CHR-2845-001: Safety and Tolerability of CHR-2845 to Treat Haematological Diseases or Lymphoid Malignancies

Sponsor

Chroma Therapeutics (Industry)

Overall Status

Completed

CT.gov ID

NCT00820508

Collaborator

(none)

Enrollment

Locations

Arm

30.9

Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hematological Disease Lymphoid Malignancies	Drug: CHR-2845	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Dec 1, 2008

Actual Primary Completion Date :

Jul 1, 2011

Actual Study Completion Date :

Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Oral, once daily administration of CHR-2845 to determine safety and tolerability	Drug: CHR-2845 Once daily oral ingestion of capsules (10, 40 or 80mg), dose depending on cohort, treatment cycle of 28 days

Arm

Intervention/Treatment

Experimental: 1

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

Drug: CHR-2845

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

Outcome Measures

Primary Outcome Measures

To determine the safety, tolerability, dose-limiting toxicities (DLT), maximum acceptable dose (MAD) and maximum tolerated dose (MTD) [28 days]

Secondary Outcome Measures

To determine pharmacokinetic parameters of CHR-2845 and the active metabolite CHR-2847 [days 1 and 28]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed, informed consent
Confirmed malignant haematological disease or lymphoid malignancy refractory to standard therapy or for which no standard therapy exists, including acute leukemias, MDS, CML, CLL, CMML, multiple myeloma and Non-Hodgkin's Lymphomas/Hodgkin's disease
Patients shall have recovered from all acute adverse effects of prior therapies, with the exception of alopecia and grade 1 neuropathy where recovery is not required
Adequate bone marrow, hepatic and renal function including the following:
Patients with high blast counts can be included if they can be controlled by the use of hydroxyurea (500 mg -3,000 mg daily).
Total bilirubin ≤ 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilbert's Syndrome
AST (SGOT), ALT (SGPT) ≤ 2.5 x upper normal limit
Creatinine ≤ 1.5 x upper normal limit
Age ≥ 18 years
Performance status (PS) ≤ 2 - Eastern Cooperative Oncology Group (ECOG) scale
Estimated life expectancy greater than 3 months
Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to start of trial. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment.

Exclusion Criteria:

Patients receiving anti-cancer therapy or use of other investigational agents within 21 days prior to trial entry (or a longer period depending on the defined characteristics of the agents used. Bisphosphonates for bone disease and corticosteroids are permitted provided the dose does not change during the trial. Patients must have recovered from all transient toxicity induced by prior therapy
Patients with co-existing active infection, graft versus host disease or serious concurrent illness
Patients who have failed to recover from or after a bone marrow transplantation or haematopoietic stem cell transplantation
The following diseases are excluded: Burkitt's lymphoma, primary effusion lymphoma, precursor B-cell lymphoblastic lymphoma, symptomatic central nervous system (CNS) lymphoma, CML blast crisis
Patients with significant cardiovascular disease as defined by:
history of congestive heart failure requiring therapy
history of angina pectoris requiring treatment or myocardial infarction within 6 months prior to trial entry
presence of severe valvular heart disease
presence of an atrial or ventricular arrhythmia requiring treatment
Left Ventricular Ejection Fraction (LVEF) below the normal range at the study centre
Uncontrolled hypertension
A history of abnormal QTc intervals or an average QTc interval at screening ≥450 msec
Any medical or other condition that in the investigator's opinion renders the patient unsuitable for this study due to unacceptable risk
Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies
Gastrointestinal disorders that may interfere with absorption of the study drug
Patients with known brain tumours or metastases
More than 6 prior chemotherapy regimens
Patients requiring growth factor support (erythropoietin, Granulocyte/monocyte Colony Stimulating Factor (GM/CSF), etc)
Patients requiring palliative radiotherapy within the last 4 weeks prior to study entry
Uncontrolled hypercalcaemia (CTCAE v3 grade 2 or higher)
Abnormal plasma potassium or magnesium levels (Common Terminology Criteria for Adverse Events (CTCAE) v3 grade 3 or greater) despite therapy
Pregnant or breast-feeding women

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ZNA Stuivenberg	Antwerp	Belgium	2060
2	Institut Paoli-Calmettes	Marseille	France
3	VU University Medical Center	Amsterdam	Netherlands	1007 MB
4	Erasmus University Medical Center	Rotterdam	Netherlands	3015 CE