Clinical and biologic activity of the famesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: A phase 1 clinical-laboratory correlative trial

Judith E. Karp, Jeffrey E. Lancet, Scott H. Kaufmann, David W. End, John J. Wright, Kees Bol, Ivan Horak, Michael L. Tidwell, Jane Liesveld, Timothy J. Kottke, Dawn Ange, Laxmi Buddharaju, Ivana Gojo, W. Edward Highsmith, Robert T. Belly, Raymond Hohl, Mary Ellen Rybak, Alain Thibault, Joseph Rosenblatt

Research output: Contribution to journalArticle

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Abstract

R115777 is a nonpeptidomimetic enzymespecific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity.

Original languageEnglish (US)
Pages (from-to)3361-3369
Number of pages9
JournalBlood
Volume97
Issue number11
DOIs
StatePublished - Jun 1 2001

Fingerprint

tipifarnib
Clinical laboratories
Transferases
Refractory materials
Leukemia
Bone Marrow
Toxicity
Proteins
Lamin Type A
ras Proteins
Signal transduction
Pharmacokinetics
Protein Prenylation
Extracellular Signal-Regulated MAP Kinases
Polydipsia
Dysarthria
Pharmaceutical Preparations
ras Genes
Paresthesia
Ataxia

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Karp, Judith E. ; Lancet, Jeffrey E. ; Kaufmann, Scott H. ; End, David W. ; Wright, John J. ; Bol, Kees ; Horak, Ivan ; Tidwell, Michael L. ; Liesveld, Jane ; Kottke, Timothy J. ; Ange, Dawn ; Buddharaju, Laxmi ; Gojo, Ivana ; Edward Highsmith, W. ; Belly, Robert T. ; Hohl, Raymond ; Rybak, Mary Ellen ; Thibault, Alain ; Rosenblatt, Joseph. / Clinical and biologic activity of the famesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias : A phase 1 clinical-laboratory correlative trial. In: Blood. 2001 ; Vol. 97, No. 11. pp. 3361-3369.
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abstract = "R115777 is a nonpeptidomimetic enzymespecific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4{\%}) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29{\%}) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity.",
author = "Karp, {Judith E.} and Lancet, {Jeffrey E.} and Kaufmann, {Scott H.} and End, {David W.} and Wright, {John J.} and Kees Bol and Ivan Horak and Tidwell, {Michael L.} and Jane Liesveld and Kottke, {Timothy J.} and Dawn Ange and Laxmi Buddharaju and Ivana Gojo and {Edward Highsmith}, W. and Belly, {Robert T.} and Raymond Hohl and Rybak, {Mary Ellen} and Alain Thibault and Joseph Rosenblatt",
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Karp, JE, Lancet, JE, Kaufmann, SH, End, DW, Wright, JJ, Bol, K, Horak, I, Tidwell, ML, Liesveld, J, Kottke, TJ, Ange, D, Buddharaju, L, Gojo, I, Edward Highsmith, W, Belly, RT, Hohl, R, Rybak, ME, Thibault, A & Rosenblatt, J 2001, 'Clinical and biologic activity of the famesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: A phase 1 clinical-laboratory correlative trial', Blood, vol. 97, no. 11, pp. 3361-3369. https://doi.org/10.1182/blood.V97.11.3361

Clinical and biologic activity of the famesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias : A phase 1 clinical-laboratory correlative trial. / Karp, Judith E.; Lancet, Jeffrey E.; Kaufmann, Scott H.; End, David W.; Wright, John J.; Bol, Kees; Horak, Ivan; Tidwell, Michael L.; Liesveld, Jane; Kottke, Timothy J.; Ange, Dawn; Buddharaju, Laxmi; Gojo, Ivana; Edward Highsmith, W.; Belly, Robert T.; Hohl, Raymond; Rybak, Mary Ellen; Thibault, Alain; Rosenblatt, Joseph.

In: Blood, Vol. 97, No. 11, 01.06.2001, p. 3361-3369.

Research output: Contribution to journalArticle

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T1 - Clinical and biologic activity of the famesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias

T2 - A phase 1 clinical-laboratory correlative trial

AU - Karp, Judith E.

AU - Lancet, Jeffrey E.

AU - Kaufmann, Scott H.

AU - End, David W.

AU - Wright, John J.

AU - Bol, Kees

AU - Horak, Ivan

AU - Tidwell, Michael L.

AU - Liesveld, Jane

AU - Kottke, Timothy J.

AU - Ange, Dawn

AU - Buddharaju, Laxmi

AU - Gojo, Ivana

AU - Edward Highsmith, W.

AU - Belly, Robert T.

AU - Hohl, Raymond

AU - Rybak, Mary Ellen

AU - Thibault, Alain

AU - Rosenblatt, Joseph

PY - 2001/6/1

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N2 - R115777 is a nonpeptidomimetic enzymespecific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity.

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