The fact that CCI-779 induced tumor regression at relatively nontoxic doses is noteworthy, he said, because it suggests that the optimal therapeutic dose of CCI-779 may be lower than the maximum-tolerated dose. Since clinical responses have been seen at a variety of doses, definition of the biologically active dose would require further research, he noted.
Dr. Hidalgo suggested that trials focusing solely on tumor regression may not be optimal for this new class of compounds and for other rationally developed agents in which tumor growth inhibition and delay are the predominant therapeutic effects. Other endpoints and surrogate markers such as inhibition of the target may prove more useful in determining efficacy.
Another promising aspect of CCI-779 is the potential to target therapy to subsets likely to benefit due to alterations in genes involved in the signal transduction pathway and/or cell cycle regulation mechanisms inhibited by the agent. These subsets may include patients with mutations of the PTEN tumor-suppressor gene or the cell proteins pRB, p16, p27, and cyclin D1.
CCI-779 is currently in clinical trials for glioblastoma, and efficacy studies in a broad range of tumor types are planned. Accrual has been completed on a phase II study in patients with refractory renal cell cancer. Phase I studies evaluating the feasibility of CCI-779 administration in combination with gemcitabine(Drug information on gemcitabine) (Gemzar) and fluorouracil(Drug information on fluorouracil) have also been initiated. Dr. Hidalgo noted that an oral formulation of the agent is in early clinical development.