Faculty Bibliography

Future studies with daunorubicin involve mainly comparative evaluations with other anthracycline antibiotics and related compounds. Efforts are ongoing to improve the therapeutic index of these drugs. This includes not only laboratory development but also clinical evaluation of analogs, manipulations in dose schedules, and the use of protectors of toxic manifestations, primarily of cardiomyopathy. Technological advances in the clinical area permit, for example, the exploration of daunorubicin and related compounds by continuous infusion under more precise pharmacologic and cardiologic monitoring than was possible when they were initially introduced

All Phase II studies with diglycoaldehyde with leukemia and solid tumors have been reviewed. The dose schedules employed ranged from 1.5 to 2.0 g/m2/day for 3 to 5 days. The most common side effects have been gastrointestinal (nausea and vomiting), which occurred in 22% of the patients. Renal toxicity (rise in BUN, creatinine, and urinary proteins) was seem in 17% of the patients treated. Other infrequent toxicities include hypocalcemia (9%) and local complications such as phlebitis. Leukopenia, thrombocytopenia, positive Coombs' test and impairment in coagulation profile were also reported. In contrast to the hints of therapeutic efficacy described during Phase I trials, in phase II trials no activity was noted among 96 patients with solid tumors and only minimal antileukemic action among 49 other patients. These disappointing Phase II trials coupled with prominent toxicities have prompted the decision to terminate further clinical testing. This report summarizes all clinical observations as an example of circumstances which curtail clinical testing of anticancer drugs.

This brief overview illustrates the role of cisplatin in current cancer chemotherapy. This new agent is increasingly utilized in first line regimens for a variety of tumor types notably testicular, head and neck and bladder cancer. Large scale investigations are taking place to evaluate these regimens in combined modality approaches to early stages of these diseases.

This analysis was carried out to assess quantitative and qualitative relationships between animal and human toxicology data with anticancer drugs. Among 21 chemotherapeutic agents, one-sixth LD10 in the mouse or one-third toxic dose low (TDL) in the dog corresponded to acceptable doses in man when experimental and clinical data were obtained at identical schedules and compared on a mg/m2 basis. The mouse and the dog largely differed in their tolerance to individual drugs. One-tenth LD10 in the mouse seemed always tolerated in the dog. On the average, these species were equally relevant for establishing the initial dose in man. A similar number of dose escalation steps would have been required in phase I clinical trials if the starting dose had been based on one-tenth LD10 in the mouse or the lowest value of one-sixth LD10 in the mouse and one-third TDL in the dog. These observations indicate that the starting dose in phase I clinical trials could be safely and efficiently based on one-tenth LD10 in the mouse. Prior verification that the resulting dose is not lethal or life-threatening in the dog could add further safety to this procedure. The predictive value (PV+) in man of organ system toxicity in animals depends upon the prevalence of this toxicity in man. In our study, PV+ was high (greater than 0.85) for common toxic effects in man, i.e., gastrointestinal intolerance and myelosuppression. PV+ declined dramatically (0.05 to 0.54) with rarer toxic manifestations. There was no clear superiority of animal findings over the mere knowledge of the prevalence of these findings in man. Thus, it would appear that routine and undiscerned investigation of organ system toxicity in animals is of questionable usefulness for the clinician experienced in early clinical trials with chemotherapeutic agents.

Phase I trials in 1979 include some drugs representing totally new structures, new schedules of old compounds undergoing reevaluation, and second generation compounds. The rational development of analogs based on structure-activity relationships and on overcoming pharmacologic or toxicologic problems of parent compounds requires much future emphasis; two such examples (pentamethylmelamine and AZQ) are cited here. For all drugs, a plan of clinical development should ensure a more thorough initial evaluation as well as validation of concepts and systems that have prompted their introduction into the clinic. Establishment of clinical usefulness for the new structures, and particularly for three compounds herein reintroduced after a long period of oblivion, would constitute tangible proof of methodological and technological advances that have taken place in the development and clinical evaluation of anticancer drugs.