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.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 45
- 试验地点
- 22
- 主要终点
- Percentage of Patients With Overall Haematological Response at Week 12.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written Informed Consent.
- •Age ≥18 years.
- •Confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization (WHO) criteria.
- •JAK2V617F positivity.
- •Non-response to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.
- •ECOG (Eastern Cooperative Oncology Group) performance status <
- •Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential.
- •Willingness and capability to comply with the requirements of the study.
排除标准
- •Active bacterial or mycotic infection requiring antimicrobial treatment.
- •Pregnancy or lactation.
- •A marked baseline prolongation of QT/QTc (corrected) interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula).
- •Use of concomitant medications that prolong the QT/QTc interval.
- •Clinically significant cardiovascular disease including:
- •Uncontrolled hypertension, myocardial infarction, unstable angin, within 6 months from study start;
- •New York Heart Association (NYHA) Grade II or greater congestive heart failure;
- •History of any cardiac arrhythmia requiring medication (irrespective of its severity);
- •A history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
- •Positive blood test for HIV (Human Immunodeficiency Virus)
- •Active HBV (Hepatitis B Virus) and/or HCV (Hepatitis C Virus) infection.
- •Platelets count <100x109/L within 14 days before enrolment.
- •Absolute neutrophil count <1.2x109/L within 14 days before enrolment.
- •Serum creatinine >2xULN (upper limit of normal).
- •Total serum bilirubin >1.5xULN.
- •Serum aspartate aminotransferase (AST) / alanine aminotransferase (ALT) > 3xULN.
- •History of other diseases, 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.
- •Interferon alpha within 14 days before enrolment.
- •Anagrelide within 7 days before enrolment.
- •Any other investigational drug within 28 days before enrolment.
研究组 & 干预措施
GIVINOSTAT + MTD Hydroxyurea (HU)_1
50 mg o.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy
干预措施: GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea (Drug)
GIVINOSTAT + MTD Hydroxyurea (HU)_2
50 mg b.i.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy
干预措施: GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea (Drug)
结局指标
主要结局
Percentage of Patients With Overall Haematological Response at Week 12.
时间窗: At week 12 of treatment
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.
次要结局
- Percentage of Patients With Overall Haematological Response at Week 24 by Dose Escalation After Week 12.(At week 24 of treatment)
- Change From Baseline of the JAK2V617F Allele Burden by Quantitative RT-PCR(At weeks 12, 24, at "drop out visit" and at "End of Study" (EOS). EOS stays for 7 days after last drug intake if patient is withdrawn from the study before week 24.)
- Percentage of Patients With a Reduction of the Fraction of JAK2V617F Positive Clonogenic Progenitor by Timepoints(Baseline, at weeks 12 and 24)