Article

Phase I study of the farnesyltransferase inhibitor BMS-214662 given weekly in patients with solid tumors.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clinical Cancer Research (impact factor: 7.74). 07/2005; 11(11):4151-9. DOI:10.1158/1078-0432.CCR-04-1659 pp.4151-9
Source: PubMed

ABSTRACT A phase I trial of BMS-214662, a selective farnesyltransferase inhibitor with significant preclinical antitumor activity in which drug was given as a weekly 1-hour infusion for four of six weeks, was conducted to evaluate the tolerability, pharmacokinetics, and pharmacodynamic effect on farnesyltransferase activity in peripheral blood mononuclear cells.
BMS-214662 was given to 27 patients with solid tumors at 10 escalating dose levels (28-220 mg/m(2)) allowing intrapatient dose escalation; pharmacokinetics and pharmacodynamics were done at the first seven dose levels.
Grade 4 neutropenia (four patients) was the most common dose-limiting toxicity followed by aminotransferase elevation (grade 3 alanine aminotransferase and grade 4 aspartate aminotransferase) and grade 3 dehydration. Most frequent toxicities were neutropenia in 11 (14%), anemia in 15 (19%), fatigue in 9 (12%), and nausea and diarrhea in 6 (8%) of courses, respectively. One minor response lasting 18 weeks in a patient with non-small cell lung cancer, serum calcitonin level reduction accompanied by disease stabilization in two of four patients with medullary thyroid carcinoma, and stable disease in 16 of 25 evaluable patients was seen. No correlation was observed between dose and C(max), total body clearance (mean, 26.15 +/- 10.88 L per hour per m(2)), volume of distribution at steady state (mean, 39.51 +/- 17.91 L/m(2)), or half-life (mean, 2.63 +/- 1.81 hours); a moderate correlation existed between dose given and systemic drug exposure (AUC). Substantial inhibition of peripheral blood mononuclear cell farnesyltransferase activity but near complete recovery by 24 hours was seen.
BMS-214667 was well tolerated as a weekly 1-hour i.v. infusion for four of six weeks with evidence of pharmacodynamic effect. The study was terminated before maximum tolerated dose was reached. Alternative schedules of drug administration might result in improved pharmacodynamic profile.

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    Article: Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation.
    Richard T Eastman, Frederick S Buckner, Kohei Yokoyama, Michael H Gelb, Wesley C Van Voorhis
    [show abstract] [hide abstract]
    ABSTRACT: Protein farnesylation is a form of posttranslational modification that occurs in most, if not all, eukaryotic cells. Inhibitors of protein farnesyltransferase (PFTIs) have been developed as anticancer chemotherapeutic agents. Using the knowledge gained from the development of PFTIs for the treatment of cancer, researchers are currently investigating the use of PFTIs for the treatment of eukaryotic pathogens. This "piggy-back" approach not only accelerates the development of a chemotherapeutic agent for protozoan pathogens but is also a means of mitigating the costs associated with de novo drug design. PFTIs have already been shown to be efficacious in the treatment of eukaryotic pathogens in animal models, including both Trypanosoma brucei, the causative agent of African sleeping sickness, and Plasmodium falciparum, one of the causative agents of malaria. Here, current evidence and progress are summarized that support the targeting of protein farnesyltransferase for the treatment of parasitic diseases.
    The Journal of Lipid Research 03/2006; 47(2):233-40. · 5.56 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

25 evaluable patients
 
27 patients
 
Alternative schedules
 
aminotransferase elevation
 
common dose-limiting toxicity
 
complete recovery
 
dose levels
 
grade 3 alanine aminotransferase
 
grade 3 dehydration
 
grade 4 aspartate aminotransferase
 
Grade 4 neutropenia
 
intrapatient dose escalation
 
medullary thyroid carcinoma
 
non-small cell lung cancer
 
peripheral blood mononuclear cell farnesyltransferase activity
 
peripheral blood mononuclear cells
 
selective farnesyltransferase inhibitor
 
systemic drug exposure
 
weekly 1-hour i.v. infusion
 
weekly 1-hour infusion