A Multicenter Phase II Study of Single-Agent Enzastaurin in Previously Treated Waldenström Macroglobulinemia

Abstract

Purpose: Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenstr€ om macroglobulinemia (WM) model. These findings provided the rationale for a multicenter phase II trial of oral enzastaurin in previously treated patients with WM.Experimental design: Patients who were treated with 1 to 5 prior regimens and who had a baseline immunoglobulin M level 2 times or more the upper limit of normal received oral enzastaurin 250 mg twice daily (500 mg total) after a single loading dose (day 1, cycle 1) of 375 mg 3 times daily (1,125 mg total) for 8 cycles of 28 days each or until progressive disease. Six patients who progressed during treatment with enzastaurin had dexamethasone added per protocol.Results: From July 2008 to December 2010, 42 patients were enrolled. The objective response rate (RR) was 38.1% (2 partial and 14 minor responses). One patient had grade 3 leukopenia and one patient died during the study from septic shock; both events were considered drug related. A statistically significant association between RR and interleukin 15 (IL-15) was observed, suggesting that higher concentration levels of IL-15 may be associated with better response.Conclusion: Enzastaurin was active and well tolerated in previously treated patients with WM. Because of the small sample size of this uncontrolled study, further assessment of the relationship between IL-15 and response to enzastaurin in patients with WM is required. These results warrant further investigation of enzastaurin for the treatment of WM.

Waldenström macroglobulinemia: What a hematologist needs to know

“…Enzastaurin is an investigational oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways and has been evaluated in a phase II trial of 42 patients, showing an ORR of 38% (Table 7). It was well tolerated, and grade 3 toxicities were rare with leukopenia and septic shock in 1 patient each [133]. In a recent phase III trial of diffuse large B cell lymphoma in which enzastaurin was being evaluated in a maintenance setting, the primary study end-point of disease free survival was not met, impeding its development.…”

Disruption of pre-B-cell receptor signaling jams the WNT/β-catenin pathway and induces cell death in B-cell acute lymphoblastic leukemia cell lines

“…ENZ showed strong inhibitory activity in pre-clinical studies of a variety of tumors, and has been clinically tested in a wide spectrum of solid and hematological malignancies. While ENZ failed to show significant clinical benefit in solid tumors, it has showed promising results as a single agent in a variety of pretreated B-cell malignancies, including Waldenström macroglobulinemia (overall response rate (ORR) of 38.1%) [18] and follicular lymphoma (ORR of 26.4% including 2 complete responses) [19]. Targeting PKC␤ with ENZ and other novel PKC␤ inhibitors, such as AEB071, continues to be evaluated in CLL and DLBCL, in order to elucidate the exact mechanism of action, and to find the best synergistic combination [20,21] (www.clinicaltrials.gov; Identifier: NCT01854606).…”

Phase II clinical trials for Waldenstrom’s macroglobulinemia

“…Enzastaurin is an anti-angiogenic and antineoplastic agent, which acts by inhibition of PKC [50]. A multicenter Phase II study of single-agent enzastaurin in 42 patients with previously treated WM showed an ORR of 38%, with all being PR and MR [51]. A statistically significant association between response rate and IL-15 level was observed.…”