This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a randomized Phase II trial of Bevacizumab in combination with Cetuximab plus Irinotecan vs with Cetuximab alone in Irinotecan-refractory colorectal cancer. The trial is managed from Memorial Sloan-Kettering. The 'ideal' standard first- and second-line treatments for colorectal cancer are currently debated, with evidence for either irinotecan or oxaliplatin in combination with 5-FU and leucovorin being favored. Second-line therapy is usually a combination with the drug not used in the first round. The protocol will evaluate the use of Bevacizumab in combination with Cetuximab as an appropriate follow-up treatment to use after the failure of the first- and second-line drug regimens. Bevacizumab is an anti-VEGF and anti-angiogenic drug. Very recent results from studies with Bevacizumab in combination with IFL showed marked clinical benefit with its addition to the protocol, so there is confidence that this will be reproduced here. Cetuximab blocks binding of EGF and TGF-a to EGFR and inhibits ligand-induced activation of this tyrosine kinase receptor. Used in combination with irinotecan and also alone, response rates of ~22% and ~11% were achieved. There is, therefore, a strong rationale to try these in combination and to expect success. Since irinotecan is a major source of toxicity, the second arm of the study tests whether this drug can be dropped without significant loss of benefit. This study builds on the recent excellent results of the Bevacizumab/IFL trial by adding a drug with an expected complementary activity. Correlative studies will look at gene expression levels and, in consenting patients, germline polymorphisms associated with progression-free survival, tumor response, overall survival and toxicity in each of the treatments to be employed. In the future such data could hopefully be used to better tune treatments to the individual patient.
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