Design of clinical trials with biological response modifiers.

Biological response modifiers (BRMs) include biological and chemical agents which can increase host resistance against tumor growth and also biological agents which can have direct effects on tumor cells, by inducing cytolysis, growth inhibition, and/or differentiation. It is becoming increasingly clear that initial phase I clinical trials with BRMs need to be designed considerably differently from those for chemotherapeutic agents. In addition to determining the toxicity of each agent and its maximal tolerated dose, it is important to evaluate its effects on relevant immunologic and other host responses and to determine the optimal biological response modifying dose (OBRMD). Also, since most BRMs are likely to be effective mainly for treatment of cancer patients with low tumor burdens, and the biological response modifying effects of an agent may vary with the extent of disease, it seems necessary to first perform a phase IA trial in patients with advanced cancer, with an emphasis on determining toxicity and possibly the maximal tolerated dose. Then a phase IB trial will be performed, with patients with minimal or even undetectable tumor burden, to determine the OBRMD. These phase I trials will then allow planning for phase II trials for evaluation of antitumor effects, at doses and in cancer patients which might be expected to be favorable for detection of efficacy.