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 Interval 1.0 to 3.98	2.05 hours Interval 1.05 to 4.0	3.90 hours Interval 3.83 to 4.0	—
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 Interval 0.0 to 8.0	2.00 hours Interval 1.05 to 4.05	—	—
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 Interval 1.0 to 3.98	4.00 hours Interval 0.0 to 4.05	2.00 hours Interval 2.0 to 2.0	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=6 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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 0.00	8.00 hours Standard Deviation 0.00	7.97 hours Standard Deviation 0.0462	—
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 0.00	8.00 hours Standard Deviation 0.00	—	—
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 0.00	8.00 hours Standard Deviation 0.00	—	—
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	8.02 hours Standard Deviation 0.0252	8.05 hours Standard Deviation 0.249	—
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	8.02 hours Standard Deviation 0.0252	—	—
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	6.70 hours Standard Deviation 2.30	3.00 hours Standard Deviation 1.41	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=6 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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	429 ng*h/mL Standard Deviation 109	208 ng*h/mL Standard Deviation 136	—
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 19.0	29.6 ng*h/mL Standard Deviation 9.64	—	—
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	611 ng*h/mL Standard Deviation 146	—	—
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	1100 ng*h/mL Standard Deviation 1050	132 ng*h/mL Standard Deviation 45.1	—
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	158 ng*h/mL Standard Deviation 42.6	—	—
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	1780 ng*h/mL Standard Deviation 1190	263 ng*h/mL Standard Deviation 192	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=6 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=3 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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	2340 ng*h/mL Standard Deviation 970	863 ng*h/mL Standard Deviation NA NA=Not available. Only 1 patient analyzed for this parameter so standard deviation value is not applicable.	—
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	508 ng*h/mL Standard Deviation 107	235 ng*h/mL Standard Deviation 146	—
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	870 ng*h/mL Standard Deviation 182	—	—
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	1180 ng*h/mL Standard Deviation 1050	161 ng*h/mL Standard Deviation 51.8	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=12 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=2 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=34 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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	—
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	—
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	—
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	62.6 ng/mL Standard Deviation 21.8	90.8 ng/mL Standard Deviation 33.5	—
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	21.4 ng/mL Standard Deviation 0.424	32.3 ng/mL Standard Deviation 21.0	—
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	—	320 ng/mL Standard Deviation 238	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=12 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=2 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=34 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study Givinostat Cycle 1 Day 1	—	—	2.00 hours Interval 0.0 to 8.0	—
Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study ITF2374 Cycle 1 Day 1	—	—	8.00 hours Interval 2.08 to 8.17	—
Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study ITF2375 Cycle 1 Day 1	—	—	3.00 hours Interval 1.83 to 8.0	—
Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study Givinostat Cycle 2 Day 28	2.00 hours Interval 1.0 to 8.0	0.985 hours Interval 0.0 to 1.97	2.00 hours Interval 0.0 to 4.07	—
Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study ITF2374 Cycle 2 Day 28	3.04 hours Interval 1.0 to 8.0	5.99 hours Interval 3.97 to 8.0	4.00 hours Interval 0.0 to 8.0	—
Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study ITF2375 Cycle 2 Day 28	2.00 hours Interval 1.0 to 8.0	—	2.00 hours Interval 0.0 to 4.0	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=12 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=2 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=34 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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	—
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	—
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	—
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	7.99 hours Standard Deviation 0.0212	8.00 hours Standard Deviation 0.0340	—
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	7.99 hours Standard Deviation 0.0212	8.00 hours Standard Deviation 0.0340	—
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 0.00	—	7.75 hours Standard Deviation 1.00	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=12 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=2 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=34 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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	—
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 14.0	—
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	—
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	269 ng*h/mL Standard Deviation 78.5	459 ng*h/mL Standard Deviation 145	—
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	145 ng*h/mL Standard Deviation 20.9	216 ng*h/mL Standard Deviation 127	—
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	—	1830 ng*h/mL Standard Deviation 1660	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Givinostat 75 mg b.i.d. (Part B PK Analysis Set) n=12 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 75 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 50 mg b.i.d. (Part B PK Analysis Set) n=2 Participants This dataset was used for PK analysis and included patients who received givinostat at the reduced dose of 50 mg b.i.d. in Part B of the study and for whom PK data was available for analysis. This dataset only applied for PK analysis from Cycle 2 onwards (i.e. Cycle 2 Day 28).	Givinostat 100 mg b.i.d. (Part B PK Analysis Set) n=34 Participants This dataset was used for PK analysis and included patients who received givinostat at the MTD (100 mg b.i.d.) in Part B of the study and for whom PK data was available for analysis. This dataset was used for PK analysis after Cycle 1 Day 1 (34 patients) and after Cycle 2 Day 28 (17 patients remaining at this dose).	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.
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	—
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	—
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	326 ng*h/mL Standard Deviation 54.0	561 ng*h/mL Standard Deviation 176	—
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	—	2460 ng*h/mL Standard Deviation 2450	—

Adverse Events

Givinostat DL0 (50 mg b.i.d.) (Part A)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Givinostat DL1 (100 mg b.i.d.) (Part A)

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Givinostat DL1 Expanded (100 mg b.i.d.) (Part A)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Givinostat DL6 (100 mg + 50 mg) (Part A)

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Givinostat at MTD (100 mg b.i.d.) (Part B)

Serious events: 2 serious events

Other events: 35 other events

Deaths: 0 deaths

Serious adverse events

Measure	Givinostat DL0 (50 mg b.i.d.) (Part A) n=3 participants at risk In Part A, 3 patients were assigned to receive givinostat by oral administration at DL0 (50 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; 50 mg b.i.d. (DL0) was the third DL to be administered.	Givinostat DL1 (100 mg b.i.d.) (Part A) n=3 participants at risk 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.	Givinostat DL1 Expanded (100 mg b.i.d.) (Part A) n=3 participants at risk 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.	Givinostat DL6 (100 mg + 50 mg) (Part A) n=3 participants at risk 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.	Givinostat at MTD (100 mg b.i.d.) (Part B) n=35 participants at risk 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.
Cardiac disorders Myocardial infarction	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	2.9% 1/35 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Infections and infestations Pneumonia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	2.9% 1/35 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Vascular disorders Thrombophlebitis	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).

Other adverse events

Measure	Givinostat DL0 (50 mg b.i.d.) (Part A) n=3 participants at risk In Part A, 3 patients were assigned to receive givinostat by oral administration at DL0 (50 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; 50 mg b.i.d. (DL0) was the third DL to be administered.	Givinostat DL1 (100 mg b.i.d.) (Part A) n=3 participants at risk 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.	Givinostat DL1 Expanded (100 mg b.i.d.) (Part A) n=3 participants at risk 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.	Givinostat DL6 (100 mg + 50 mg) (Part A) n=3 participants at risk 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.	Givinostat at MTD (100 mg b.i.d.) (Part B) n=35 participants at risk 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.
Blood and lymphatic system disorders Anaemia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	17.1% 6/35 • Number of events 14 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Blood and lymphatic system disorders Haemolytic anaemia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Blood and lymphatic system disorders Neutropenia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	66.7% 2/3 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	66.7% 2/3 • Number of events 4 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	45.7% 16/35 • Number of events 22 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Blood and lymphatic system disorders Thrombocytosis	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Cardiac disorders Palpitations	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	8.6% 3/35 • Number of events 4 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Endocrine disorders Hypothyroidism	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Abdominal pain	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	22.9% 8/35 • Number of events 9 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Abdominal pain upper	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	11.4% 4/35 • Number of events 5 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Constipation	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	8.6% 3/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Diarrhoea	33.3% 1/3 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	66.7% 2/3 • Number of events 4 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	66.7% 2/3 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	66.7% 2/3 • Number of events 5 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	57.1% 20/35 • Number of events 39 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Dry mouth	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Dyspepsia	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	66.7% 2/3 • Number of events 6 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	14.3% 5/35 • Number of events 5 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Faeces soft	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Flatulence	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Haemorrhoids	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Gastrointestinal disorders Nausea	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	28.6% 10/35 • Number of events 13 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
General disorders Asthenia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	28.6% 10/35 • Number of events 22 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
General disorders Chest pain	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
General disorders Early satiety	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
General disorders Fatigue	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
General disorders Oedema peripheral	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
General disorders Pyrexia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	11.4% 4/35 • Number of events 4 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Infections and infestations Localised infection	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Infections and infestations Parainfluenzae virus infection	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Infections and infestations Urinary tract infection	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Investigations Blood bilirubin increased	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Investigations Blood creatinine increased	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	40.0% 14/35 • Number of events 21 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Investigations Blood lactate dehydrogenase increased	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Investigations Electrocardiogram qt prolonged	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Investigations Gamma-glutamyltransferase increased	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Investigations Weight decreased	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Metabolism and nutrition disorders Decreased appetite	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	11.4% 4/35 • Number of events 4 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	14.3% 5/35 • Number of events 6 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Metabolism and nutrition disorders Iron deficiency	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Musculoskeletal and connective tissue disorders Chondrocalcinosis	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Nervous system disorders Dizziness	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Nervous system disorders Dysgeusia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	66.7% 2/3 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	8.6% 3/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Nervous system disorders Head discomfort	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Nervous system disorders Headache	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	2.9% 1/35 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Nervous system disorders Hypoaesthesia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Nervous system disorders Memory impairment	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Psychiatric disorders Confusional state	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Psychiatric disorders Irritability	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Renal and urinary disorders Acute kidney injury	33.3% 1/3 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Renal and urinary disorders Chromaturia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Renal and urinary disorders Chronic kidney disease	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Reproductive system and breast disorders Pelvic pain	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	8.6% 3/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Respiratory, thoracic and mediastinal disorders Dyspnoea	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	66.7% 2/3 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	2.9% 1/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	11.4% 4/35 • Number of events 4 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	8.6% 3/35 • Number of events 3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Vascular disorders Erythromelalgia	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Vascular disorders Flushing	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Vascular disorders Hypertension	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Vascular disorders Lymphoedema	33.3% 1/3 • Number of events 1 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/35 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).
Vascular disorders Thrombosis	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	0.00% 0/3 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).	5.7% 2/35 • Number of events 2 • 168 days for Part A and 168 days for Part B (Cycle 1 through Cycle 6 for each phase of study; each cycle 28 days). TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).

Additional Information

Medical Expert

ITALFARMACO S.p.A.

Phone: +39 026443 258

Email: p.bettica@italfarmaco.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place