Repeated administration of short infusions of bendamustine: a phase I study in patients with advanced progressive solid tumours

Purpose: The cytotoxic agent bendamustine combines a purine-like benzimidaz ol and bifunctionally alkylating nitrogen mustard group. The drug has clini cal antitumour activity in lymphoma, myeloma and breast cancer. Tn earlier dose-finding studies, the clinically tolerated dose for single-bolus bendam ustine was 215 mg/m(2); for fractionated therapy on 4 consecutive days it w as 85 mg/m(2) Anticholinergic symptoms, myelosuppression and cardiac dysrhy thmia were dose-limiting. Our trial was designed to define the maximum tole rated dose of a short infusion schedule and to establish a recommended dose for ongoing and future clinical studies. Methods: Patients with refractory malignant rumours qualified for the trial after written informed consent h ad been obtained. Bendamustine was given as a 30-min iv. infusion on days 1 and 8 of a 4 week cycle, with a starting dose of 100 mg/m(2) and an increm ent per group of 20 mg/m(2). Results: Nineteen patients (13 male, 6 female; median age 57 years, range 37-74 years) were treated for one to two cycles with up to 180 mg/m(2) bendamustine. At 160 mg/m(2), fatigue grade 3 (NCI Common Toxicity Criteria) and dryness of the mouth grade 3 occurred in 2 pa tients, diarrhoea grade 3 in 1 patient, another patient with a history of m yocardial infarction and arrhythmia developed a reversible total atrioventr icular block after the first administration of 160 mg/m(2) bendamustine. Ot her events, such as nausea/ vomiting, loss of appetite, fever or chills, we re not dose-limiting. Haematological toxicity was mild, except for sudden a nd long-lasting grade 3-4 lymphocytopenia, which occurred in all treatment cycles. Opportunistic infections were not observed. Conclusions: The maximu m tolerated dose of a days-1 and -8 schedule of bendamustine, given as a 30 -min i.v. infusion, is 160 mg/m(2) mouth dryness and fatigue are dose-limit ing. The recommended dose for future trials is 140 mg/m(2).