A dose-finding and pharmacodynamic study of bortezomib in combination with weekly paclitaxel in patients with advanced solid tumors.
OBJECTIVE
A phase I study to determine the maximum tolerated dose (MTD) of bortezomib (B) when combined with weekly paclitaxel in patients with advanced solid tumors.


METHODS
Eligible patients received escalating doses of intravenous (IV) bortezomib (0.6-2 mg/m(2)) on days 2 and 9 and IV paclitaxel at 100 mg/m(2) on days 1 and 8 of a 21-day cycle. Dose escalation was based on two end-points: not exceeding 80% 20S-proteasome inhibition (20-S PI) and the development of dose-limiting toxicity defined as grade 3 or greater non-hematologic or grade 4 hematologic toxicities.


RESULTS
Forty-five patients with advanced solid tumors and a median of 3 prior chemotherapy regimens (range 0-9), received 318 doses (median 5, range 1-34) of bortezomib and paclitaxel. Dose-related inhibition of 20-S PI was observed with a maximum inhibition of 70-80% at the MTD of 1.8 mg/m(2) of bortezomib. At the MTD (N = 9) the following toxicities were observed: grade 4 neutropenia without fever (n = 2) and cerebrovascular ischemia (n = 1); grade 3 neutropenia (n = 3), diarrhea (n = 2), nausea (n = 1), and fatigue (n = 1); grade 2 fatigue (n = 5), diarrhea (n = 4), and dyspnea (n = 2). There was one partial response in a patient with an eccrine porocarcinoma. Stabilization of disease was observed in 7 (16%) patients, 3 of whom had advanced pancreatic cancer.


CONCLUSIONS
Sequential paclitaxel and bortezomib in previously treated patients with advanced solid tumors resulted in acceptable toxicity and no evidence of interaction. The recommended phase II dose of bortezomib in combination with weekly paclitaxel was 1.8 mg/m(2).
Ramaswamy
Bhuvaneswari
B
The Ohio State University, B401, Starling Loving Hall, 320 W 10th av, Columbus, OH 43210, USA. Bhuvaneswari.Ramaswamy@osumc.edu
Bekaii-Saab
Tanios
T
Schaaf
Larry J
LJ
Lesinski
Gregory B
GB
Lucas
David M
DM
Young
Donn C
DC
Ruppert
Amy S
AS
Byrd
John C
JC
Culler
Kristy
K
Wilkins
Diedre
D
Wright
John J
JJ
Grever
Michael R
MR
Shapiro
Charles L
CL
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009369:Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D018809:Proliferating Cell Nuclear Antigen / Q000097:blood; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein / Q000097:blood
D001897:Boronic Acids; D016207:Cytokines; D018809:Proliferating Cell Nuclear Antigen; D061988:Proteasome Inhibitors; D011719:Pyrazines; D051028:bcl-2-Associated X Protein; C413374:p27 antigen; D000069286:Bortezomib; D017239:Paclitaxel