Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Polycythemia Vera

Polycythemia

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Bone Marrow Diseases

Myeloproliferative Disorders

Chronic Myeloproliferative Disorders

Antineoplastic Agents

Antisickling Agents

All Drugs and Chemicals

Hydroxyurea

Givinostat hydrochloride

Histone Deacetylase Inhibitors

Enzyme Inhibitors

50 mg o.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy

50 mg b.i.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy

50 mg o.d. of GIVINOSTAT + MTD of HU monotherapy

GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea

50 mg b.i.d. of GIVINOSTAT + MTD HU monotherapy

GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea

Alessandro Rambaldi, MD

The primary objective of the study was to evaluate the efficacy of Givinostat in combination with hydroxyurea in patients with JAK2V617F-positive Polycythemia Vera (PV) non-responders to the maximum tolerated dose of hydroxyurea monotherapy.

The secondary objectives of this study were:

* To evaluate the safety and tolerability of Givinostat in combination with hydroxyurea in patients with JAK2V617Fpositive PV non-responders to the maximum tolerated dose of hydroxyurea monotherapy;
* To explore the impact in terms of efficacy and tolerability of Givinostat 50 mg dose escalation in patients not achieving at least a partial response at the time when the primary endpoint was assessed (week 12);
* To evaluate the molecular response (JAK2 mutated allele burden) by quantitative Real Time-Polymerase Chain Reaction (RT-PCR);
* To evaluate the reduction of the fraction of JAK2V617F positive clonogenic progenitors.

This is a multicentre, randomized, open-label, phase II study testing GIVINOSTAT (ITF2357) in combination with hydroxyurea in a population of patients with JAK2V617F positive Polycythemia Vera non-responders to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.

Recruited patients will be randomly assigned to one of the following treatment groups:

* group A: 50 mg o.d. of oral GIVINOSTAT (ITF2357) in combination with the maximum tolerated dose of hydroxyurea monotherapy already in use before admission to the study;
* group B: 50 mg b.i.d. of oral GIVINOSTAT (ITF2357) in combination with the maximum tolerated dose of hydroxyurea monotherapy already in use before admission to the study.

The two groups will be balanced for number and for Centre in order to provide valuable information on both treatment regimens.

In both groups assigned doses shall remain stable until week 12, which is when the primary endpoint is assessed, unless specific tolerability issues arise which impose dose reduction.

After the primary endpoint assessment at week 12, one of the following treatment schedules will be chosen case by case on the basis of the achieved clinical response and continued for up to 12 further weeks:

* Partial or Complete Response at week 12:
* group A: continue 50 mg o.d.;
* group B: continue 50 mg b.i.d.;
* No Response at week 12:
* group A: increase to 50 mg b.i.d.;
* group B: increase to 50 mg t.i.d.. At any time during study course, if toxicity is observed, GIVINOSTAT (ITF2357) treatment will be discontinued until recovery and then restarted at a reduced dose level. The drug will be definitively withdrawn in case of reappearance of toxicity even at a reduced daily dose. Overall, the treatment will last up to a maximum of 24 cumulative weeks of drug administration.

The study will recruit subjects of both genders with an established diagnosis of JAK2V617F positive Polycythemia Vera according to the revised WHO criteria, in need of cytoreductive therapy, non-responders to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.

Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera

Phase II Study of the Histone-deacetylase Inhibitor GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Patients With JAK2V617F Positive Polycythemia Vera Non-responder to Hydroxyurea Monotherapy.

The percentage of patients with overall (complete or partial) response at week 12 were assessed. · Complete response: 1. HCT (Hematocrit) \< 45% without phlebotomy, and 2. platelets ≤ 400 x109/L, and 3. WBC (white blood cell) ≤ 10 x 109/L, and 4. no splenomegaly, and 5. no disease related systemic symptoms (microvascular disturbances, pruritus, headache); · Partial response: 1. HCT \< 45% without phlebotomy, or 2. fulfilment of at least 3 of the other above mentioned criteria; · No response: any response that did not satisfy the criteria set for partial response.

Haematological response after a 50 mg increase of the initial Givinostat dose in non-responder patients at the time when the primary endpoint was assessed (week 12).

* Complete response:

  1. HCT\< 45% without phlebotomy, and
  2. platelets ≤ 400 x109/L, and
  3. WBC ≤ 10 x 109/L, and
  4. no splenomegaly, and
  5. no disease related systemic symptoms (microvascular disturbances, pruritus, headache);
* Partial response:

  1. HCT \< 45% without phlebotomy, or
  2. fulfilment of at least 3 of the other above mentioned criteria;
* No response:

any response that did not satisfy the criteria set for partial response.

To determine JAK2V617F mutational status, a quantitative RT-PCR (Real Time-Polymerase Chain Reaction) is executed on peripheral blood granulocyte and haematopoietic colonies (with and without hepatocyte growth factors - HGFs).

JAK2V617F genotyping and quantification were performed on gradient-separated mononuclear cells during the pre-treatment evaluations (baseline), halfway through the study (12th weeks) and at the end of the study period (24th weeks).

Baseline: n=22 (50 mg od); 22 (50 mg bid) Week 12: n=20 (50 mg od); 19 (50 mg bid) Week 24: n=18 (50 mg od); 18 (50 mg bid)

Italfarmaco

50 mg o.d. of GIVINOSTAT + MTD of HU monotherapy

GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea: 50 mg o.d. of GIVINOSTAT + MTD of HU monotherapy

GIVINOSTAT + MTD Hydroxyurea_1

50 mg b.i.d. of GIVINOSTAT + MTD of HU monotherapy

GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea: 50 mg b.i.d. of GIVINOSTAT + MTD HU monotherapy

GIVINOSTAT + MTD Hydroxyurea_2

Total

Age, Categorical

Sex: Female, Male

Italy

Region of Enrollment

Safety/Intention-to-treat (ITT) population, which included all randomized subjects who received at least one dose of study medication.

Carlo Bianchini, MD

Responder

Non responder

Safety/ITT population: included all randomized subjects who received at least one dose of study medication.

Percentage of Patients With Overall Haematological Response at Week 12.

Safety/Intention to treat (ITT) population included all randomized subjects who received at least one dose of study medication.

Percentage of Patients With Overall Haematological Response at Week 24 by Dose Escalation After Week 12.

Week 12

Week 24

Drop-out

Change From Baseline of the JAK2V617F Allele Burden by Quantitative RT-PCR

Baseline - heterozygous

Baseline - homozygous

Baseline - not done

week 12 - heterozygous

week 12 - homozygous

week 12 - not done

week 24 - heterozygous

week 24 - homozygous

week 24 - not done

Percentage of Patients With a Reduction of the Fraction of JAK2V617F Positive Clonogenic Progenitor by Timepoints

50 mg o.d. of GIVINOSTAT + maximum tolerated dose (MTD) of hydroxyurea (HU) monotherapy

GIVINOSTAT (ITF2357) 50 mg o.d. + maximum tolerated dose (MTD) of Hydroxyurea (HU): 50 mg o.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy

GIVINOSTAT +Maximum Tolerated Dose (MTD) of Hydroxyurea (HU)_1

50 mg b.i.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy

GIVINOSTAT (ITF2357) 50 mg b.i.d. + maximum tolerated dose (MTD) of Hydroxyurea (HU): 50 mg b.i.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy

GIVINOSTAT +Maximum Tolerated Dose (MTD) of Hydroxyurea (HU)_2

Overall Study

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Chronic Graft Versus Host Disease

Essential Thrombocythemia

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

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

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

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

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

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

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

Givinostat

Paolo Bettica, MD

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

TEAEs are reported for Part A and Part B and include events with an onset on or after the first administration of study drug until the end of study visit (or 7 days after the last drug intake for any patient permanently discontinuing study treatment).

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 DL0 (50 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 (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 DL1 Expanded (100 mg b.i.d.) (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 DL6 (100 mg + 50 mg) (Part A)

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.

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

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.

Total Title

Race (NIH/OMB)

The overall baseline population consists of all enrolled patients in either Part A or Part B of the study.

Medical Expert

TEAE

Drug-related TEAE

TESAE

Drug-related TESAE

Death due to any cause

Grade 3 TEAE

Grade 3 drug-related TEAE

Grade 4 TEAE

Grade 4 drug-related TEAE

Grade 5 TEAE

Discontinuation due to TEAE

Discontinuation due to drug-related TEAE

Discontinuation due to TESAE

Discontinuation due to drug-related TESAE

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

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

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.

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

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

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

ORR (CR + PR)

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.

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

Cycle 3 Day 28

Cycle 6 Day 28

This dataset comprised all patients in the ITT analysis set who received givinostat in Part A of the study. It represents the 4 Part A treatment arms and includes patients who received givinostat at DL0 (50 mg b.i.d.), DL1 (100 mg b.i.d. \[i.e. including DL1 expanded\] and DL6 (100 mg + 50 mg) in Part A.

Givinostat Total (Part A)

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

ORR After 6 Cycles in Part B of the Study

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

Givinostat Cycle 1 Day 1

ITF2374 Cycle 1 Day 1

ITF2375 Cycle 1 Day 1

Givinostat Cycle 1 Day 28

ITF2374 Cycle 1 Day 28

ITF2375 Cycle 1 Day 28

This dataset was used for PK analysis and included the patients who received givinostat at DL0 (50 mg b.i.d.) in Part A of the study and for whom PK data was available for analysis.

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

This dataset was used for PK analysis and included the patients who received givinostat at DL1 (100 mg b.i.d. \[i.e. including DL1 expanded\]) in Part A of the study and for whom PK data was available for analysis.

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

This dataset was used for PK analysis and included the patients who received givinostat at DL6 (100 mg in the morning and 50 mg in the evening) in Part A of the study and for whom PK data was available for analysis.

Givinostat DL6 (100 mg + 50 mg) (Part A PK Analysis Set)

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.

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

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

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

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

Assessment of 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 2 Day 28

ITF2374 Cycle 2 Day 28

ITF2375 Cycle 2 Day 28

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 100 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 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 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 50 mg b.i.d. (Part B PK Analysis Set)

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

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

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

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

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

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera	NCT00928707	Polycythemia Ve...	GIVINOSTAT (ITF... GIVINOSTAT (ITF...	18 Years - 80 Years	Italfarmaco
A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera	NCT01901432	Polycythemia Ve...	Givinostat	18 Years -	Italfarmaco

Spots Global Cancer Trial Database for givinostat

Every month we try and update this database with for givinostat cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for givinostat

Every month we try and update this database with for givinostat cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for givinostat cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.