Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

Abstract

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 ≥3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m2 to 1000 mg/m2 with bortezomib 1.0 mg/m2 to 1.5 mg/m2 were planned.RESULTS.There were no DLTs in patients receiving bortezomib 1.0 mg/m2 and gemcitabine 500 mg/m2 to 1000 mg/m2 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/m2, gemcitabine 800 mg/m2), establishing bortezomib 1.0 mg/m2 and gemcitabine 1000 mg/m2 as the MTD. Most common Grade ≥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. Cancer 2006. © 2006 American Cancer Society

Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib

“…Drug sensitivity testing was done using WST-1 assay and direct cell count for Caco-2 and HRT-18 cells, at different times (24,48,72, and 96 h) and doses (range, 0.01-0.1 μmol/L) of bortezomib. These concentrations are within those achieved clinically in the plasma of patients treated with bortezomib (17). To screen for IC 50 values, an indirect measure of cell viability and proliferation was done by determination of the metabolic activity of cells with a colorimetric assay based on cleavage of the tetrazolium salt WST-1 by mitochondrial dehydrogenases (cell proliferation reagent WST1; Roche Diagnostics).…”

Inhibition of NF-κB Signaling by Quinacrine Is Cytotoxic to Human Colon Carcinoma Cell Lines and Is Synergistic in Combination with Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) or Oxaliplatin

“…Studies using bortezomib (PS-341), also a proteasomal inhibitor that inhibits NF-B activation, have demonstrated enhanced sensitization to radiation therapy in the LOVO xenograft model (98), increased chemosensitivity to CPT-11 in colorectal cancer cells (99), and enhancement of the cytotoxic effect of several chemotherapeutic agents including carboplatin and CPT-11 in glioma cells (100). Recently, phase I studies using bortezomib in combination with irinotecan (101) or with gemcitabine (102) or with capecitabine and L-OHP (103) in patients with advanced solid tumors have shown that these drug combinations are safe, with manageable toxicities, and are currently in Phase II trials, indicating that inhibition of NF-B may play an important role in new developmental therapeutic approaches in cancer. Although very recently Hideshima et al (104) showed that bortezomib and other proteasome inhibitors can also induce canonical NF-B signaling in MM cells through phosphorylation of receptor-interacting protein 2 as well as IKK␤ (105), which clearly indicates that the action of bortezomib and other proteasome inhibitors is not limited to NF-B inhibition and that other mechanisms may play a role in its anti-tumor activity.…”

The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype

“…These agents inhibit the degradation of multiubiquitinated target proteins, i.e., cell cycle regu- Bortezomib is the first proteasome inhibitor that has been introduced into clinical practice for the treatment of relapsed multiple myeloma, 2,28,47,48 and active clinical investigation is ongoing in other malignancies. [49][50][51][52][53][54][55] In this study we provide the framework for more intensive clinical investigation of bortezomib in AML. MTT uptake experiments on AML cell lines, sensitive and resistant to conventional chemotherapeutic agents, indicate that bortezomib is efficient at concentrations in the low nanomolar range, within pharmacologically achievable doses.…”