We have conducted a Phase I and initial clinical pharmacological evaluation of
LM985, the first of a series of compounds based on the
flavone ring structure to be considered for clinical trial in malignant disease. The
drug was administered i.v. to 26 patients with advanced
cancer on an every-21-day schedule. Patients were treated at 14 dosage levels ranging from 10 to 1500 mg/m2. Dose limiting toxicity was identified as acute reversible
hypotension occurring during
drug infusion; no
leukopenia,
alopecia, hepatic toxicity, or renal toxicity was observed, but at the higher dose range, mild sedation was apparent. Twenty patients had measurable disease and were evaluable for response. One patient with
colorectal carcinoma had stable disease after three courses of
LM985; however, no other responses were seen. Pharmacokinetic and in vitro
drug degradation studies imply that the
ester LM985 is hydrolyzed to LM975 (
flavone acetic acid) rapidly in vivo. LM975 is active in a variety of animal
tumor models, but it does not have the cardiovascular side effects seen with
LM985 (
hypotension and
bradycardia) in pithed or anesthetized rats. We would recommend that LM975 be considered for clinical trial, because it seems likely that substantially higher doses of LM975 than of
LM985 can be given without dose limiting cardiovascular toxicity.