Since our original proposal 4 years ago, considerable support has evolved for the concept of pharmacologically guided dose escalation in phase I clinical trials with new anticancer drugs. The original focus has been broadened to develop additional links between preclinical testing and phase I clinical trials. Recent experiences with very lengthy phase I trials for at least eight drugs have provided particular impetus for this project. The original pharmacodynamic hypothesis for the proposal was equal toxicity at equal plasma levels. Specifically, two facets of the concept were that (a) dose-limiting toxicity correlates with, and in turn is predicted by, drug concentrations in plasma and (b) that the quantitative relationship between toxicity and drug exposure, as measured by plasma drug concentration times time (C x T), holds across species. If true, this hypothesis would suggest that dose escalations in humans could be safely based on measurement of drug levels in plasma, rather than on empirical escalation schemes. In addition to the collection of a larger retrospective data base to validate this hypothesis, practical results have already been achieved. In two studies sponsored by the National Cancer Institute (NCI), the escalation pattern was prospectively modified on the basis of measurements of drug levels in plasma. In addition, for three NCI-sponsored drugs, more careful matching of schedules between clinical and preclinical testing produced entry doses that were up to 25 times higher than doses used in standard procedures. Consequently, the phase I trials for each drug were completed with a savings of 12-24 months. As a result of work in both the United States and Europe, a substantial collection of data now demonstrates that coordination with preclinical pharmacology and toxicology studies can save both time and resources in early clinical trials without a loss of safety.

This review analysis consists of the antitumor activity and toxic deaths reported in single agent Phase I clinical trials using cytotoxic compounds published from 1972 to 1987. A total of 6639 patients with a variety of solid tumors and hematological malignancies were accrued in 211 trials studying 87 compounds. The median number of patients per trial was 28 (range: 7-111) and the median of the median ages reported in the individual trial was 56 (range of individual age: 2 to 93 years). Ten percent of the trials enrolled pediatric patients (less than 18 years), but the exact numbers of children were not always given or separated from the adult patients. Nine percent of the patients had received no prior treatment, 75% were pretreated either with chemotherapy alone (50%) or radio- plus chemotherapy (25%). Radiotherapy alone was administered to 11% of the patients and the remaining 5% of the patients received prior treatments which was not specified. The most frequent tumor types were those of the gastrointestinal tract (22%) and the respiratory tract (19%). The frequency of the remaining malignancies was less than 10% of all patients. There were 23 (0.3%) complete responders and 279 (4.2%) partial responders for an overall response rate of 4.5% among all entries. Toxic deaths were rare and reported in only 31 patients (0.5% of the entire population). Responses were usually observed in chemosensitive tumor types. Despite a low response rate reported during the first phase of cytotoxic drug development, the present analysis shows that some therapeutic benefit can be achieved.

Leuprorelin acetate, a highly potent luteinizing hormone releasing hormone agonist, was originally launched in the USA to be administered once daily by self-injection for the treatment of metastatic prostatic cancer. A once-monthly intramuscularly or subcutaneously injectable depot form of leuprorelin acetate has, subsequently, been developed. Biodegradable copoly(DL-lactic acid/glycolic acid) was chosen as the release-controlling polymer and the microcapsules containing leuprorelin acetate were prepared by an in-water drying method. Results of studies in rats showed that a copolymer with a molecular weight of 14,000 and a lactic acid/glycolic acid ratio of 75/25 had the most satisfactory releasing properties. Microcapsules given once monthly reduced serum testosterone levels in rats, dogs and man. In clinical studies, the depot preparation effectively reduced the dose of leuprorelin acetate required to up to one-eighth of that needed when injected daily. A sophisticated manufacturing system has now been developed and a very reliable controlled-release product is now available that has many advantages.