A Phase I trial has been conducted in patients with refractory/relapsed acute
leukemia in which escalating doses of the
protein kinase C (PKC) activator and down-regulator
bryostatin 1 (NSC399555), administered as a 24-h continuous infusion on days 1 and 11, were given immediately before and after a split course of high-dose 1-beta-D-arabinofuranosylcytosine (HiDAC; 1.5 g/m(2) every 12 h x 4) administered on days 2 and 3, and 9 and 10. The
bryostatin 1 maximally tolerated dose (MTD) was identified as 50 microg/m(2), with myalgias representing the major dose-limiting toxicity (DLT). Other DLTs included prolonged
neutropenia and
thrombocytopenia, and hepatotoxicity. Of the 23 patients who completed their course of
therapy and were fully evaluable for response, the large majority of whom had unfavorable prognostic characteristics, 4 complete remissions (CRs) were obtained. An additional 3 patients were treated at a 3 g/m(2)
ara-C (1-beta-D-arabinofuranosylcytosine) dose level to determine whether this HiDAC dose could be administered in conjunction with
bryostatin 1. All 3 of these patients experienced DLT, and this dose was considered above the MTD. However, one of the latter patients, who was heavily pretreated, also achieved a CR that persisted 5+ months without maintenance. Finally, 1 patient post-HiDAC and autologous
bone marrow transplantation achieved a 5+ month
leukemia-free survival although she did not meet the criteria for a CR because of persistent transfusion requirements. Correlative laboratory studies performed on blasts from 9 patients revealed that in vivo administration of
bryostatin 1 resulted in variable effects on total blast PKC activity, including decreases in 4 samples, increases in 2, and no change in 3. Previous in vivo
bryostatin 1 exposure also exerted disparate effects on the extent of apoptosis observed in blasts exposed to
ara-C ex vivo, although increases were noted in a subset of patient samples. Interestingly, in vivo administration of
bryostatin 1 by itself induced lethality in some patient specimens. No clear relationship between the in vivo effects of
bryostatin 1 on blast PKC activity and the extent of
ara-C-related apoptosis that occurred ex vivo was apparent. Together, these findings demonstrate that
bryostatin 1 can be safely administered as a continuous infusion before and after a split course of HiDAC in patients with refractory
leukemia, and identify the
bryostatin 1 MTD as 50 microg/m(2) when given by this schedule. Furthermore, the achievement of several CRs in the setting of a Phase I trial in which many patients had particularly high-risk features (e.g., short initial remission, previous HiDAC or autologous
bone marrow transplantation, and multiple previous salvage regimens) suggests that this regimen has activity in acute
leukemia and warrants additional investigation.