Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia
Gerald E Marti, Maryalice Stetler-Stevenson, Nicole Drbohlav Grant, Therese White, William D Figg, Tanyifor Tohnya, Elaine S Jaffe, Kieron Dunleavy, John E Janik, Seth M Steinberg, Wyndham H Wilson, Gerald E Marti, Maryalice Stetler-Stevenson, Nicole Drbohlav Grant, Therese White, William D Figg, Tanyifor Tohnya, Elaine S Jaffe, Kieron Dunleavy, John E Janik, Seth M Steinberg, Wyndham H Wilson
Abstract
This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.
Conflict of interest statement
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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Source: PubMed