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. CONCLUSION: Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.
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. CONCLUSION: Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.
Authors: G S Falchook; M Duvic; D S Hong; J Wheler; A Naing; J Lim; R Kurzrock Journal: Cancer Chemother Pharmacol Date: 2011-12-29 Impact factor: 3.333
Authors: J Portnow; P Frankel; S Koehler; P Twardowski; S Shibata; C Martel; R Morgan; M Cristea; W Chow; D Lim; V Chung; K Reckamp; L Leong; T W Synold Journal: Cancer Chemother Pharmacol Date: 2011-08-18 Impact factor: 3.333
Authors: B C Potts; M X Albitar; K C Anderson; S Baritaki; C Berkers; B Bonavida; J Chandra; D Chauhan; J C Cusack; W Fenical; I M Ghobrial; M Groll; P R Jensen; K S Lam; G K Lloyd; W McBride; D J McConkey; C P Miller; S T C Neuteboom; Y Oki; H Ovaa; F Pajonk; P G Richardson; A M Roccaro; C M Sloss; M A Spear; E Valashi; A Younes; M A Palladino Journal: Curr Cancer Drug Targets Date: 2011-03 Impact factor: 3.428
Authors: Callum M Sloss; Fang Wang; Rong Liu; Lijun Xia; Michael Houston; David Ljungman; Michael A Palladino; James C Cusack Journal: Clin Cancer Res Date: 2008-08-15 Impact factor: 12.531
Authors: J H Mendler; J Kelly; S Voci; D Marquis; L Rich; R M Rossi; S H Bernstein; C T Jordan; J Liesveld; R I Fisher; J W Friedberg Journal: Ann Oncol Date: 2008-05-25 Impact factor: 32.976