Responses and toxic deaths in Phase I clinical trials

Abstract

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.

Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy

“…A recent systematic review, however, has questioned whether participation in clinical trials is of any benefit to participants (Peppercorn et al, 2004). Various studies have reported that the chance of therapeutic response for those volunteering to take part in phase I trial is less than 5% (Estey et al, 1986;Decoster et al, 1990;Von Hoff and Turner, 1991;Smith et al, 1996;Roberts et al, 2004). In phase II clinical trials, the overall objective response rate (partial and complete) is also usually low.…”

Comparison of prognostic factors in patients in phase I trials of cytotoxic drugs vs new noncytotoxic agents

“…Despite the emphasis on evaluation of side effects, and determination of a maximum tolerated dose (MTD), tumour responses remain an important secondary end point. Reported response rates for phase I trials are generally between 1 and 10% (Estey et al, 1986;Decoster et al, 1990;Bachelot et al, 2000) with most responses seen at 80 -120% of the recommended phase II dose (Von Hoff and Turner, 1991). Cytotoxic drugs that do not show antitumour activity in phase I trials rarely undergo further evaluation (Von Hoff and Turner, 1991;American Society of Clinical Oncology, 1997;Sekine et al, 2002).…”

Patients in phase I trials of anti-cancer agents in Japan: motivation, comprehension and expectations

“…In addition, in phase I trials, early cohorts of patients are treated at very low and sometimes ineffective dosages. The overall response rate in phase I trials is low (Estey et al, 1986;Decoster et al, 1990;Von Hoff and Turner, 1991;Penta et al, 1992;Itoh et al, 1994). Furthermore, physicians as investigators conducting phase I trials of anti-cancer agents must always be vigilant in safeguarding the patients' best interests when confronted with ethical issues (e.g.…”