960 Phase I trial of a new nitrosurea in a weekly schedule

Cystemustine (Cys) is a new nitrosurea that has demonstrated a cyto-static activity against glioma, melanoma and renal carcinoma in previous trials (EORTC Clinical Screening Group). The dose-intensity was 30 mg/m 2 /w at the recommended dose. With the aim to optimize these results, a new phase I trial was performed at IGR. From April to Dec. 1994, 27 patients (pts) with refractory cancer were treated with Cys administered as a 15 min IV bolus every week, during 4 weeks, in an escalating dose schedule from 30 mg/m 2 to 60 mg/m 2 with a pharmacokinetic study at each 1st injection. Twenty out of the 27 pts are evaluable. Tumor types are: Head & Neck 4 pts, renal 3 pts, mesothelioma 3 pts, colorectal 3 pts, ovary 2 pts and other tumor 5 pts. All pts were previously treated with chemotherapy and/or radiotherapy. Median age was 54 (25–73), sex ratio 15 male/5 female, Performance status (WHO) means 1 (0–2). AH pts were treated according to the schedule and were asked for a written informed consent. The main side effect is thrombopenia, probably dose-related. We observed thrombopenia grade 3–4 in 1/5 pts at 40 mg/m 2 , 3/9 pts at 50 mg/m 2 and 2/4 pts at 60 mg/m 2 . Three pts needed platelet transfusions. Grade 3–4 neutropenia was observed in 2/10 pts at 50 mg/m 2 and 1/4 pts at the 60 mg/m 2 dose level. No febrile neutropenia was noted. Nausea and vomiting were moderate. The 60 mg/m 2 /w level was actually explored and could be the MTD. We observed a stabilisation of disease in 7 patients. One may conclude that Cystemustine can be used in a weekly schedule at a higher dose-intensity than previously reported, with tolerable toxicity.