Safety Study of the Histone Deacetylase Inhibitor, CHR-3996, in Patients With Advanced Solid Tumours

NCT00697879 | Completed Phase 1

• 2 other identifiers: CHR-3996-001EudraCT Number: 2007-005043-19
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 3

Brief Summary

CHR-3996 is one of a new class of anti-cancer agents - histone deacetylase inhibitors (HDACi) - that has exhibited pleiotropic activity both in vitro and in vivo against a range of human cancer cells. Regulation of the acetylation of both histone and non-histone proteins by histone deacetylase enzymes is one of the key mechanisms involved in epigenetic control of gene expression. HDACi have demonstrated activity in both in vitro cytotoxicity, and in vivo tumour xenograft studies

Conditions

Solid Tumor

Keywords

tumour; Solid tumour; histone deacetylase inhibitor; dose escalation; cancer

Outcome Measures

Primary Outcomes (1)

• To determine the safety, tolerability, dose-limiting toxicities (DLT), maximum acceptable dose (MAD) and maximum tolerated dose (MTD) of CHR-3996 when administered orally to patients with advanced or treatment refractory solid tumours

  After 28 days treatment

Secondary Outcomes (2)

• To determine pharmacokinetic parameters of CHR-3996

  After 1 and 28 days treatment

• To perform a preliminary assessment of the anti-tumour activity of CHR-3996

  During treatment

Study Arms (1)

1

EXPERIMENTAL

Oral, once daily administration of CHR-3996 to determine safety and tolerability

Drug: CHR-3996

Interventions

CHR-3996 DRUG

Once daily oral ingestion of capsules (5, 10, 20 or 40 mg), dose depending on cohort, treatment cycle of 28 days

Also known as: Histone deacetylase inhibitor, HDACi

1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed, informed consent
• Histologically or cytologically confirmed malignant solid tumour refractory to standard therapy or for which no standard therapy exists
• Recovered from all acute adverse effects of prior therapies (excluding alopecia and grade 1 neuropathy)
• Adequate bone marrow, hepatic and renal function including the following
• Hb ≥ 9.0 g/dL, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L
• Total bilirubin ≤ 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
• AST (SGOT), ALT (SGPT) ≤ 2.5 x upper normal limit (or 5x UNL in the presence of liver metastases)
• Creatinine ≤ 1.5 x upper normal limit
• Age ≥ 18 years
• Performance status (PS) ≤ 2 (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. Acceptable methods of contraception include IUD, oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge)

You may not qualify if:

• Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 4 weeks 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). In patients with progressive disease, continuation of LHRH agonists for prostate cancer, bisphosphonates for bone disease and corticosteroids are permitted provided the dose does not change during the trial
• Patients with a prior allogeneic haematopoietic stem cell transplant
• Co-existing active infection or serious concurrent illness
• 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
• LVEF below the normal range at the study centre
• Uncontrolled hypertension
• A history of QTc abnormalities or with a mean QTc interval \>450 msec at screening
• 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 should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

Sponsors & Collaborators

• Chroma Therapeutics: lead

Study Sites (3)

Erasmus MC University Medical Center - Location Centrum

Rotterdam, 3015 CE, Netherlands

Location

Erasmus University Medical Center - Location Daniel den Hoed

Rotterdam, 3075 EA, Netherlands

Location

The Royal Marsden Hospital

Sutton, Surrey, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Neoplasms

Interventions

2-(6-(((6-fluoroquinolin-2-yl)methyl)amino)bicyclo(3.1.0)hex-3-yl)-N-hydroxypyrimidine-5-carboxamide; Histone Deacetylase Inhibitors

Intervention Hierarchy (Ancestors)

Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• F ALM Eskens, Dr

  Erasmus MC University Medical Center

  PRINCIPAL INVESTIGATOR

• Udai Banerji, Dr

  The Royal Marsden Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2008
• First Posted: June 16, 2008
• Study Start: February 1, 2008
• Primary Completion: November 1, 2010
• Study Completion: November 1, 2011
• Last Updated: November 28, 2011

Record last verified: 2011-11

Locations

NL (2); GB (1)