Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.
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.
Orlowski
Robert Z
RZ
Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA. r_orlowski@med.unc.edu
Voorhees
Peter M
PM
Garcia
Reynaldo A
RA
Hall
Melissa D
MD
Kudrik
Fred J
FJ
Allred
Tammy
T
Johri
Anandhi R
AR
Jones
Paul E
PE
Ivanova
Anastasia
A
Van Deventer
Hendrik W
HW
Gabriel
Don A
DA
Shea
Thomas C
TC
Mitchell
Beverly S
BS
Adams
Julian
J
Esseltine
Dixie-Lee
DL
Trehu
Elizabeth G
EG
Green
Marie
M
Lehman
Mary Jo
MJ
Natoli
Susan
S
Collins
Jason M
JM
Lindley
Celeste M
CM
Dees
E Claire
EC
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
D000903:Antibiotics, Antineoplastic; D001897:Boronic Acids; D008081:Liposomes; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011092:Polyethylene Glycols; D000069286:Bortezomib; D004317:Doxorubicin