Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer.
OBJECTIVE
Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients.


METHODS
Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection.


RESULTS
Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m(2). Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m(2). The clearance and terminal half-life of Brostallicin were dose-independent, with mean (+/-SD) values of 9.33 +/- 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor.


CONCLUSIONS
Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m(2).
Ten Tije
Albert J
AJ
Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam 3075 EA, the Netherlands.
Verweij
Jaap
J
Sparreboom
Alex
A
Van Der Gaast
Ate
A
Fowst
Camilla
C
Fiorentini
Francesco
F
Tursi
Jennifer
J
Antonellini
Alessandro
A
Mantel
Marijke
M
Hartman
Carla M
CM
Stoter
Gerrit
G
Planting
Andre S T
AS
De Jonge
Maja J A
MJ
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004268:DNA-Binding Proteins; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007364:Intercalating Agents / Q000494:pharmacology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D004268:DNA-Binding Proteins; D006146:Guanidines; D007364:Intercalating Agents; D011758:Pyrroles; C455279:brostallicin