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 benzimidazol and bifunctionally alkylating nitrogen mustard group. The drug has clinical antitumour activity in lymphoma, myeloma and breast cancer. In earlier dose-finding studies, the clinically tolerated dose for single-bolus bendamustine was 215 mg/m2; for fractionated therapy on 4 consecutive days it was 85 mg/m2. Anticholinergic symptoms, myelosuppression and cardiac dysrhythmia were dose-limiting. Our trial was designed to define the maximum tolerated dose of a short infusion schedule and to establish a recommended dose for ongoing and future clinical studies.
METHODS: Patients with refractory malignant tumours qualified for the trial after written informed consent had 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/m2 and an increment per group of 20 mg/m2.
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/m2 bendamustine. At 160 mg/m2, fatigue grade 3 (NCI Common Toxicity Criteria) and dryness of the mouth grade 3 occurred in 2 patients, diarrhoea grade 3 in 1 patient; another patient with a history of myocardial infarction and arrhythmia developed a reversible total atrioventricular block after the first administration of 160 mg/m2 bendamustine. Other events, such as nausea/vomiting, loss of appetite, fever or chills, were not dose-limiting. Haematological toxicity was mild, except for sudden and long-lasting grade 3-4 lymphocytopenia, which occurred in all treatment cycles. Opportunistic infections were not observed.
CONCLUSIONS: The maximum tolerated dose of a days-1 and -8 schedule of bendamustine, given as a 30-min i.v. infusion, is 160 mg/ m2; mouth dryness and fatigue are dose-limiting. The recommended dose for future trials is 140 mg/m2.