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Sub-category:
Pediatric Solid Tumors
Category:
Pediatric Cancer
Meeting:
2008 ASCO Annual Meeting
Abstract No:
10012
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 10012)
Author(s):
M. Fouladi, J. R. Park, J. Sun, A. M. Ingle, M. M. Ames, C. F. Stewart, R. Gilbertson, J. A. Zwiebel, P. C. Adamson, S. M. Blaney
Abstract:
Background: Synergistic anti-tumor activity between histone deacetylase inhibitors and retinoids has been observed in a variety of preclinical models, including pediatric CNS and solid tumors. A pediatric phase I trial of SAHA in combination with 13cRA was performed to define the dose limiting toxicities (DLT), determine the MTD, describe the PK of SAHA in combination with 13cRA, and assess accumulation of histone acetylation in peripheral blood mononuclear cells (PBMCs). Methods: 13cRA, 80 mg/m2/dose po bid, was administered on days 1-14 of each 28 day course. Oral SAHA was administered at a starting dose of 180 mg/m2/d once daily with planned escalation to the pediatric single agent MTD of 230 mg/m2/d, or dose de-escalation to 180 mg/m2/d 4 days/wk if daily dosing proved intolerable. PK analysis was performed during the first course. Acetyl-histone (H3) accumulation in vivo was studied by western blot analysis on day 1 at 0, 1, 6 and 24 h after SAHA dosing. Results: 13 eligible patients, 7 males, median age 9 years (range, 2-20) with medulloblastoma (n=4), PNET (n=6), ATRT (n=1) and neuroblastoma (n=2) were enrolled. 4/13 pts were not fully evaluable for toxicity; 2 patients continue on their first course of therapy; 1 patient had PD prior to start of therapy and 1 patient developed unrelated myelosuppression after 1 dose of SAHA . DLT occurred in 2/6 patients at the initial dose level (thrombocytopenia [n=2], neutropenia, hypophosphatemia and anorexia). 0/3 evaluable patients have experienced a DLT at 180 mg/m2/d dosed 4 times per week. Non-dose limiting grade 3 or 4 toxicities included elevated ALT (n=1), leucopenia (n=2), and lymphopenia (n=3). Western blot analysis of PBMC-derived protein isolates demonstrated accumulation of acetylated H3 histones. Conclusion: SAHA 180 mg/m2/d 4 x per week, in combination with daily 13cRA (days 1-14) appears to be well-tolerated in children and inhibits histone deacetylase activity in PBMCs.
Abstract Disclosures
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy
and are designated with a caret symbol (^) here and in the print version.
 Associated Presentation(s):
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1. A Phase I of Vorinostat in Combination with 13 Cis-retinoic Acid in Children and Refractory Neuroblastomas, Medulloblastomas, Primitive Neuroectodermal Tumors, and Atypical Teratoid Rhabdoid Tumors
Meeting:
2008 ASCO Annual Meeting
Presenter:
Maryam Fouladi, MD
Session:
Pediatric Cancer II
(Oral Presentation)
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Other Abstracts in this Sub-Category:
Abstracts by M. Fouladi :
Presentations by M. Fouladi :
Educational Book Manuscripts by M. Fouladi :
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