Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies Journal Article

  

Authors:	O'Connor, O. A.; Heaney, M. L.; Schwartz, L.; Richardson, S.; Willim, R.; Macgregor-Cortelli, B.; Curly, T.; Moskowitz, C.; Portlock, C.; Horwitz, S.; Zelenetz, A. D.; Frankel, S.; Richon, V.; Marks, P.; Kelly, W. K.
Article Title:	Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies
Abstract:	Purpose: To document the toxicity and activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with pretreated hematologic malignancies. Patients and Methods: Two formulations of SAHA (intravenous [IV] and oral) have been assessed in two consecutive phase I trials. In both trials, dose escalation was performed in parallel and independently in patients with solid tumors and hematologic malignancies. Eligible patients were required to have adequate hepatic and renal function, an absolute neutrophil count ≥ 500/μL and a platelet count more than 25,000/mL. All patients provided informed consent for study inclusion. Results: A total of 39 patients with hematologic malignancy were enrolled (14 on IV SAHA and 25 on oral SAHA), of whom 35 were treated. The spectrum of diseases included patients with diffuse large B-cell lymphoma (n = 12), Hodgkin's disease (HD; n = 12), multiple myeloma (n = 2), T-cell lymphoma (n = 3), mantle cell lymphoma (n = 2), small lymphocytic lymphoma (n = 2), and myeloid leukemia (n = 2). Major adverse events with the oral formulation included fatigue, diarrhea, anorexia, and dehydration, whereas myelosuppression and thrombocytopenia were more prominent with the IV formulation. Typically, the hematologic toxicities resolved shortly after SAHA was stopped. There was no neutropenic fever or neutropenic sepsis. Reduction in measurable tumor was observed in five patients. One patient with transformed small lymphocytic lymphoma met criteria for complete response, whereas another met the criteria for partial response (PR). One patient with refractory HD had a PR, whereas three patients had stable disease for up to 9 months. Conclusion: These results suggest that SAHA has activity in hematologic malignancies including HD and select subtypes of non-Hodgkin's lymphoma. © 2006 by American Society of Clinical Oncology.
Keywords:	adult; clinical article; controlled study; aged; histone deacetylase inhibitor; clinical trial; advanced cancer; area under the curve; diarrhea; liver function; solid tumor; anorexia; controlled clinical trial; mantle cell lymphoma; multiple myeloma; neutrophil count; bone marrow suppression; thrombocytopenia; dehydration; hodgkin disease; drug dose escalation; fever; b cell lymphoma; t cell lymphoma; hematologic malignancy; myelodysplastic syndrome; kidney function; drug response; promyelocytic leukemia; vorinostat; thrombocyte count; cancer fatigue; sepsis; large cell lymphoma; phase 1 clinical trial; lymphatic leukemia; informed consent; drug formulation; myeloid leukemia
Journal Title:	Journal of Clinical Oncology
Volume:	24
Issue:	1
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2006-01-01
Start Page:	166
End Page:	173
Language:	English
DOI:	10.1200/jco.2005.01.9679
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33644836549&partnerID=40&md5=503367f5d2a6777088cd3c146a84cc3e
Notes:	--- - "Cited By (since 1996): 211" - "Export Date: 4 June 2012" - "CODEN: JCOND" - "Source: Scopus"