In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 18_suppl ( 2006-06-20), p. 13137-13137
Abstract:
13137 Background: The benzyl styryl sulfone analog ON 01910.Na is a novel anticancer agent that inhibits mitotic progression and induces apoptosis; it has activity against most human cancer cells in vitro and against a broad spectrum of human xenografts in mice. Cell kill effects are exposure time-dependent in vitro. After 3d exposure 200 nM ON 01910.Na killed 〉 90% of Daudi lymphoma cells, whereas 40-fold higher drug concentration killed only 50% of cells after 24h exposure. Dogs that received CI of 325 mg/kg/d ×3 failed to reach MTD. Methods: Starting dose 50 mg/m 2 /d as a 72 hr CI was 1/10 th MTD of rats’ daily dose given × 28 d. Treatment cycles were repeated every 2 wks until progressive disease, intolerable toxicity, or withdrawal of consent. Dose was escalated by Fibonacci progression in single pts until grade 2 toxicity when cohorts of 3 are to be studied. Volunteers may be retreated at a higher dose if tolerated by a preceding naïve subject. Results: One man and four women (61–77 yrs) have been studied in 21 cycles in 5 mos as of 1/10/06. Doses of 50, 100, 150 and 250 mg/m 2 /d × 3 have been given for 1 to 10 cycles. Grade 1 granulocytopenia (2/4 pts with carcinoma) indicates biologic activity. Grade 1 fatigue (3/5) was less than in prior chemotherapy regimens. No grade 2 toxicity has yet occurred. Cumulative toxicity has not been seen. Two pts have had stable disease 6+ and 22+ wks. After deproteinization with acetonitrile, plasma or serum samples were measured by mass spectrometry. At 100 mg/m 2 /d steady state levels were 730 nM after the 1st cycle and 1190 nM after the 4th cycle. Drug levels were maximal at 3 to 6 h despite CI suggesting induction of a metabolizing pathway. Levels fell precipitously at the end of infusion on the 1 st cycle but a low level persisted in one pt for 48h after the major drop in the 4 th cycle, suggesting drug accumulation. Conclusion: Levels effective in vitro have been obtained in vivo by CI without limiting toxicity. Hints of activity already seen suggest that this compound has clinical promise. This phase I study continues. [Table: see text]
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2006.24.18_suppl.13137
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2006
detail.hit.zdb_id:
2005181-5
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