Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks.
Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activity in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m2 and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m2. At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m2 consisted of ocular symptoms ('light flashes') accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m2/1 hour was considered the MTD. There were four deaths on study, all considered disease-related. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center. The recommended dose for phase II trials derived from our results is 12,550 mg/m2/2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Fromm
M
M
Department of Medicine I, Technische Universität, Munich, FRG.
Berdel
W E
WE
Schick
H D
HD
Danhauser-Riedl
S
S
Fink
U
U
Remy
W
W
Reichert
A
A
Ankele
A
A
Präuer
H W
HW
Siewert
J R
JR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011108:Polymers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors
D000970:Antineoplastic Agents; D011108:Polymers; C022084:carboxyimamidate