Preclinical studies have demonstrated that the macrocyclic lactone bryostatin 1 (NSC 399555), which initially activates and subsequently down-regulates the serine/threonine kinase protein kinase C, sensitizes human leukemia cells to 1 -B-D-arabinofuranosylcytosine (ara-C)-induced apoptosis in a dose- and schedule-dependent manner, resulting in synergistic antileukemic effects for the combination. Based upon these and other findings, a multi-institutional Phase I trial in which escalating doses of bryostatin 1 were given as a 24-hr continuous infusion before and after 4 doses of high-dose-ara-C (HiDAC; 1.5 gm/sq.m. q 12h x 4 on days 2-4 and 9-10; 8 total doses) in patients with refractory/relapsed acute leukemia has recently been completed and has identified the bryostatin 1 MTD as 50 ug/sq.m. Initial results of this Phase I trial were encouraging, with 5 objective CRs and one 6+ month leukemia-free interval obtained in a heavily pretreated patient population. The goal of the present application is to conduct a formal multi-institutional Phase II trial of bryostatin 1 and HiDAC in patients with refractory or relapsed acute leukemia, CML-myeloid blast crisis, or untreated high-risk acute leukemia to define the toxicities and antileukemic activity of this regimen more rigorously. Correlative laboratory studies will be conducted in parallel to determine whether in vivo administration of bryostatin 1 (a) down-regulates leukemic blast PKC activity; (b) modifies ex vivo expression of p21 CIP 1, Bcl-2, or phospho-MAPK in ara-C-treated blasts; (c) sensitizes blasts to ara-C-induced mitochondrial damage and apoptosis ex vivo; or (d) increases ara-CTP formation. Additional studies will establish whether sequential ex vivo exposure of blasts to ara-C followed by bryostatin 1 maximizes apoptosis in the subset of leukemic specimens susceptible to bryostatin 1-induced maturation. Finally, attempts will be made to determine which if any of these laboratory determinants correlates with clinical responsiveness to the HiDAC/bryostatin 1 regimen. Information derived from this trial will aid in the design of successor studies in which bryostatin 1 or other novel agents acting through signal transduction pathways are combined with established cytotoxic agents in the treatment of leukemia and possibly other hematologic malignancies.
| Cragg, Louise H; Andreeff, Michael; Feldman, Eric et al. (2002) Phase I trial and correlative laboratory studies of bryostatin 1 (NSC 339555) and high-dose 1-B-D-arabinofuranosylcytosine in patients with refractory acute leukemia. Clin Cancer Res 8:2123-33 |
