A phase i study of vorinostat in combination with bortezomib in patients with advanced malignancies

William R. Schelman, Anne M. Traynor, Kyle D. Holen, Jill M. Kolesar, Steven Attia, Tien Hoang, Jens Eickhoff, Zhisheng Jiang, Dona Alberti, Rebecca Marnocha, Joel M Reid, Matthew M. Ames, Renee M. McGovern, Igor Espinoza-Delgado, John J. Wright, George Wilding, Howard H. Bailey

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m2). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m 2 to 1.5 mg/m2. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m2. DLTs consisted of grade 3 fatigue in three patients (1 mg/m2,1.3 mg/m2 and 1.5 mg/m 2) and grade 3 hyponatremia in one patient (1.5 mg/m2). The most common grade 1/2 toxicities included nausea (60.9 %), fatigue (34.8 %), diaphoresis (34.8 %), anorexia (30.4 %) and constipation (26.1 %). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle.

Original languageEnglish (US)
Pages (from-to)1539-1546
Number of pages8
JournalInvestigational New Drugs
Volume31
Issue number6
DOIs
StatePublished - Dec 2013

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Maximum Tolerated Dose
Neoplasms
Fatigue
Bortezomib
vorinostat
Hyponatremia
Anorexia
Constipation
Sarcoma
Nausea
Area Under Curve
Pharmacokinetics
Acids
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Schelman, W. R., Traynor, A. M., Holen, K. D., Kolesar, J. M., Attia, S., Hoang, T., ... Bailey, H. H. (2013). A phase i study of vorinostat in combination with bortezomib in patients with advanced malignancies. Investigational New Drugs, 31(6), 1539-1546. https://doi.org/10.1007/s10637-013-0029-6

A phase i study of vorinostat in combination with bortezomib in patients with advanced malignancies. / Schelman, William R.; Traynor, Anne M.; Holen, Kyle D.; Kolesar, Jill M.; Attia, Steven; Hoang, Tien; Eickhoff, Jens; Jiang, Zhisheng; Alberti, Dona; Marnocha, Rebecca; Reid, Joel M; Ames, Matthew M.; McGovern, Renee M.; Espinoza-Delgado, Igor; Wright, John J.; Wilding, George; Bailey, Howard H.

In: Investigational New Drugs, Vol. 31, No. 6, 12.2013, p. 1539-1546.

Research output: Contribution to journalArticle

Schelman, WR, Traynor, AM, Holen, KD, Kolesar, JM, Attia, S, Hoang, T, Eickhoff, J, Jiang, Z, Alberti, D, Marnocha, R, Reid, JM, Ames, MM, McGovern, RM, Espinoza-Delgado, I, Wright, JJ, Wilding, G & Bailey, HH 2013, 'A phase i study of vorinostat in combination with bortezomib in patients with advanced malignancies', Investigational New Drugs, vol. 31, no. 6, pp. 1539-1546. https://doi.org/10.1007/s10637-013-0029-6
Schelman, William R. ; Traynor, Anne M. ; Holen, Kyle D. ; Kolesar, Jill M. ; Attia, Steven ; Hoang, Tien ; Eickhoff, Jens ; Jiang, Zhisheng ; Alberti, Dona ; Marnocha, Rebecca ; Reid, Joel M ; Ames, Matthew M. ; McGovern, Renee M. ; Espinoza-Delgado, Igor ; Wright, John J. ; Wilding, George ; Bailey, Howard H. / A phase i study of vorinostat in combination with bortezomib in patients with advanced malignancies. In: Investigational New Drugs. 2013 ; Vol. 31, No. 6. pp. 1539-1546.
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abstract = "Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m2). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m 2 to 1.5 mg/m2. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m2. DLTs consisted of grade 3 fatigue in three patients (1 mg/m2,1.3 mg/m2 and 1.5 mg/m 2) and grade 3 hyponatremia in one patient (1.5 mg/m2). The most common grade 1/2 toxicities included nausea (60.9 {\%}), fatigue (34.8 {\%}), diaphoresis (34.8 {\%}), anorexia (30.4 {\%}) and constipation (26.1 {\%}). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle.",
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AU - Traynor, Anne M.

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AU - Kolesar, Jill M.

AU - Attia, Steven

AU - Hoang, Tien

AU - Eickhoff, Jens

AU - Jiang, Zhisheng

AU - Alberti, Dona

AU - Marnocha, Rebecca

AU - Reid, Joel M

AU - Ames, Matthew M.

AU - McGovern, Renee M.

AU - Espinoza-Delgado, Igor

AU - Wright, John J.

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AU - Bailey, Howard H.

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N2 - Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m2). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m 2 to 1.5 mg/m2. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m2. DLTs consisted of grade 3 fatigue in three patients (1 mg/m2,1.3 mg/m2 and 1.5 mg/m 2) and grade 3 hyponatremia in one patient (1.5 mg/m2). The most common grade 1/2 toxicities included nausea (60.9 %), fatigue (34.8 %), diaphoresis (34.8 %), anorexia (30.4 %) and constipation (26.1 %). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle.

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