title: A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly.
abstract: The anthracenedione analogue, BBR 2778 is an active antitumour agent preclinically and has reduced potential for cardiotoxicity compared with other similar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapidly from 20 to 240 mg/m2. The dose-limiting toxicity (DLT) was neutropenia, common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Other toxicities > or = CTC grade 3 were: vomiting, lymphopenia, thrombocytopenia and lethargy. Blue discoloration of veins and urine was also noted. In 1 patient (120 mg/m2, four cycles) left ventricular ejection reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2) at 180 mg/m2 = 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a patient with previously treated small cell lung carcinoma (SCLC), a 49% reduction in measurable disease was noted with resolution of pericardial and pleural effusions (120 mg/m2 x eight cycles). From the results of this phase I study a dose of 180 mg/m2 as a 1 h infusion every 3 weeks would be recommended for phase II trials.
authors.affiliation: ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
authors.forename: L K
authors.initials: LK
authors.lastname: Dawson
authors.forename: D I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: A
authors.initials: A
authors.lastname: Bowman
authors.forename: R
authors.initials: R
authors.lastname: Rye
authors.forename: B
authors.initials: B
authors.lastname: Byrne
authors.forename: A
authors.initials: A
authors.lastname: Bernareggi
authors.forename: G
authors.initials: G
authors.lastname: Camboni
authors.forename: J F
authors.initials: JF
authors.lastname: Smyth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; C086548:pixantrone