Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies

Suresh S. Ramalingam, Robert A. Parise, Ramesh K. Ramananthan, Theodore F. Lagattuta, Lori A. Musguire, Ronald G. Stoller, Douglas M. Potter, Athanassios E. Argiris, James A. Zwiebel, Merrill J. Egorin, Chandra Belani

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Abstract

Purpose: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental Design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxelwere escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. Results: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non - dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25p atients evaluable for response, partial responses occurred in 11 (10 non - small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. Conclusions: Both schedules of vorinostat (400 mg oral qd × 14 days or 300 mg bd × 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6mg/mL × min) and paclitaxel (200mg/m2). Encouraging anticancer activity wasnoted in patients with previously untreated non - small cell lung cancer.

Original languageEnglish (US)
Pages (from-to)3605-3610
Number of pages6
JournalClinical Cancer Research
Volume13
Issue number12
DOIs
StatePublished - Jun 15 2007

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Histone Deacetylase Inhibitors
Carboplatin
Paclitaxel
Pharmacokinetics
Neoplasms
Head and Neck Neoplasms
Non-Small Cell Lung Carcinoma
Appointments and Schedules
vorinostat
Neutropenia
Thrombocytopenia
Nausea
Vomiting
Fatigue
Half-Life
Anemia
Diarrhea
Research Design
Fever

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ramalingam, Suresh S. ; Parise, Robert A. ; Ramananthan, Ramesh K. ; Lagattuta, Theodore F. ; Musguire, Lori A. ; Stoller, Ronald G. ; Potter, Douglas M. ; Argiris, Athanassios E. ; Zwiebel, James A. ; Egorin, Merrill J. ; Belani, Chandra. / Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 12. pp. 3605-3610.
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title = "Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies",
abstract = "Purpose: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental Design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxelwere escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. Results: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non - dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25p atients evaluable for response, partial responses occurred in 11 (10 non - small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. Conclusions: Both schedules of vorinostat (400 mg oral qd × 14 days or 300 mg bd × 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6mg/mL × min) and paclitaxel (200mg/m2). Encouraging anticancer activity wasnoted in patients with previously untreated non - small cell lung cancer.",
author = "Ramalingam, {Suresh S.} and Parise, {Robert A.} and Ramananthan, {Ramesh K.} and Lagattuta, {Theodore F.} and Musguire, {Lori A.} and Stoller, {Ronald G.} and Potter, {Douglas M.} and Argiris, {Athanassios E.} and Zwiebel, {James A.} and Egorin, {Merrill J.} and Chandra Belani",
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Ramalingam, SS, Parise, RA, Ramananthan, RK, Lagattuta, TF, Musguire, LA, Stoller, RG, Potter, DM, Argiris, AE, Zwiebel, JA, Egorin, MJ & Belani, C 2007, 'Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies', Clinical Cancer Research, vol. 13, no. 12, pp. 3605-3610. https://doi.org/10.1158/1078-0432.CCR-07-0162

Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. / Ramalingam, Suresh S.; Parise, Robert A.; Ramananthan, Ramesh K.; Lagattuta, Theodore F.; Musguire, Lori A.; Stoller, Ronald G.; Potter, Douglas M.; Argiris, Athanassios E.; Zwiebel, James A.; Egorin, Merrill J.; Belani, Chandra.

In: Clinical Cancer Research, Vol. 13, No. 12, 15.06.2007, p. 3605-3610.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies

AU - Ramalingam, Suresh S.

AU - Parise, Robert A.

AU - Ramananthan, Ramesh K.

AU - Lagattuta, Theodore F.

AU - Musguire, Lori A.

AU - Stoller, Ronald G.

AU - Potter, Douglas M.

AU - Argiris, Athanassios E.

AU - Zwiebel, James A.

AU - Egorin, Merrill J.

AU - Belani, Chandra

PY - 2007/6/15

Y1 - 2007/6/15

N2 - Purpose: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental Design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxelwere escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. Results: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non - dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25p atients evaluable for response, partial responses occurred in 11 (10 non - small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. Conclusions: Both schedules of vorinostat (400 mg oral qd × 14 days or 300 mg bd × 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6mg/mL × min) and paclitaxel (200mg/m2). Encouraging anticancer activity wasnoted in patients with previously untreated non - small cell lung cancer.

AB - Purpose: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. Experimental Design: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxelwere escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. Results: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non - dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25p atients evaluable for response, partial responses occurred in 11 (10 non - small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. Conclusions: Both schedules of vorinostat (400 mg oral qd × 14 days or 300 mg bd × 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6mg/mL × min) and paclitaxel (200mg/m2). Encouraging anticancer activity wasnoted in patients with previously untreated non - small cell lung cancer.

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