Primary objective:* To determine the safety, tolerability, dose-limiting toxicities (DLT), maximum acceptable dose (MAD) and maximum tolerated dose (MTD) of CHR-2845 when administered orally to patients with advanced or treatment refractory…
ID
Source
Brief title
Condition
- Haematological disorders NEC
- Lymphomas NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameter is to define the maximum acceptable dose (MAD) and
maximum tolerated dose (MTD).
Secondary outcome
The secundary study parameters are to define the
pharmacokinetics/pharmacodynamics of CHR-2845.
Background summary
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, by the action of an intracellular esterase (human
carboxylesterase-1) that is only found in cells of the monocyte lineage.
CHR-2847, being a charged molecule, cannot readily leave cells and hence,
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 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 which results from the intracellular accumulation of the active
metabolite CHR-2847, compared with the pan-cellular HDACi activity of the
parent molecule * CHR-2845.
Study objective
Primary objective:
* To determine the safety, tolerability, dose-limiting toxicities (DLT),
maximum acceptable dose (MAD) and maximum tolerated dose (MTD) of CHR-2845 when
administered orally to patients with advanced or treatment refractory
haematological or lymphoid malignancies
Secondary objectives:
* To determine pharmacokinetic parameters of CHR-2845 and the active metabolite
CHR-2847
* To perform a preliminary assessment of the anti-disease activity of CHR-2845
in diseases where monocyte derived cells play an important role versus general
haematological malignancies
Study design
This study is an open-label, dose escalating, non-randomised, multi-centre,
Phase I study of oral CHR-2845 administered once a day over a 28 day course of
treatment. Cohorts of 3 to 6 patients will be treated at increasing dose levels
to establish the maximum tolerated dose (MTD) based on the occurrence of DLTs.
The study will incorporate two phases for evaluation of dose level: (1) dose
escalation over a 28 day duration until the MTD is reached; and (2) evaluation
of treatment of up to 12 patients at the MAD. The MTD is defined as the dose at
which DLT occurs in two or more patients. The dose below the MTD will be
referred to as the maximum acceptable dose (MAD). Pharmacokinetic (PK) analyses
will be performed on blood samples taken from all patients in all cohorts.
Pharmacodynamic (PD) analyses will be performed on samples taken from all
patients in all cohorts.
The maximum volume of blood to be taken from each patient during a one month
period for safety, PK and PD evaluation will be 250 mL.
The exact sample size cannot be pre-defined, as the number of patients treated
will depend on the toxicity observed. It is expected that approximately 30 to
36 patients will be enrolled in the study at 5 sites in France, Netherlands and
Belgium.
Intervention
Cohorts of 3-6 patients each will be treated with escalating, once daily, oral
doses of CHR-2845 to determine the maximum acceptable dose (MAD) based on the
occurence of DLTs. There will be two study phases: (a) dose escalation to
determine MTD and MAD and (b) expansion of a cohort (max 12 patients) at the
maximum acceptable dose level.
Study burden and risks
The potentially expected side effects are listed below:
- During the ECG patients may have mild irritation, slight redness, and itching
at the sites on your skin where the recording patches are placed.
- During and after having either blood drawn or a bone marrow aspirate taken
patients may experience pain and bruising at the needle site. It is also
possible to experience lightheadedness and fainting during or after having
blood or bone marrow drawn, and it*s rare but possible for an infection,
bleeding or a blood clot to occur.
- Evidence from the available animal safety studies indicates potential side
effects that include anaemia, changes in parameters involved in the coagulation
of blood and adverse effects on the liver and the thymus. These effects appear
to be reversible if treatment is withdrawn in a timely manner.
Burden:
During the study patients will undergo the following assessments:
- Sign informed consent
- Physical Examination
- Performance Status
- Vital signs (incl. length, weight, heart rate, blood pressure, temperature)
- Hematology, Coagulation, Blood chemistry
- Urinalysis
- Chest X-ray
- Disease/tumour measurements
- ECGs
- Blood sampling for pharmacokinetics and pharmacodynamics
- Serum pregnancy test
- Echocardiography
- Bone marrow aspirate
- Complete patient diary (incl. time of study medication intake, dose level,
concomitant medication and AEs)
- Patients might be asked to remain in the hospital over night on the evening
prior to the first dose of CHR-2845. They will have to remain in the hospital
over night until the second day of treatment so that all the necessary
remaining ECG recordings and blood samples can be done. On day 28 patients will
have the option of remaining in the hospital over night until day 29 of
treatment so that all the necessary remaining blood samples can be done.
PK sampling will be done at the following time points (3 mL for each sample):
- day 1: pre-dose (2 samples)
- day 1: 20 min., 1 (2 samples), 2, 4 (2 samples), 6, 8 hours post dose
- day 2: 2 additional blood samples at the 24 hour time point after the first
dose
- day 28: pre-dose (2 samples)
- day 28: 20 min., 1 (2 samples), 2, 4 (2 samples), 6, 8 hours post dose
- day 29: One blood sample will be taken (at approximately 24 hours after you
have taken the previous dose of CHR-2845)(End of Treatment: 1 PK sample if
patient withdrew due to an AE)
PD sampling will be done at the following time points (8 mL for each sample):
- day 1: pre-dose
- day 1: 1 and 4 hours post dose
- day 2: pre-dose (at the 24 hour time point after the first dose)
- day 28: pre-dose
- day 28: 1 and 4 hours post dose
93 Milton Park
OXON OX 14 4RY, Abingdon
United Kingdom
93 Milton Park
OXON OX 14 4RY, Abingdon
United Kingdom
Listed location countries
Age
Inclusion criteria
1. Signed, informed consent
2. Histologically or cytologically confirmed malignant haematological disease or lymphoid malignancy refractory to standard therapy or for which no standard therapy exists, including acute leukemias, myelodysplastic syndrome (MDS), Chronic myeloid leukemia (CML), Chronic lymphoid leukemia (CLL), Chronic myelomonocytic leukemia (CMML), multiple myeloma and Non-Hodgkin*s Lymphomas/Hodgkin*s disease
3. 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
4. Adequate bone marrow, hepatic and renal function including the following
a. Patients with high blast counts can be included in the trial only if they can be controlled by the use of hydroxyurea (500 mg -3,000 mg daily).
b. Total bilirubin * 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilbert*s Syndrome
c. AST (SGOT), ALT (SGPT) * 2.5 x upper normal limit
d. Creatinine * 1.5 x upper normal limit
5. Age * 18 years
6. Performance status (PS) * 2 - Eastern Cooperative Oncology Group (ECOG) scale
7. Estimated life expectancy greater than 3 months
8. 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. Acceptable methods of contraception include an Intrauterine Device, oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge)
Exclusion criteria
1. Patients receiving anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy 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 e.g. 6 weeks for mitomycin or nitrosourea, 3 months for antibodies). 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
2. Patients with co-existing active infection, graft versus host disease or serious concurrent illness
3. Patients who have failed to recover from or after a bone marrow transplantation or haematopoietic stem cell transplantation
4. 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
5. Patients with significant cardiovascular disease as defined by:
a. history of congestive heart failure requiring therapy
b. history of angina pectoris requiring treatment or myocardial infarction within 6 months prior to trial entry
c. presence of severe valvular heart disease
d. presence of an atrial or ventricular arrhythmia requiring treatment
e. Left Ventricular Ejection Fraction (LVEF) below the normal range at the study centre
f. Uncontrolled hypertension
g. A history of abnormal QTc intervals or an average QTc interval at screening *450 msec
6. Any medical or other condition that in the investigator*s opinion renders the patient unsuitable for this study due to unacceptable risk
7. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies
8. Gastrointestinal disorders that may interfere with absorption of the study drug
9. Patients with known brain tumours or metastases
10. More than 6 prior chemotherapy regimens
11. Patients requiring growth factor support (erythropoietin, Granulocyte/monocyte Colony Stimulating Factor (GM/CSF), etc)
12. Patients requiring palliative radiotherapy within the last 4 weeks prior to study entry
13. Uncontrolled hypercalcaemia (CTCAE v3 grade 2 or higher)
14. Abnormal plasma potassium or magnesium levels (Common Terminology Criteria for Adverse Events (CTCAE) v3 grade 3 or greater) despite therapy
15. Pregnant or breast-feeding women
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-005241-27-NL |
| ClinicalTrials.gov | NCT00820508 |
| CCMO | NL25586.029.08 |