A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), A Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors

Albert Lockhart, Martin Howard, Kenneth R. Hande, Bruce J. Roth, Jordan D. Berlin, Franzanne Vreeland, Angela Campbell, Erminia Fontana, Francesca Fiorentini, Camilla Fowst, Victoria A. Paty, Odessa Lankford, Mace L. Rothenberg

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Abstract

Purpose: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion. Experimental Design: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m2/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients. Results: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m 2/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m2/week. The mean ± SD terminal half-life at the maximum tolerated dose was 4.6 ± 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was ∼20% of the hepatic blood flow. The area under the concentration time curveo0-∞ of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment. Conclusions: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m2 on days 1, 8, and 15 of a 28-day cycle.

Original languageEnglish (US)
Pages (from-to)468-475
Number of pages8
JournalClinical Cancer Research
Volume10
Issue number2
DOIs
StatePublished - Jan 15 2004
Externally publishedYes

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Pharmacokinetics
DNA
Maximum Tolerated Dose
Neoplasms
Febrile Neutropenia
brostallicin
Neutropenia
Half-Life
Research Design
Liver

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), A Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors. / Lockhart, Albert; Howard, Martin; Hande, Kenneth R.; Roth, Bruce J.; Berlin, Jordan D.; Vreeland, Franzanne; Campbell, Angela; Fontana, Erminia; Fiorentini, Francesca; Fowst, Camilla; Paty, Victoria A.; Lankford, Odessa; Rothenberg, Mace L.

In: Clinical Cancer Research, Vol. 10, No. 2, 15.01.2004, p. 468-475.

Research output: Contribution to journalArticle

Lockhart, A, Howard, M, Hande, KR, Roth, BJ, Berlin, JD, Vreeland, F, Campbell, A, Fontana, E, Fiorentini, F, Fowst, C, Paty, VA, Lankford, O & Rothenberg, ML 2004, 'A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), A Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors', Clinical Cancer Research, vol. 10, no. 2, pp. 468-475. https://doi.org/10.1158/1078-0432.CCR-0658-03
Lockhart, Albert ; Howard, Martin ; Hande, Kenneth R. ; Roth, Bruce J. ; Berlin, Jordan D. ; Vreeland, Franzanne ; Campbell, Angela ; Fontana, Erminia ; Fiorentini, Francesca ; Fowst, Camilla ; Paty, Victoria A. ; Lankford, Odessa ; Rothenberg, Mace L. / A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), A Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 2. pp. 468-475.
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abstract = "Purpose: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion. Experimental Design: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m2/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients. Results: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m 2/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m2/week. The mean ± SD terminal half-life at the maximum tolerated dose was 4.6 ± 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was ∼20{\%} of the hepatic blood flow. The area under the concentration time curveo0-∞ of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment. Conclusions: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m2 on days 1, 8, and 15 of a 28-day cycle.",
author = "Albert Lockhart and Martin Howard and Hande, {Kenneth R.} and Roth, {Bruce J.} and Berlin, {Jordan D.} and Franzanne Vreeland and Angela Campbell and Erminia Fontana and Francesca Fiorentini and Camilla Fowst and Paty, {Victoria A.} and Odessa Lankford and Rothenberg, {Mace L.}",
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T1 - A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), A Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors

AU - Lockhart, Albert

AU - Howard, Martin

AU - Hande, Kenneth R.

AU - Roth, Bruce J.

AU - Berlin, Jordan D.

AU - Vreeland, Franzanne

AU - Campbell, Angela

AU - Fontana, Erminia

AU - Fiorentini, Francesca

AU - Fowst, Camilla

AU - Paty, Victoria A.

AU - Lankford, Odessa

AU - Rothenberg, Mace L.

PY - 2004/1/15

Y1 - 2004/1/15

N2 - Purpose: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion. Experimental Design: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m2/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients. Results: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m 2/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m2/week. The mean ± SD terminal half-life at the maximum tolerated dose was 4.6 ± 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was ∼20% of the hepatic blood flow. The area under the concentration time curveo0-∞ of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment. Conclusions: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m2 on days 1, 8, and 15 of a 28-day cycle.

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