A Phase i study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors

Dustin A. Deming, Jacob Ninan, Howard H. Bailey, Jill M. Kolesar, Jens Eickhoff, Joel M Reid, Matthew M. Ames, Renee M. McGovern, Dona Alberti, Rebecca Marnocha, Igor Espinoza-Delgado, John Wright, George Wilding, William R. Schelman

Research output: Contribution to journalArticle

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Abstract

Background Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Methods Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. Results 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. Conclusions The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

Original languageEnglish (US)
Pages (from-to)323-329
Number of pages7
JournalInvestigational New Drugs
Volume32
Issue number2
DOIs
StatePublished - 2014

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Neoplasms
Fatigue
Appointments and Schedules
Sarcoma
Thrombocytopenia
International Normalized Ratio
Population Dynamics
vorinostat
Bortezomib
Area Under Curve
Diarrhea
Adenocarcinoma
Breast

Keywords

  • Bortezomib
  • Phase I
  • PS-341
  • SAHA
  • Vorinostat

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

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A Phase i study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors. / Deming, Dustin A.; Ninan, Jacob; Bailey, Howard H.; Kolesar, Jill M.; Eickhoff, Jens; Reid, Joel M; Ames, Matthew M.; McGovern, Renee M.; Alberti, Dona; Marnocha, Rebecca; Espinoza-Delgado, Igor; Wright, John; Wilding, George; Schelman, William R.

In: Investigational New Drugs, Vol. 32, No. 2, 2014, p. 323-329.

Research output: Contribution to journalArticle

Deming, DA, Ninan, J, Bailey, HH, Kolesar, JM, Eickhoff, J, Reid, JM, Ames, MM, McGovern, RM, Alberti, D, Marnocha, R, Espinoza-Delgado, I, Wright, J, Wilding, G & Schelman, WR 2014, 'A Phase i study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors', Investigational New Drugs, vol. 32, no. 2, pp. 323-329. https://doi.org/10.1007/s10637-013-0035-8
Deming, Dustin A. ; Ninan, Jacob ; Bailey, Howard H. ; Kolesar, Jill M. ; Eickhoff, Jens ; Reid, Joel M ; Ames, Matthew M. ; McGovern, Renee M. ; Alberti, Dona ; Marnocha, Rebecca ; Espinoza-Delgado, Igor ; Wright, John ; Wilding, George ; Schelman, William R. / A Phase i study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors. In: Investigational New Drugs. 2014 ; Vol. 32, No. 2. pp. 323-329.
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abstract = "Background Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Methods Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. Results 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. Conclusions The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.",
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T1 - A Phase i study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors

AU - Deming, Dustin A.

AU - Ninan, Jacob

AU - Bailey, Howard H.

AU - Kolesar, Jill M.

AU - Eickhoff, Jens

AU - Reid, Joel M

AU - Ames, Matthew M.

AU - McGovern, Renee M.

AU - Alberti, Dona

AU - Marnocha, Rebecca

AU - Espinoza-Delgado, Igor

AU - Wright, John

AU - Wilding, George

AU - Schelman, William R.

PY - 2014

Y1 - 2014

N2 - Background Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Methods Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. Results 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. Conclusions The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

AB - Background Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. Methods Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. Results 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. Conclusions The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

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KW - SAHA

KW - Vorinostat

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