A Study of the Efficacy of MK-0683 in Patients With Polycythaemia Vera and Essential Thrombocythaemia

A Phase II Study of MK-0683 in Patients With Polycythaemia Vera and Essential Thrombocythaemia.

The aim of the present study is to evaluate the efficacy and safety of MK-0683 in the treatment of PV and ET. This agent has most recently been shown to be a potent inhibitor of the autonomous proliferation of haematopoietic cells of PV and ET patients carrying the JAK2 V617F mutation. Accordingly, it may be anticipated that MK-0683 - by decreasing the JAK2 allele burden - may influence clonal myeloproliferation and in vivo granulocyte, platelet and endothelial activation , which are considered to be major determinants of morbidity and mortality ( thrombosis, bleeding, extramedullary haematopoiesis , myelofibrosis ) in these disorders. The effects of MK-0683 at the molecular level will be studied by global/ focused gene expression profiling, epigenome profiling and proteomics.

Study Overview

• Status: Unknown
• Conditions: Polycythemia Vera; Essential Thrombocythemia
• Intervention / Treatment: Drug: HDAC inhibitor (MK-0683)

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Copenhagen University Hospital Rigshospitalet
  • Esbjerg, Denmark, DK-6700
    • Esberg Hospital
  • Herlev, Denmark, DK-2730
    • Herlev Hospital
  • Odense, Denmark, DK-5000
    • Odense University Hospital
  • Roskilde, Denmark, DK-4000
    • Roskilde Hospital
  • Viborg, Denmark, DK-8800
    • Regional Hospital Viborg
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Centre
• Sweden
  • Orebro, Sweden, S-70185
    • University hospital Örebro
  • Stockholm, Sweden, S-11883
    • Stockholm South General Hospital (Sodersjukhuset)
  • Stockholm, Sweden, S-14186
    • Karolinska University Hospital Huddinge
  • Uddevalla, Sweden, S-45180
    • Sahlgrenska University Hospital & Uddevalla Hospital
  • Uppsala, Sweden, S-75185
    • Uppsala University Hospital
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XN
    • Cardiff University
  • Dudley, United Kingdom, DY1 2HQ
    • Russell's Hall Hospital
  • London, United Kingdom, SE1 7EH
    • St Thomas' Hospital
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT9 7AB
      • Centre for Cancer Research and Cell Biology, Queen's University Belfast

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patient > 18 years of age AND
• A confirmed diagnosis of PV AND

• Biochemical evidence of active disease as defined by:

  • a need for phlebotomy within last 3 months
  • a leukocyte count > 10 x 10^9/L in the absence of infection or inflammation (normal CRP) and/or (PV/ET)
  • a platelet count > 450 x 10^9/L in the absence of infection or inflammation (normal CRP)(PV/ET) OR
• Male or female patient > 18 years of age AND
• A confirmed diagnosis of ET AND
• Biochemical evidence of active disease as defined by *a platelet count > 450 x 10^9/L in the absence of infection or inflammation

Inclusion Criteria for both PV and ET:

• Newly diagnosed or previously treated patient in chronic phase OR
• Advanced phase PV or ET as defined by blasts of > 1 x 10^9/L in the peripheral blood and/or white cell count > 30 x 10^9/L OR
• Resistant or refractory PV or ET as defined by haemoglobin < 10.5 gm/dl with a platelet count > 600 x 10^9/L on current therapy OR
• Cycling platelet counts on therapy OR
• 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)

Exclusion Criteria:

• A platelet count > 1500 x 10^9/L (a need for cytoreduction in platelet count)
• Patients of childbearing potential without a negative pregnancy test prior to initiation of study drug
• Women who are breast feeding
• Males and females not using contraceptives if sexually active.
• EGOC Performance status Score > or = 3
• Serum creatinine more than 2 x's teh ULN
• Total serum bilirubin more than 1.5 x's the ULN
• Serum AST/ALT more than 3 x's the ULN
• Interferon alpha within 1 week of day 1
• Hydroxycarbamide within 1 week of day 1
• Anagrelide within 1 week of day 1
• Valproic acid (as an anticonvulsant) within 28 days of day 1
• Any other investigational drug within 28 days of day 1
• Active HIV, HBV or HCV infection
• 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.
• 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.
• Patient has a known allergy or hypersensitivity to study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; Treatment with study drug approximately 6 months and follow-up for 3 months	Drug: HDAC inhibitor (MK-0683); 400 mg once daily for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To evaluate the efficacy of study drug (MK-0683) in the treatment of patients with PV and ET.	one year

Secondary Outcome Measures

Outcome Measure	Time Frame
To study changes in bone marrow morphology before and after treatment with study drug.	one year

Collaborators and Investigators

• Sponsor: Copenhagen University Hospital at Herlev
• Investigators: Principal Investigator: Hans C Hasselbalch, MD, Department of Hematology, Copenhagen University Hospital Herlev

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (ANTICIPATED): August 1, 2012
• Study Completion (ANTICIPATED): December 1, 2012

Study Registration Dates

• First Submitted: March 17, 2009
• First Submitted That Met QC Criteria: March 19, 2009
• First Posted (ESTIMATE): March 20, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): December 12, 2011
• Last Update Submitted That Met QC Criteria: December 9, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: Essential Thrombocythemia; Hematology; Haematology; Haematological disease; Polycythemia Vera; Hematological disorder; Hematological disease; Polycythaemia Vera; Essential Thrombocythaemia; HDAC-inhibitor; Haematological disorder
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Thrombocytosis; Thrombocythemia, Essential; Polycythemia Vera; Polycythemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Vorinostat
• Other Study ID Numbers: MK-0683/092-0