Phase lb Trial of Bryostatin 1 in Patients with Refractory Malignancies1

Abstract

A Phase lb trial of bryostatin 1, a macrocyclic lactone and protein kinase C (PKC) activator, was conducted in patients with refractory nonhematological malignancies with the primary goal of determining whether down-regulation of peripheral blood mononuclear cell (PBMNC) PKC activity could be achieved in vivo in humans. Patients (four patients/cohort) received bryostatin 1 (25 jig/m2) as a 1-h infusion weekly three times every 4 weeks, but to study the schedule dependence of pharmacokinetics and pharmacodynamics, the first dose was administered according to one of three schedules: (a) a 1-h infusion; (b) a 24-h infusion; or (c) a split course (12.5 iWm2 as a 30-mm infusion) on days 1 and 4. Conventional toxicities (grades I-Ill) included myalgias, fever, anemia, fatigue, phlebitis, and headache; in addition, two patients in cohort 3 experienced transient elevations in liver function tests, although these patients had preexisting liver metastases. No objective clinical responses were encountered. Effects on PBMNC PKC activity were heterogeneous. Several patients in cohorts 1 and 2 expenenced significant declines in activity (-50%) that were sustamed in some cases for periods of 72 h. Comparison of 72-h with baseline values for all three patient cohorts cornbined revealed a trend toward PKC down-regulation (P = 0.06; signed rank test). For each schedule, plasma bryostatin 1 levels were below the level of detection of a platelet aggregation-based bioassay (3-4 nM). Bryostatin 1 administration failed to produce consistent alterations in lymphocyte immunophenotypic profiles, interleukin 2-induced proliferaReceived 5/30/97: revised I 1/25/97: accepted 12/19/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked adt’ertise,nent in accordance with I 8 U.S.C. Section 1734 solely to indicate this fact. I Supported by NIH Grants R03 CA66990 and RO1 CA63753 and Award P30 CA16059 to the Massey Cancer Center and in part by NIH General Clinical Research Center Grant MO1 RR00065. Portions of this work were presented in preliminary form at the AACR Annual Meeting, Washington, D.C., April 20-24, 1996. 2 To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Massey Cancer Center, Medical College of Virginia. Virginia Commonwealth University. P. 0. Box 980230, Richmond, VA 23298-0230. Phone: (804) 828-5211: Fax: (804) 828-8079. tion, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatrnent increases in proliferation. Moreover, in some patients, bryostatin 1 treatment increased lymphokine-activated killer cell activity. These findings indicate that bryostatin 1 doses of 25 ig/rn2 can induce in vivo PBMNC PKC down-regulation in at least a subset of patients and raise the possibility that higher bryostatin 1 doses may be more effective in achieving this effect.

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@inproceedings{Grant2005PhaseLT, title={Phase lb Trial of Bryostatin 1 in Patients with Refractory Malignancies1}, author={Steven Grant and John D. Roberts and Elizabeth A. Poplin and Mary Beth Tombes and Brenda Kyle and Dawn Welch and Marc Carr and Harry D Bear}, year={2005} }