Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors

Tabernero, Josep; Rojo, F.; Marimón, Irene; Voi, Maurizio; Albanell, Joan; Guix, Marta; Vázquez, Federico; Carulla, Joan; Cooper, Michael R.; Andreu, Jordi; Vreckem, Anne Van; Bellmunt, Joaquim; Manne, Veeraswamy; Manning, James A.; Garrido, Carmen; Felip, Enriqueta; Campo, J. M. Del; García, Mónica; Valverde, Silvia; Baselga, J.

doi:10.1200/jco.2005.00.398

Cited by 25 publications

(22 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The maximal decrease in activity was estimated at 49%, indicating that FTase could not completely be inhibited. Similar inhibition values were found in studies with single FTase inhibitors (Cohen et al, 2003;Alsina et al, 2004;Cortes et al, 2005;Tabernero et al, 2005). In the Calu-6 xenograft model, inhibition of FTase by 66% was associated with a reduction of the tumour volume of 15% (unpublished data).…”

Section: Discussionsupporting

confidence: 65%

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

et al. 2008

View full text Add to dashboard Cite

AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase (FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49±11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens.

show abstract

Section: Discussionsupporting

confidence: 65%

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Again, inhibition could not be related to tumor response. Similar inhibition values were observed in phase I trials with i.v.-administered BMS-214662 [57,58]. There was no correlation between the levels of FTase activity and clinical response.…”

Section: Ftase Activitysupporting

confidence: 68%

“…When the administration scheme was extended to continuous weekly i.v. administration, MTDs of 209 mg/m 2 for a 1-hour infusion and 275 mg/m 2 for a 24-hour infusion were reached [58]. Besides nausea, vomiting, and diarrhea, creatinine elevation, acute pancreatitis, and renal failure (only with long exposure) were also dose-limiting.…”

Section: Bms-214662mentioning

confidence: 96%

Development of Farnesyl Transferase Inhibitors: A Review

2005

View full text Add to dashboard Cite

Learning Objectives After completing this course, the reader will be able to: Describe the potential mechanisms by which farnesyl transferases inhibit tumor growth. Explain possible mechanisms by which tumor cells may develop resistance to this class of agents. Discuss the scientific requirements for developing targeted cancer treatments that will actually be useful in patients. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at http://CME.TheOncologist.com

show abstract

“…An additional phase I study exploring weekly dosing demonstrated activity in 5 patients with acute leukemia or high-risk MDS (among 30 patients), including two complete responses (213). Phase I studies exploring weekly 1 h infusions and weekly 24 h infusions in solid tumor patients have also been reported (214,215). The toxicity profiles for the two regimens differed significantly.…”

Section: Clinical Activity Of Bms-214662mentioning

confidence: 99%

Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors

Basso¹,

Kirschmeier²,

Bishop³

2006

Journal of Lipid Research

282

246

View full text Add to dashboard Cite

Some proteins undergo posttranslational modification by the addition of an isoprenyl lipid (farnesyl-or geranylgeranyl-isoprenoid) to a cysteine residue proximal to the C terminus. Protein isoprenylation promotes membrane association and contributes to protein-protein interactions. Farnesylated proteins include small GTPases, tyrosine phosphatases, nuclear lamina, cochaperones, and centromereassociated proteins. Prenylation is required for the transforming activity of Ras. Because of the high frequency of Ras mutations in cancer, farnesyl transferase inhibitors (FTIs) were investigated as a means to antagonize Ras function. Evaluation of FTIs led to the finding that both K-and N-Ras are alternatively modified by geranylgeranyl prenyltransferase-1 in FTI-treated cells. Geranylgeranylated forms of Ras retain the ability to associate with the plasma membrane and activate substrates. Despite this, FTIs are effective at inhibiting the growth of human tumor cells in vitro, suggesting that activity is dependent on blocking the farnesylation of other proteins. FTIs also inhibit the in vivo growth of human tumor xenografts and sensitize these models to chemotherapeutics, most notably taxanes. Several FTIs have entered clinical trials for various cancer indications. In some clinical settings, primarily hematologic malignancies, FTIs have displayed evidence of single-agent activity. Clinical studies in progress are exploring the antitumor activity of FTIs as single agents and in combination. This review will summarize the basic biology of FTIs, their antitumor activity in preclinical models, and the current status of clinical studies with these agents.-Basso, A. D., P. Kirschmeier, and W. R. Bishop. Farnesyl transferase inhibitors. J. Lipid Res. 2006. 47: 15-31.

show abstract

Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors

Abstract: BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.

Cited by 25 publications

References 47 publications

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

Development of Farnesyl Transferase Inhibitors: A Review

Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors

Contact Info

Product

Resources

About