A phase I trial of the farnesyl transferase inhibitor SCH66336: Evidence for biological and clinical activity

Alex Adjei, Charles Erlichman, Jenny N. Davis, David L. Cutler, Jeff A Sloan, Randolph Stuart Marks, Lorelei J. Hanson, Phyllis A. Svingen, Pamela Atherton, W. Robert Bishop, Paul Kirschmeier, Scott H Kaufmann

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Abstract

Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first FT inhibitors to undergo clinical testing. We report a Phase I trial to assess the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid tumors received 92 courses of escalating SCH66336 doses given orally twice a day (b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336 b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation in buccal mucosa cells of patients treated with SCH66336 was demonstrated, confirming that SCH66336 inhibits protein farnesylation in vivo. One partial response was observed in a patient with previously treated metastatic non-small cell lung cancer, who remained on study for 14 months. This study not only establishes the dose for future testing on this schedule (350 mg b.i.d.) but also provides the first evidence of successful inhibition of FT in the clinical setting and the first hint of clinical activity for this class of agents.

Original languageEnglish (US)
Pages (from-to)1871-1877
Number of pages7
JournalCancer Research
Volume60
Issue number7
StatePublished - Apr 1 2000

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Adjei, A., Erlichman, C., Davis, J. N., Cutler, D. L., Sloan, J. A., Marks, R. S., Hanson, L. J., Svingen, P. A., Atherton, P., Bishop, W. R., Kirschmeier, P., & Kaufmann, S. H. (2000). A phase I trial of the farnesyl transferase inhibitor SCH66336: Evidence for biological and clinical activity. Cancer Research, 60(7), 1871-1877.