Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors.
BACKGROUND
Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated.


METHODS
Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion) on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m(2) to 1000 mg/m(2) with bortezomib 1.0 mg/m(2) to 1.5 mg/m(2) were planned.


RESULTS
There were no DLTs in patients receiving bortezomib 1.0 mg/m(2) and gemcitabine 500 mg/m(2) to 1000 mg/m(2) in the first 3 dose levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2)), establishing bortezomib 1.0 mg/m(2) and gemcitabine 1000 mg/m(2) as the MTD. Most common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration.


CONCLUSIONS
Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.
Ryan
David P
DP
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA. dpryan@partners.org
Appleman
Leonard J
LJ
Lynch
Thomas
T
Supko
Jeffrey G
JG
Fidias
Panagiotis
P
Clark
Jeffrey W
JW
Fishman
Mayer
M
Zhu
Andrew X
AX
Enzinger
Peter C
PC
Kashala
Oscar
O
Cusack
James
J
Eder
Joseph P
JP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D000093542:Gemcitabine
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D003841:Deoxycytidine; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D000093542:Gemcitabine