A Phase I Clinical-Pharmacodynamic Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with the Proteasome Inhibitor Bortezomib in Advanced Acute Leukemias
Open Access
- 1 March 2011
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 17 (5), 1140-1146
- https://doi.org/10.1158/1078-0432.ccr-10-1878
Abstract
Purpose: To determine the safety, target inhibition, and signals of clinical activity of tipifarnib in combination with bortezomib in patients with advanced acute leukemias. Experimental Design: In a “3 + 3” design, patients received escalating doses of tipifarnib (days 1–14) and bortezomib (days 1, 4, 8, 11) every 3 weeks until maximum tolerated dose was reached. Peripheral blood mononuclear cells (PBMC) were collected at days 1, 8, and 22 for measurement of chymotrypsin-like and farnesyltransferase activity. Purified bone marrow leukemic blasts were collected at baseline and at day 8 for measurement of NF-κB activity. Results: The combination was well-tolerated, and maximum tolerated dose was not reached. Dose-limiting toxicities included diarrhea, fatigue, and sensorimotor neuropathy. Chymotrypsin-like and farnesyltransferase activity within PBMCs were decreased in a majority of patients at day 8. NF-κB activity within leukemic blasts was decreased in a majority of patients at day 8. Complete response with incomplete count recovery was observed in 2 patients, and additional 5 patients had stable disease. Conclusions: Tipifarnib and bortezomib combination in patients with advanced leukemias was well-tolerated, demonstrated relevant target inhibition, and was associated with signals of clinical activity in patients with advanced and refractory acute leukemias. Future studies of this combination may be warranted in more selected groups of patients in whom these molecular targets are of particular importance. Clin Cancer Res; 17(5); 1140–6. ©2011 AACR.Keywords
This publication has 24 references indexed in Scilit:
- A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or olderBlood, 2009
- A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and overLeukemia, 2008
- Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic eventsGenes & Development, 2008
- Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor ActivityJournal of Clinical Oncology, 2008
- A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemiaBlood, 2007
- Identification of Molecular Predictors of Response in a Study of Tipifarnib Treatment in Relapsed and Refractory Acute Myelogenous LeukemiaClinical Cancer Research, 2007
- A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemiaBlood, 2006
- Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion–Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid LeukemiaClinical Cancer Research, 2006
- Phase I Study of Bortezomib in Refractory or Relapsed Acute LeukemiasClinical Cancer Research, 2004
- Nuclear factor-κB is constitutively activated in primitive human acute myelogenous leukemia cellsBlood, 2001