Phase I clinical and pharmacokinetic study of BBR 3576, a novel aza-anthrapyrazole, administered i.v. every 4 weeks in patients with advanced solid tumors: a phase I study group trial of the Central European Society of Anticancer-Drug Research (CESAR).
BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.
Mross
Klaus
K
Tumor Biology Center Albert-Ludwigs University, Freiburg, Germany. mross@tumorbio.uni-freiburg.de
Scheulen
Max E
ME
Licht
Thomas
T
Unger
Clemens
C
Richly
Heike
H
Stern
Angelika C
AC
Kutz
Klaus
K
Camboni
Maria G
MG
Barbieri
Paola
P
Verdi
Elena
E
Vincenzi
Beatrice
B
Bernareggi
Alberto
A
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D007260:Infusion Pumps; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015394:Molecular Structure; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D009503:Neutropenia / Q000139:chemically induced; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013280:Stomatitis / Q000139:chemically induced
D018943:Anthracyclines; D000970:Antineoplastic Agents; C492575:BBR 3576; D006576:Heterocyclic Compounds, 4 or More Rings; D011720:Pyrazoles; C055925:anthrapyrazole