title: Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.
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.
authors.affiliation: Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA. r_orlowski@med.unc.edu
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.forename: Peter M
authors.initials: PM
authors.lastname: Voorhees
authors.forename: Reynaldo A
authors.initials: RA
authors.lastname: Garcia
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Hall
authors.forename: Fred J
authors.initials: FJ
authors.lastname: Kudrik
authors.forename: Tammy
authors.initials: T
authors.lastname: Allred
authors.forename: Anandhi R
authors.initials: AR
authors.lastname: Johri
authors.forename: Paul E
authors.initials: PE
authors.lastname: Jones
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Van Deventer
authors.forename: Don A
authors.initials: DA
authors.lastname: Gabriel
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Shea
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Mitchell
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Trehu
authors.forename: Marie
authors.initials: M
authors.lastname: Green
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Lehman
authors.forename: Susan
authors.initials: S
authors.lastname: Natoli
authors.forename: Jason M
authors.initials: JM
authors.lastname: Collins
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Lindley
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D001897:Boronic Acids; D008081:Liposomes; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011092:Polyethylene Glycols; D000069286:Bortezomib; D004317:Doxorubicin