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.
OBJECTIVE
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.


METHODS
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.
Lockhart
A Craig
AC
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
Howard
Martin
M
Hande
Kenneth R
KR
Roth
Bruce J
BJ
Berlin
Jordan D
JD
Vreeland
Franzanne
F
Campbell
Angela
A
Fontana
Erminia
E
Fiorentini
Francesca
F
Fowst
Camilla
C
Paty
Victoria A
VA
Lankford
Odessa
O
Rothenberg
Mace L
ML
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002138:Calibration; D004249:DNA Damage; D005260:Female; D006146:Guanidines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013997:Time Factors
D000970:Antineoplastic Agents; D006146:Guanidines; D011758:Pyrroles; C455279:brostallicin