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Histone Deacetylase Inhibitors

Oral, once daily administration of CHR-2845 to determine safety and tolerability

Once daily oral ingestion of capsules (10, 40 or 80mg), dose depending on cohort, treatment cycle of 28 days

CHR-2845

Bob Löwenberg, M.D

Gert Ossenkoppele, M.D

Pierre Zachee, MD

Norbert Vey, MD

The purpose of this study is to determine whether the histone deacetylase inhibitor CHR-2845 is tolerated in patients with haematological diseases and lymphoid malignancies.

CHR-2845 is a novel type of histone deacetylase inhibitor (HDACi) for use in cancer that, in addition to having broad ranging anti-proliferative activity against transformed cells, is designed to have an increased therapeutic window against diseases which involve cells of the monocyte-macrophage lineage. There are several HDACi's in clinical development and one, SAHA (Vorinostat, Zolinza®), has recently been approved for use in the treatment of cutaneous T-cell lymphoma. CHR-2845 is a cell-permeant ester that is metabolised to give an active acid, CHR-2847, which selectively accumulates in monocytes and macrophages. This results in a 20-100 fold increase in anti-proliferative potency of CHR-2845 for monocytic over non-monocytic tumour cells. This selectivity should lead to an increased therapeutic window in haematological malignancies involving cells of the monocyte lineage (AML M4, AML M5 and CMML). In addition, there is increasing evidence that monocytes and macrophages associated with some haematological tumours (tumour-associated macrophages (TAMs)) are involved in supporting the growth and spread of the tumour. This clinical trial will focus on haematological and lymphoid malignancies with the intention of evaluating the safety and tolerability of CHR-2845. Additionally it will compare response in patients where monocytes/macrophages are important disease drivers, with the response in other patients. This will allow an early determination of the potential improvement in therapeutic window afforded by the monocyte/macrophage directed HDACi activity.

Safety and Tolerability of CHR-2845 to Treat Haematological Diseases or Lymphoid Malignancies

A Phase I Study to Evaluate the Safety and Tolerability of the Histone Deacetylase Inhibitor, CHR-2845, in Patients With Advanced or Treatment Refractory Haematological Diseases or Lymphoid Malignancies

Chroma Therapeutics

Neoplasms

Heart and Blood Diseases

Rare Diseases

Polycythemia Vera

Polycythemia

Thrombocytosis

Thrombocythemia, Essential

Bone Marrow Neoplasms

Hematologic Neoplasms

Bone Marrow Diseases

Myeloproliferative Disorders

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Essential Thrombocythemia

Chronic Myeloproliferative Disorders

Antineoplastic Agents

Vorinostat

Enzyme Inhibitors

Treatment with study drug approximately 6 months and follow-up for 3 months

HDAC inhibitor (MK-0683)

Hans C Hasselbalch, MD

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.

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.

Copenhagen University Hospital at Herlev

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Tolerability of CHR-2845 to Treat Haematological Diseases or Lymphoid Malignancies	NCT00820508	Hematological D... Lymphoid Malign...	CHR-2845	18 Years -	Chroma Therapeutics
A Study of the Efficacy of MK-0683 in Patients With Polycythaemia Vera and Essential Thrombocythaemia	NCT00866762	Polycythemia Ve... Essential Throm...	HDAC inhibitor ...	18 Years -	Copenhagen University Hospital at Herlev

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