A high priority for CTEP has been combining molecularly targeted agents to achieve optimal treatment effects. To that end, CTEP has initiated a proof-of-principle project called Critical Molecular Pathways to define a series of clinical trials to evaluate the concept of enhanced activity with rational molecular combinations. CTEP has initiated about a dozen early phase trials testing various novel combinations of targeted agents for the treatment of three tumor types — glioma, melanoma, and renal cell cancer. The doublet combinations encompass a variety of strategies to intersect signaling via interruption of horizontal or vertical signaling pathways as well as incorporating anti-angiogenesis therapies that have proven successful in the treatment of solid tumors. These studies will provide significant insights into the efficacy and potential toxicities of targeted agent combinations. As part of this initiative, a translational studies program is being implemented that will collect samples from patients entered in these trials. The randomized trial for doublet combinations (sorafenib with tipifanib, erlotinib or temsirolimus) in glioblastoma has been completed and the results presented at the 2009 ASCO Annual Meeting. Unfortunately, all three arms were negative in this indication, with possible reasons being dose reductions required with the agent combinations and lack of patient selection. On the other hand, preliminary results for sorafenib plus bevacizumab and temsirolimus plus bevacizumab were promising in renal cell carcinoma, as reported at the 2007 ASCO Annual Meeting. The 4-arm phase 2 study in renal cell cancer (the BeST trial) has recently completed accrual and the results are pending.
CTEP has also initiated more than 100 combination trials of targeted agents, and CTEP staff members continue to seek proof of principle in the administration of novel agents in properly selected patients whose tumors express or are driven by the relevant molecular targets. The current era holds great promise in therapeutics development as a result of advances in understanding the molecular biology of the cancer cell, cell signaling pathways, and abnormal processes associated with the malignant phenotype.