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

Phase 2CompletedNCT01901432

Italfarmaco48 enrolled

Overview

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patients must be able to provide informed consent and be willing to sign an informed consent form; 2. Patients must have an age ≥18 years; 3. Patients must have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria; 4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease; 5. Patients must have an active/not controlled disease defined as 1. hematocrit ≥ 45% or hematocrit \<45% in need of phlebotomy, and 2. platelet count \> 400 x109/L, and 3. white blood cell count \> 10 x109/L; 6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 in Part A, ECOG performance status ≤ 2 in Part B within 7 days of initiating study drug; 7. Female patient of childbearing potential has a negative serum or urine pregnancy test within 72 hours of the first dose of study therapy; 8. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential; 9. Adequate and acceptable organ function within 7 days of initiating study drug; 10. Willingness and capability to comply with the requirements of the study. Note that if the enrolment in Part A is slow (i.e. \< 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with chronic myeloproliferative neoplasms. In this case, the inclusion criteria 5 will be modified as following only for Part A: 5\. Patients must have an active/not controlled disease defined as: 1. Essential Thrombocythemia patients: Platelet count \> 600 x109/L; 2. Myelofibrosis patients: no response according to European Myelofibrosis Network criteria. Exclusion Criteria: 1. Active bacterial or mycotic infection requiring antimicrobial treatment; 2. Pregnancy or nursing; 3. A clinically significant corrected QT interval prolongation at baseline; 4. Use of concomitant medications known to prolong the corrected QT interval; 5. Clinically significant cardiovascular disease including: 1. Uncontrolled hypertension despite medical treatment, myocardial infarction, unstable angina within 6 months from study start; 2. New York Heart Association Grade II or greater congestive heart failure; 3. History of any cardiac arrhythmia requiring medication (irrespective of its severity); 4. A history of additional risk factors for torsade de pointes; 6. Known positivity for human immunodeficiency; 7. Known active hepatitis B virus and/or hepatitis C virus infection; 8. Platelet count \< 100 x109/L within 14 days before enrolment; 9. Absolute neutrophil count \< 1.2x109/L within 14 days before enrolment; 10. Serum creatinine \> 2 times the upper limit of normal; 11. Total serum bilirubin \> 1.5 times the upper limit of normal except in case of Gilbert's disease; 12. Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) \> 3 times the upper limit of normal; 13. History of other diseases (including active tumours), metabolic dysfunctions, physical examination findings, or clinical laboratory findings giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications; 14. Prior treatment with a Janus Kinase 2 or Histone Deacetylase inhibitor or participation in an interventional clinical trial for chronic myeloproliferative neoplasms; 15. Systemic treatment for chronic myeloproliferative neoplasms other than aspirin/cardio aspirin; 16. Hydroxyurea within 28 days before enrolment; 17. Interferon alpha within 14 days before enrolment; 18. Anagrelide within 7 days before enrolment; 19. Any other investigational drug or device within 28 days before enrolment; 20. Patient with known hypersensitivity to the components of study therapy.

Locations (25)

CHU Amiens - Hôpital Sud

Amiens, France

Hôpital Morvan - CHRU de Brest

Brest, France

Hopital Saint Vincent de Paul - GHICL Lille

Lille, France

Hôpital Saint-Louis (AP-HP), Centre Investigations Cliniques

Paris, France

Charite Research Organisation GmbH

Berlin, Germany

Universitaetsklinikum Koeln

Cologne, Germany

Universitaetsklinikum Carl Gustav Carus TU Dresden

Dresden, Germany

Universitaetsklinikum Freiburg

Freiburg im Breisgau, Germany

Azienda ospedaliero universitaria Consorziale Policlinico di Bari

Bari, BA, Italy

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, BG, Italy

...and 15 more locations

Outcomes

Primary Outcomes

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

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

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

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

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

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

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

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

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

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

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

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

Secondary Outcomes

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

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

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

ORR After 6 Cycles in Part B of the Study

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

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

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

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

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

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

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

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

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

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

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

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

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