title: 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).
abstract: 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.
authors.affiliation: Tumor Biology Center Albert-Ludwigs University, Freiburg, Germany. mross@tumorbio.uni-freiburg.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Mross
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
authors.forename: Thomas
authors.initials: T
authors.lastname: Licht
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
authors.forename: Heike
authors.initials: H
authors.lastname: Richly
authors.forename: Angelika C
authors.initials: AC
authors.lastname: Stern
authors.forename: Klaus
authors.initials: K
authors.lastname: Kutz
authors.forename: Maria G
authors.initials: MG
authors.lastname: Camboni
authors.forename: Paola
authors.initials: P
authors.lastname: Barbieri
authors.forename: Elena
authors.initials: E
authors.lastname: Verdi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Alberto
authors.initials: A
authors.lastname: Bernareggi
mesh_terms: 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
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; C492575:BBR 3576; D006576:Heterocyclic Compounds, 4 or More Rings; D011720:Pyrazoles; C055925:anthrapyrazole