A phase I clinical-pharmacodynamic study of the farnesyltransferase inhibitor tipifarnib in combination with the proteasome inhibitor bortezomib in advanced acute leukemias.

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.

• Authors: Jeffrey E Lancet, Vu H Duong, Elliott F Winton, Robert K Stuart, Michelle Burton, Shumin Zhang, Christopher Cubitt, Michelle A Blaskovich, John J Wright, Said Sebti, Daniel M Sullivan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 5 Pg. 1140-6 (Mar 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21233404 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)
• Copyright: ©2011 AACR.

Chemical References

• Boronic Acids
• NF-kappa B
• Proteasome Inhibitors
• Pyrazines
• Quinolones
• Bortezomib
• Farnesyltranstransferase
• Chymotrypsin
• tipifarnib

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Boronic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Bortezomib
• Chymotrypsin (blood, metabolism)
• Farnesyltranstransferase (antagonists & inhibitors, blood)
• Female
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Leukemia, Myeloid, Acute (drug therapy)
• Leukocytes, Mononuclear (metabolism)
• Male
• Maximum Tolerated Dose
• Middle Aged
• NF-kappa B (metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Proteasome Inhibitors
• Pyrazines (administration & dosage, adverse effects, pharmacokinetics)
• Quinolones (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)