The purine analog F-ara-AMP (fludarabine) is among the most active agents available against B cell malignancies such as CLL and indolent non-Hodgkin's lymphoma. The signal transduction modulator bryostatin 1 (NSC 339555), a macrocyclic lactone activator/down-regulator of PKC currently under extensive clinical evaluation, has also displayed activity against these disorders in early Phase I trials. Furthermore, preclinical in vitro and in vivo studies have documented synergistic, sequence-dependent anti-leukemic interactions between these agents, a phenomenon that may involve either (a) a diminished threshold for apoptosis or (b) potentiation of leukemic cell differentiation. Based upon these considerations, a multicenter Phase I trial has been initiated in which patients with progressive CLL or refractory indolent NHL are randomized to receive escalating doses of bryostatin 1 as a 24-hr infusion (initial dose 16 mcg/sq m) either before, or after, a 5-day course of fludarabine (initial dose 12.5 mg/sq m/d). Preliminary results of this study are encouraging, with 2 complete and 3 partial objective responses (out of 12 patients) at the initial Phase I drug dose levels.
The specific aims of this application are (1) To determine the MTD for bryostatin 1 when given before or after a standard course of fludarabine; (2) To characterize the dose-limiting and sequence-dependent toxicities of this regimen; (3) To test the hypotheses that in vivo administration of bryostatin 1 can down-regulate total PKC activity in primary CLL lymphocytes, and that this activity correlates with biological actions; (4) To determine (a) whether prior in vivo administration of bryostatin 1 sensitizes CLL lymphocytes to fludarabine-mediated apoptosis ex vivo, and (b) whether subsequent ex vivo exposure to bryostatin 1 promotes apoptosis in CLL cells previously exposed to fludarabine in vivo; (5) To test the hypothesis that in vivo administration of bryostatin 1 and fludarabine can induce differentiation of CLL lymphocytes. Information derived from these studies will assist in the rational design of successor Phase II efficacy trials of bryostatin 1 and fludarabine in B-cell malignancies, provide mechanistic insights into in vivo interactions between these agents and help to identify intermediate laboratory-based markers that are capable of predicting disease responsiveness to this regimen.
| Roberts, John D; Smith, Mitchell R; Feldman, Eric J et al. (2006) Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma. Clin Cancer Res 12:5809-16 |
| Roberts, John D; Smith, Mitchell R; Feldman, Eric J et al. (2002) Phase I study of bryostatin-1 and fludarabine in patients with chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma. Clin Lymphoma 3:184-8 |
