A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly.
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.
Dawson
L K
LK
ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
Jodrell
D I
DI
Bowman
A
A
Rye
R
R
Byrne
B
B
Bernareggi
A
A
Camboni
G
G
Smyth
J F
JF
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
D000970:Antineoplastic Agents; D007546:Isoquinolines; C086548:pixantrone