Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia.

Abstract

BACKGROUND:

In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia.

DESIGN AND METHODS:

Patients received cytarabine 400 mg/m(2)/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients.

RESULTS:

Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m(2)/day for 5 days along with tanespimycin 300 mg/m(2) on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest.

CONCLUSIONS:

Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423).

• Authors: Scott H Kaufmann, Judith E Karp, Mark R Litzow, Ruben A Mesa, William Hogan, David P Steensma, Karen S Flatten, David A Loegering, Paula A Schneider, Kevin L Peterson, Matthew J Maurer, B Douglas Smith, Jacqueline Greer, Yuhong Chen, Joel M Reid, S Percy Ivy, Matthew M Ames, Alex A Adjei, Charles Erlichman, Larry M Karnitz
• Journal: Haematologica (Haematologica) Vol. 96 Issue 11 Pg. 1619-26 (Nov 2011) ISSN: 1592-8721 [Electronic] Italy
• PMID: 21791475 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Cytarabine
• tanespimycin
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1

Topics

• Acute Disease
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Benzoquinones (administration & dosage, adverse effects)
• Checkpoint Kinase 1
• Cytarabine (administration & dosage, adverse effects)
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Lactams, Macrocyclic (administration & dosage, adverse effects)
• Leukemia (drug therapy, metabolism)
• Male
• Middle Aged
• Protein Kinases (metabolism)
• Recurrence
• Time Factors