Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Abstract

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)

Phase I trial of a 5-day course of carbetimer

“…Our analysis of multiple stool guaiac determinations and endoscopic evaluation of the rare patients with repeated guaiac positivity yielded no sign of significant upper gastrointestinal mucositis. These results have been confirmed by the lack of gastrointestinal hemorrhage in several other phase I studies [9,10], and Carbetimer is not considered to induce upper gastrointestinal mucositis.…”

“…The patient treated at a daily dose of 4200 mg/m 2 who received the highest number of treatment cycles in the study (6 cycles) developed severe hypercalcemia during her last cycle. The occurrence of hypercalcemia has now been confirmed in several other phase I studies using both daily x 5 [9] and daily x 1 [10,11] schedules. Fromm et al [10] observed mild hypercalcemia but no severe hypercalcemia after single doses ranging from 180 to 16690 mg/m 2.…”

“…The occurrence of hypercalcemia has now been confirmed in several other phase I studies using both daily x 5 [9] and daily x 1 [10,11] schedules. Fromm et al [10] observed mild hypercalcemia but no severe hypercalcemia after single doses ranging from 180 to 16690 mg/m 2. Hanauske et al [11] observed severe hypercalcemia in 2 patients receiving single doses of 8500 mg/m 2 and mild hypercalcemia in 3 patients receiving lower doses.…”

“…Arm pain during infusion has been noted by our group and by Fromm et al [10] but can be controlled with warm packs, slowing of the infusion rate, or increased dilution of the drug and may disappear on repeated administration through the same vein. The use of a central venous catheter also prevents occurrence of this toxicity.…”

Phase II study of carbetimer in non-small cell lung cancer

“…Antitumor activity has been demonstrated in vitro to various human tumor types in the human tumor cloning assay [2]. Phase one studies have found Carbetimer to have low systemic toxicity with hypercalcemia being the dose limiting toxicity [3][4][5][6]. This report presents the results of Carbetimer in the treatment of non-small cell lung cancer.…”