E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients with polycythaemia vera or essential thrombocythaemia or myelofibrosis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036057 |
E.1.2 | Term | Polycythaemia vera |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015493 |
E.1.2 | Term | Essential thrombocythaemia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028537 |
E.1.2 | Term | Myelofibrosis |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
(1) To evaluate efficacy of vorinostat in the treatment of patients with polycythaemia vera (PV) or essential thrombocythaemia (ET) (2) To evaluate if vorinostat as monotherapy of patients with PV or ET is followed by a decline in clonal myeloproliferation as assessed by conventional disease activity parameters (a decrease in the need of phlebotomy ( PV), leukocyte and platelet count)
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E.2.2 | Secondary objectives of the trial |
(1) To study changes in bone marrow morphology before and after treatment with vorinostat. (2) To investigate whether treatment with vorinostat influences the JAK2 mutation status as assessed by quantitative PCR. (3) To perform integrated gene expression (global and focused) profiling, epigenome profiling and proteome studies (serum-based) before and during treatment with vorinostat in order to describe in detail the various (heterogeneous) response patterns at the molecular level. (4) To study immune cells and function (dendritic cells, regulatory T-cells, NK-cells and specific T-cell responses) before and during treatment with vorinostat. (5) To study in vivo granulocyte, platelet and endothelial activation before and during treatment with vorinostat. (6) To evaluate the safety of vorinostat in the treatment of patients with polycythaemia vera (PV) and essential thrombocythaemia (ET).
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Amendment 1: Long-term Efficacy and Safety of Vorinostat in Patients with Polycythaemia Vera & Essential Thrombocythemia. 22-NOV-2010, Version 1. Primary objective: To study long term efficacy vorinostat in the treatment of PV and ET. Secondary objective: To study long term safety of vorinostat in the treatment of PV and ET.
Amendment 2: A Phase II Study of Vorinostat (MK-0683) in Patients with Primary Myelofibrosis, Post-Polycythaemia Vera Myelofibrosis and Post-Essential Thrombocythaemia Myelofibrosis including Long-Term Efficacy and Safety Evaluation. 22-10-2010, Version 1. Primary Objectives 1. To evaluate the safety and efficacy of vorinostat in the treatment of patients with myelofibrosis (MF) (primary myelofibrosis, post-polycythaemia vera myelofibrosis, post-essential thrombocythaemia myelofibrosis). 2. To evaluate if treatment with vorinostat as monotherapy of patients with MF is followed by a decline in clonal myeloproliferation as assessed by conventional disease activity parameters ( an increase in Hb-concentration, a decrease in leucocyte and platelet count and a decrease in p-LDH and a reduction in spleen size on clinical examination. 3. To study if treatment with vorinostat influences the JAK2 mutation status as assessed by quantitative PCR 4. To study if differences exist in response patterns (time to response, depth of response) in JAK-2 positive and JAK2-negative patients. Secondary Objectives 1. To perform integrated gene expression (global and focused), miRNA- and epigenome profiling proteome studies (serum-based) and studies of immune cells (including dendritic cells, Tregs, NK-cells, B-cells) and cytokines before and during treatment with vorinostat in order to describe in detail the various (heterogeneous) response patterns at the molecular and immunological level 2. To study changes in bone marrow morphology (cellularity, bone marrow fibrosis, angiogenesis) during treatment with vorinostat. 3. To study the relationship between JAK2-status, in vivo granulocyte activation, CD34+ count, markers of extracellular matrix metabolism (circulating procollagen propeptides, metalloproteases, YKL-40) before and during treatment with vorinostat. 4. To study global hemostasis as assessed by trombelastography and studies of vivo granulocyte, platelet and endothelial activation before and during treatment with vorinostat.
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E.3 | Principal inclusion criteria |
PV: 11. Male or female patient > 18 years of age and 2. A confirmed diagnosis of PV (see appendix 1) and 3. Biochemical evidence of active disease as defined by a) A need for phlebotomy within the last 3 months b) a leukocyte count > 10 x 109/L in the absence of infection or inflammation (normal CRP) and/or (PV/ET) c) a platelet count > 450 x 109/L in the absence of infection or inflammation (normal CRP) (PV/ET).
ET: 1. Male or female patient > 18 years of age and 2. A confirmed diagnosis of high risk ET (see appendix 1) and 3. Biochemical evidence of active disease as defined by a) a platelet count > 450 x 109/L in the absence of infection or inflammation (normal CRP).
PV + ET: 1. Newly diagnosed or previously treated patients in chronic phase or 2. Advanced phase PV or ET as defined by blasts of > 1 x 109/L in the peripheral blood and/or white cell count > 30 x 109/L or 3. Resistant or refractory PV or ET as defined by a haemoglobin < 10.5gm/dl with a platelet count > 600 x 109/L on current therapy or 4. Cycling platelet counts on therapy or 5. Intolerant to other therapies defined by patients with PV or ET who have side effects on current therapies preventing continuation (leg ulcers on hydroxycarbamide, unacceptable fatigue etc on interferon).
MF: 1. Male or female patient > 18 years of age and 2. A confirmed diagnosis of primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis (12,13,55) and 3. Splenomegaly as assessed clinically or by abdominal ultrasound (patients who have had splenectomy for huge splenomegaly can be included ) 4. Newly diagnosed or previously treated patients in chronic phase or advanced phase MF.
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E.4 | Principal exclusion criteria |
1. A platelet count > 1500 x 109/L (a need for cytoreduction in platelet count) 2. Patients of childbearing potential without a negative pregnancy test prior to initiation of study drug. 3. Women who are breast feeding 4. Males and females not using contraceptives if sexually active. It is recommended that 2 reliable forms of contraception be used simultaneously unless abstinence is the chosen method of contraception. Non-pregnant, non-breast-feeding women may be enrolled if they are considered highly unlikely to conceive. Highly unlikely to conceive is defined as (a) surgically sterilized, or (b) postmenopausal, or (c) not heterosexually active for the duration of the study, or (d) heterosexually active and willing to use 2 birth control methods. The 2 birth control methods can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy, used throughout the study starting with Visit 1. A woman who is ≥45 years of age and has not had menses for greater than 2 years will be considered postmenopausal. 5. ECOG Performance Status Score ≥ 3 6. Serum creatinine more than 2 x’s the ULN 7. Total serum bilirubin more than 1.5 x’s the ULN 8. Serum AST/ALT more than 3 x’s the ULN 9. Interferon alpha within 1 week of day 1 10. Hydroxycarbamide within 1 week of day 1 11. Anagrelide within 1 week of day 1 12. Valproic acid (as an anticonvulsant) within 28 days of day 1 13. Any other investigational drug within 28 days of day 1 14. Active HIV, HBV or HCV infection. 15. Any serious concomitant disease or circumstances that could limit compliance with the study, including but not limited to the following: CTCAE grade 3-4 cardiac general & arrhythmia, or psychiatric or social conditions that may interfere with patient compliance. 16. Any prior malignancy with the exception of cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or other localized malignancy that has undergone potentially curative therapy with no evidence of that disease for five years, and who is deemed to be at low risk for recurrence by his/her treating physician. 17. Patient has a known allergy or hypersensitivity to vorinostat capsules.
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E.5 End points |
E.5.1 | Primary end point(s) | |
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |