Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies
Robert Z Orlowski, Peter M Voorhees, Reynaldo A Garcia, Melissa D Hall, Fred J Kudrik, Tammy Allred, Anandhi R Johri, Paul E Jones, Anastasia Ivanova, Hendrik W Van Deventer, Don A Gabriel, Thomas C Shea, Beverly S Mitchell, Julian Adams, Dixie-Lee Esseltine, Elizabeth G Trehu, Marie Green, Mary Jo Lehman, Susan Natoli, Jason M Collins, Celeste M Lindley, E Claire Dees, Robert Z Orlowski, Peter M Voorhees, Reynaldo A Garcia, Melissa D Hall, Fred J Kudrik, Tammy Allred, Anandhi R Johri, Paul E Jones, Anastasia Ivanova, Hendrik W Van Deventer, Don A Gabriel, Thomas C Shea, Beverly S Mitchell, Julian Adams, Dixie-Lee Esseltine, Elizabeth G Trehu, Marie Green, Mary Jo Lehman, Susan Natoli, Jason M Collins, Celeste M Lindley, E Claire Dees
Abstract
Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.
Source: PubMed