A PHASE 3, THREE-ARM, RANDOMIZED, OPEN-LABEL STUDY OF INTERFERON ALFA ALONE, CCI-779 ALONE, AND THE COMBINATION OF INTERFERON ALFA AND CCI-779 IN FIRST-LINE POOR PROGNOSIS SUBJECTS WITH ADVANCED RENAL CELL CARCINOMA
STUDY RATIONALE:
CCI-779 blocks progression from the G1 to the S phase of the cell cycle by a mechanism of action that is unique for an anticancer drug. It is suggested that CCI-779 binds to the specific cytosolic protein FK506 binding protein FKBP-12. This complex inhibits the activation of the cell cycle regulatory protein kinase mTOR, resulting in suppression of several signal transduction pathways and inhibition of several key proteins that regulate the G1 phase of the cell cycle. Because mTOR is a central regulator of G1 cell cycle protein synthesis, which precedes cellular replication, CCI-779 demonstrates a significant inhibition of tumor growth. In xenograft studies, CCI-779 produced sustained inhibition of tumor cell growth but did not cause regression. In this model, the combination of CCI-779 + IFN alfa was superior to optimum doses of either compound alone and induced a 50% regression of tumor mass, an effect not seen with single agent treatment. Thus, preclinically, there is evidence of activity of CCI-779 alone and in combination with interferon alfa (IFN alfa) in RCC.
Principal investigator: Fairooz Kabbinavar - Hematology-Oncolory |
