A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma

Abstract

The purpose of this study was to assess the safety and identify the recommended doses of enzastaurin and bortezomib in combination for future Phase II studies in patients with relapsed or refractory multiple myeloma. Three dose levels (DLs) of oral enzastaurin and intravenous bortezomib were used according to a conventional ''3 1 3'' design. A loading dose of enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by enzastaurin 125 mg BID for 1 week, after which bortezomib was added (Cycle 1, 28 days, 1.0 mg/m 2 : Days 8, 11, 15, and 18; seven subsequent 21-day cycles, 1.3 mg/m 2 : Days 1, 4, 8, and 11). Twenty-three patients received treatment; all patients received prior systemic therapy. Most patients received 3 regimens; 17 patients were bortezomib-refractory. A median of four treatment cycles (range 1-24) was completed. No dose-limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug-related Grade 3/4 toxicities were thrombocytopenia (n 5 6) and anemia (n 5 2). No patients died on therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory multiple myeloma are as follows: enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 of a 21-day cycle. The combination was well-tolerated and demonstrated some antimyeloma activity. Am. J. Hematol. 86:573-578, 2011. V

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

“…In a phase I study in 23 patients with relapsed or refractory multiple myeloma who had received 3 or more regimens, the combination of enzastaurin and bortezomib was well tolerated and showed modest activity (28). No dose-limiting toxicities were observed, and thrombocytopenia (26.1%) and anemia (8.7%) were the most common drug-related grade 3 or 4 toxicities.…”

A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer

“…No benefit was seen when the compound was added to a bevacizumab-containing first-line NSCLC regimen [44]. Ongoing combination trials with the compound include studies with rapamycin in preclinical head and neck cancer models [45], bortezomib in multiple myeloma [46], and sunitinib in renal cell carcinoma [47].…”

New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)

“…139 This gave some responses but it was difficult to assess whether dasatinib added anything to the combination of agents. Other inhibitors are the anti-VEGF-R MoAb bevacizumab, which, in combination with lenalidomide, induced 71% of PR or better, 140 and IGF1-R, 141, 142 EGF-R 143 and PKC 144 inhibitors that did not respond in monotherapy, but may have some role in combination with other agents such as bortezomib (table 5). …”