Background: Although the evaluation of new investigational drugs in phase I, II and III trials requires considerable time and patient resources, only a few of these drugs are ultimately established as anticancer drugs. Materials and methods: We collected papers of phase I trials by a Medline search using the hey words 'Neoplasms/Drug Therapy in MeSH' and 'Phase I' for the period from 1976 to 1993. A drug was defined as 'effective' if a regimen including the drug produced positive results in at least one phase III trial. We analyzed the relationship between objective (complete and partial) responses in phase I trials and the effectiveness of agents in phase III trials. Results: A total of 399 single-agent phase I trials of cytotoxic agents in adult patients with solid tumors were obtained. Further clinical investigation was not recommended in 36 trials (9%) because of severe toxicity. In the remaining 363 trials, 174 drugs were evaluated and the median number of trials for each drug was two (range one to nine). Objective responses were observed in 495 (4.1%) of 12076 patients, 178 (49%) of 363 trials, and 115 (66%) of 174 drugs. Of the 174 drugs, 48 (28%) were considered to be effective. Percentages of effective drugs rose as the number of responders in phase I trials increased. Logistic regression analyses showed the number of responders to be significantly associated with drug effectiveness [odds ratio=1.16 (1.06-1.27), P=0.001 for 174 drugs; odds ratio=1.16 (1.05-1.28), P=0.0038 for 363 trials]. Although 10 active drugs failed to produce an objective response in phase I trials, seven of them produced a tumor regression of <50%, and three reportedly produced objective responses in phase I trials conducted before 1975. The numbers of responders among patients with lung, ovarian, breast or colorectal cancer, but not those among patients with lymphoma, melanoma, sarcoma or renal-cell carcinoma, were associated significantly with drug effectiveness against the respective tumors. Conclusions: Objective responses observed in phase I trials are important for determining the future development of an anticancer drug.
