PHASE-I CLINICAL-TRIAL OF ALL-TRANS-RETINOIC ACID WITH CORRELATION OFITS PHARMACOKINETICS AND PHARMACODYNAMICS

A phase I trial of all-trans-retinoic acid (ATRA) was conducted to est ablish the maximum tolerable dose (MTD) of ATRA given once daily to pa tients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA w ere assessed on day 1 for all patients and weekly for 31 patients who received doses of greater than or equal to 110 mg/m(2) per day. Patien ts were followed for toxicity and response. Correlations of toxicity f requency and grade with pharmacokinetic parameters were sought. In add ition, correlation of changes in ATRA pharmacokinetics with the concen tration of ATRA metabolites in plasma were sought. A total of 49 patie nts received ATRA at doses ranging from 45 to 309 mg/m(2) per day. Hyp ertriglyceridemia was dose-limiting at 269 mg/m(2) per day. Other freq uent toxicities included mucocutaneous dryness and headache. With chro nic dosing, plasma ATRA concentrations fell in 59% of patients. Stable , low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients re spectively. Age, gender, smoking, or concurrent medication did not cor relate with the pharmacokinetic pattern. Severe toxicities tended to o ccur with initial peak [ATRA] of greater than or equal to 0.5 mu g/ml (1.7 mu M), and the toxicity frequency did not change if [ATRA] decrea sed with continued dosing. No consistent change in 4-oxo-ATRA or retin oid glucuronide concentrations was observed with decreases in plasma [ ATRA]. The recommended once-daily ATRA dose is 215 mg/m(2), although s ignificant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at t arget tissues, may be at least as important as the plasma ATRA concent ration in predicting toxicity and/or response.