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.

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/m(2)/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/m(2)/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 approximately 20% of the hepatic blood flow. The area under the concentration time curve(0- infinity ) 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/m(2) on days 1, 8, and 15 of a 28-day cycle.

• Authors: A Craig 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 2 Pg. 468-75 (Jan 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 14760067 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Guanidines
• Pyrroles
• brostallicin

Topics

• Aged
• Antineoplastic Agents (pharmacology, therapeutic use)
• Area Under Curve
• Calibration
• DNA Damage
• Female
• Guanidines (pharmacokinetics, therapeutic use)
• Humans
• Kinetics
• Male
• Middle Aged
• Models, Chemical
• Neoplasms (drug therapy)
• Pyrroles (pharmacokinetics, therapeutic use)
• Time Factors