Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors.

Messersmith, Wells A.; Baker, Sharyn D.; Lassiter, Lance K.; Sullivan, Rana; Dinh, Kha; Almuete, Virna; Wright, John J.; Donehower, Ross C.; Carducci, Michael A.; Armstrong, Deborah K.

doi:10.1158/1078-0432.ccr-05-1942

Cited by 50 publications

(21 citation statements)

References 27 publications

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“…Fatigue, diarrhea, flushing, and nausea were the most common adverse events, reflecting previous experience of bortezomib alone or in combination with docetaxel (12,13,32,34,45). The most common grade 3 or 4 drug-related adverse events were diarrhea, asthenia, and fatigue.…”

Section: Discussionmentioning

confidence: 61%

Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer

Dreicer

Petrylak

Agus

et al. 2007

Clinical Cancer Research

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Purpose: To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer. Experimental Design: Two bortezomib doses (1.3 and 1.6 mg/m 2 /dose) in combination with four docetaxel doses (25-40 mg/m 2 /dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines. Results: Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (z50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for z4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines,11% achieved a partial response, and an additional 67% had stable disease.The degree of proteasome inhibition was similar to that reported with single-agent bortezomib.Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred. Conclusions:The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m 2 bortezomib plus 40 mg/m 2 docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.

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Section: Discussionmentioning

confidence: 61%

Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer

Dreicer

Petrylak

Agus

et al. 2007

Clinical Cancer Research

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“…These agents have already become the standard of care for refractory multiple myeloma and mantle cell lymphoma (26,27). There are many tumor entities, such as metastatic breast cancer, non-small cell lung cancer, and cutaneous T-cell lymphoma that have produced encouraging results in phases I and II studies using proteasome inhibitor treatments (28,29). Proteasome inhibitors have a number of important mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of Vascular Endothelial Growth Factor Receptor 2 Is a Major Molecular Determinant of Proteasome Inhibitor–Mediated Antiangiogenic Action in Endothelial Cells

et al. 2009

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The ubiquitin-proteasome system is the major pathway for intracellular protein degradation in eukaryotic cells. This system controls a wide range of cellular regulatory proteins, including transcription factors and cell cycle regulatory proteins. Recent evidence also established the importance of the proteasome in tumor development, showing antitumor and antiangiogenic actions by using selective inhibitors in vivo. As signaling via the vascular endothelial growth factor receptor 2 (VEGFR2) pathway is critical for angiogenic responses to occur, we explored whether antiangiogenic effects due to proteasome inhibition were partly mediated through decreased endothelial VEGFR2 expression. This study shows that different proteasome inhibitors blocked VEGFR2 expression in a time-dependent and concentration-dependent manner. This blockade was paralleled by the respective inhibition of the formation of capillary-like structures and endothelial cell migration. In contrast, neither tie-2 nor VEGFR1 expression was significantly affected by proteasome inhibitor treatment. The suppressive effects on VEGFR2 expression were not conveyed by increased shedding or a decrease in protein half-life, suggesting that transcriptional mechanisms accounted for the observed effects. In line with this conclusion, proteasome inhibition significantly suppressed VEGFR2 mRNA accumulation. In addition, inhibitor treatment considerably decreased the transcriptional activity of 5 ¶ deletional VEGFR2 promoter gene constructs. Proteasome inhibition-mediated repression was controlled by a GC-rich region that harbored one consensus Sp1-binding site. Subsequent EMSA analyses showed decreased constitutive Sp1-dependent DNA binding in response to proteasome inhibition. In addition, we could show that proteasome inhibitors reduced VEGFR2 mRNA stability. Therefore, VEGFR2 expression may constitute a critical molecular target of proteasome inhibitors that may mediate their antiangio-

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“…Slightly higher doses were tolerated when bortezomib was administered weekly (Papandreou et al, 2004) or on days 1 and 4 every 14 days (Hamilton et al, 2005). In other combination dose-escalation studies in advanced non-small-cell lung cancer and other refractory solid tumours (Lara et al, 2006), MTDs were bortezomib 1.0 mg m À2 plus docetaxel 75 mg m À2 on the same schedule, and bortezomib 0.8 mg m À2 twice weekly for 2 weeks plus docetaxel 25 mg m À2 on days 1 and 8 of a 21-day cycle (Messersmith et al, 2006). The docetaxel dose in our study is consistent with that used in combination with chemotherapeutic agents in anthracyclinepretreated breast cancer (O'Shaughnessy et al, 2002;Chan et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…There is no evidence of a drug interaction between bortezomib and docetaxel (Messersmith et al, 2006).…”

mentioning

confidence: 99%

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

et al. 2008

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The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60 -100 mg m À2 on day 1) plus bortezomib (1.0 -1.5 mg m À2 on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n ¼ 1) and febrile neutropenia (n ¼ 4). The MTD was bortezomib 1.5 mg m À2 plus docetaxel 75 mg m À2 . All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/ docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents.

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Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors.

Cited by 50 publications

References 27 publications

Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer

Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer

Down-regulation of Vascular Endothelial Growth Factor Receptor 2 Is a Major Molecular Determinant of Proteasome Inhibitor–Mediated Antiangiogenic Action in Endothelial Cells

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

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