Phase Ib trial of bryostatin 1 in patients with refractory malignancies.
A Phase Ib 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 microg/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 microg/m2 as a 30-min infusion) on days 1 and 4. Conventional toxicities (grades I-III) 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 experienced significant declines in activity (approximately 50%) that were sustained in some cases for periods of > or = 72 h. Comparison of 72-h with baseline values for all three patient cohorts combined 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 proliferation, or cytotoxicity, although two of three samples from patients in cohort 3 did show significant posttreatment 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 microg/m2 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.
Grant
S
S
Department of Medicine, Virginia Commonwealth University, Richmond 23298-0230, USA.
Roberts
J
J
Poplin
E
E
Tombes
M B
MB
Kyle
B
B
Welch
D
D
Carr
M
M
Bear
H D
HD
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D054713:Bryostatins; D015331:Cohort Studies; D003602:Cytotoxicity, Immunologic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000494:pharmacology; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008223:Lymphoma / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D018942:Macrolides; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D018579:Patient Selection; D010974:Platelet Aggregation / Q000187:drug effects; D011493:Protein Kinase C / Q000097:blood
D000970:Antineoplastic Agents; D054713:Bryostatins; D007376:Interleukin-2; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1; D011493:Protein Kinase C