Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: A preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide

Judith E. Karp, Karen Flatten, Eric J. Feldman, Jacqueline M. Greer, David A. Loegering, Rebecca M. Ricklis, Lawrence E. Morris, Ellen Ritchie, B. Douglas Smith, Valerie Ironside, Timothy Talbott, Gail Roboz, Son B. Le, Wei Meng Xue, Paula A. Schneider, Nga T. Dai, Alex Adjei, Steven D. Gore, Mark J. Levis, John J. WrightElizabeth Garrett-Mayer, Scott H Kaufmann

Research output: Contribution to journalArticle

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Abstract

The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.

Original languageEnglish (US)
Pages (from-to)4841-4852
Number of pages12
JournalBlood
Volume113
Issue number20
DOIs
StatePublished - 2009

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tipifarnib
Farnesyltranstransferase
Etoposide
Acute Myeloid Leukemia
Phosphorylation
Ribosomal Protein S6
Induction Chemotherapy
Chemotherapy
Monomeric GTP-Binding Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia : A preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. / Karp, Judith E.; Flatten, Karen; Feldman, Eric J.; Greer, Jacqueline M.; Loegering, David A.; Ricklis, Rebecca M.; Morris, Lawrence E.; Ritchie, Ellen; Smith, B. Douglas; Ironside, Valerie; Talbott, Timothy; Roboz, Gail; Le, Son B.; Xue, Wei Meng; Schneider, Paula A.; Dai, Nga T.; Adjei, Alex; Gore, Steven D.; Levis, Mark J.; Wright, John J.; Garrett-Mayer, Elizabeth; Kaufmann, Scott H.

In: Blood, Vol. 113, No. 20, 2009, p. 4841-4852.

Research output: Contribution to journalArticle

Karp, JE, Flatten, K, Feldman, EJ, Greer, JM, Loegering, DA, Ricklis, RM, Morris, LE, Ritchie, E, Smith, BD, Ironside, V, Talbott, T, Roboz, G, Le, SB, Xue, WM, Schneider, PA, Dai, NT, Adjei, A, Gore, SD, Levis, MJ, Wright, JJ, Garrett-Mayer, E & Kaufmann, SH 2009, 'Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: A preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide', Blood, vol. 113, no. 20, pp. 4841-4852. https://doi.org/10.1182/blood-2008-08-172726
Karp, Judith E. ; Flatten, Karen ; Feldman, Eric J. ; Greer, Jacqueline M. ; Loegering, David A. ; Ricklis, Rebecca M. ; Morris, Lawrence E. ; Ritchie, Ellen ; Smith, B. Douglas ; Ironside, Valerie ; Talbott, Timothy ; Roboz, Gail ; Le, Son B. ; Xue, Wei Meng ; Schneider, Paula A. ; Dai, Nga T. ; Adjei, Alex ; Gore, Steven D. ; Levis, Mark J. ; Wright, John J. ; Garrett-Mayer, Elizabeth ; Kaufmann, Scott H. / Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia : A preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. In: Blood. 2009 ; Vol. 113, No. 20. pp. 4841-4852.
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abstract = "The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30{\%}) receiving 14-day tipifarnib versus 5 of 30 (17{\%}) receiving 21-day tipifarnib. Complete remissions occurred in 50{\%} of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.",
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AU - Greer, Jacqueline M.

AU - Loegering, David A.

AU - Ricklis, Rebecca M.

AU - Morris, Lawrence E.

AU - Ritchie, Ellen

AU - Smith, B. Douglas

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AU - Talbott, Timothy

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AU - Le, Son B.

AU - Xue, Wei Meng

AU - Schneider, Paula A.

AU - Dai, Nga T.

AU - Adjei, Alex

AU - Gore, Steven D.

AU - Levis, Mark J.

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AU - Garrett-Mayer, Elizabeth

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N2 - The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.

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