Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer

Crul, Mirjam; Klerk, de G.J.; Swart, M; Veer, van 't L.J.; Jong, de; Boerrigter, Lucie; Palmer, Peter; Bol, C.J.; Tan, Harold H G; Gast, de; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1200/jco.2002.09.116

Cited by 122 publications

(83 citation statements)

References 16 publications

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“…In the development of both compounds, effort was undertaken to increase oral bioavailability and metabolic stability. Maximal plasma concentrations are reached at 2-4 hours after administration for tipifarnib and at 6-8 hours for lonafarnib [46,47].…”

Section: Adme Studiesmentioning

confidence: 99%

“…Phase I studies showed that myelosuppression and neurotoxicity were dose-limiting toxicities. Gastrointestinal toxicities and fatigue were observed, as well [46,52,84]. …”

Section: Tipifarnibmentioning

confidence: 99%

“…Cell lines harboring no ras mutation or a mutation in the H-ras gene were most susceptible to FTI treatment [36,37]. Crul et al [46] performed a phase I study with tipifarnib in 28 patients with advanced cancer. ras mutational status was determined in 15 patients, of which five had a K-ras mutation.…”

Section: Rasmentioning

confidence: 99%

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Development of Farnesyl Transferase Inhibitors: A Review

2005

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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

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Section: Adme Studiesmentioning

confidence: 99%

“…Phase I studies showed that myelosuppression and neurotoxicity were dose-limiting toxicities. Gastrointestinal toxicities and fatigue were observed, as well [46,52,84]. …”

Section: Tipifarnibmentioning

confidence: 99%

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Development of Farnesyl Transferase Inhibitors: A Review

2005

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“…In a Phase I clinical trial, 17 was administered orally twice daily to 28 patients with advanced solid tumors in a dose-escalating protocol [89]. The dose limiting toxicities (DLTs) were myelosuppression and neurotoxicity and the maximum tolerated dose (MTD) was determined to be 300 mg twice daily.…”

Section: Therapy Using Single Agentmentioning

confidence: 99%

“…Since the Ras hypothesis has fallen out of favor, the clinical studies have targeted a variety of cancers irrespective of their historical frequency of Ras mutations. There appears to be no relationship between clinical response and Ras status [89,90]. Pharmacodynamic effects of FTIs in patients have been monitored by quantitation of FTase substrates such as HDJ2 and prelamin A [91,92].…”

Section: Clinical Development Of Ftase Inhibitorsmentioning

confidence: 99%

Inhibition of farnesyltransferase: A rational approach to treat cancer?

Puntambekar

Giridhar

Yadav

2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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This article presents in brief the development of farnesyltransferase inhibitors (FTIs) and their preclinical and clinical status. In this review the mechanism of action of FTIs is discussed and their selectivity issue towards tumor cells is also addressed. The significant efficacy of FTIs as single or combined agents in preclinical studies stands in contrast with only moderate effects in Clinical Phase II-III studies. This suggests that there is a need to further explore and understand the complex mechanism of action of FTIs and their interaction with cytotoxic agents.

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A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma

Rosenberg

Maase

Seigne

et al. 2005

Cancer

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BACKGROUND. R115777 is a potent farnesyl transferase inhibitor and has significant antitumor effects in vitro and in vivo. METHODS.The objective of the current study was to determine the objective response proportion in patients with metastatic transitional cell carcinoma (TCC) of the urothelial tract who received treatment with R115777 at a dose of 300 mg orally given twice daily for 21 days followed by 7 days of rest for every 4-week cycle.Thirty-four patients with TCC were enrolled in this Phase II study. Patients were allowed to have received a maximum of one prior systemic chemotherapy regimen, not including chemoradiation or neoadjuvant chemotherapy. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 -2 and adequate bone marrow, hepatic, and kidney function. RESULTS.Twice daily administration of oral R115777 was tolerated well. R115777 was absorbed rapidly after oral administration. Grade 3-4 neutropenia (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 5 patients (15%). Grade 3-4 nonhematologic toxicity was rare, consisting of rash and diarrhea in 1 patient each. Two patients (6%) without prior chemotherapy demonstrated partial responses. Thirteen patients (38%) achieved disease stabilization according to World Health Organization criteria that lasted a median of 4 months. No complete responses were observed. CONCLUSIONS.The objective response rate of R115777 was not sufficient to warrant future investigation in TCC as a single agent. Preliminary evidence of the activity of R115777 in 2 chemotherapy-naïve patients may warrant further investigation in combination with first-line chemotherapy.

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Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer

Abstract: Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.

Cited by 122 publications

References 16 publications

Development of Farnesyl Transferase Inhibitors: A Review

Development of Farnesyl Transferase Inhibitors: A Review

Inhibition of farnesyltransferase: A rational approach to treat cancer?

A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma

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