Irinotecan-based regimens in combination with therapeutic antibodies formulated with hyaluronan (HA): a pre-clinical evaluation

4056 INTRODUCTION : Monoclonal antibodies such as Erbitux ® (cetuximab, ERB) and Avastin ® (Bevacizumab, BEV) represent the clinical frontier for targeted therapeutics used in combination with irinotecan-based regimens for the management of metastatic colorectal cancer (mCRC). The glycosaminoglycan, HA is being developed as a targeted macromolecular drug transport vehicle for cytotoxics and therapeutic antibodies. In pre-clinical studies, the formulation of HA with irinotecan (HyCAMP) increased the efficacy of the drug substance, while an uncontrolled Phase l trial in mCRC patients showed a trend towards reduced incidence of grade 3/4 diarrhea and neutropenia. These collective data justify the pre-clinical evaluation of HyCAMP in combination with cetuximab, HyERB (HA and cetuximab), bevacizumab: HyBEV (HA and bevacizumab). METHODOLOGY: The effect of HA on the therapeutic index (TI) of irinotecan, ERB and BEV was established by treatment of orthotopic LIM1215 and GEO human colon cancer xenografts with 1 ) ERB(0.5), 2 ) HyCAMP(26.6/50), 3 ) CPT-11(50), 4 ) HyERB(150/0.5)/HyCAMP(26.6/50), 5 )ERB(0.5)/CAMP(50), 6 )ERB(0.5)/HyCAMP(26.6/50), 7 ) irinotecan/5-fluorouracil/leucovorin (IFL) + BEV(5), 8) IFL + HyBEV(150/5) and 9) IFL + saline [dose in brackets are in mg/kg]. Dosing for cytotoxics and antibodies was q7d x 5 and d1, 4 x 5 respectively. Weight loss was used as a marker of gastrointestinal toxicity and the efficacy end-point was either determined by tumor growth delay (TGD: time taken for tumor volume to reach 1000mm 3 ) or tumor volume at Day 300 after commencement of therapy. RESULTS: HyCAMP monotherapy increased the TI of CPT-11 in both the LIM 1215 and GEO xenografts. Combination therapy of the LIM1215 tumor demonstrated superior efficacy of HyERB/HyCAMP when compared to ERB/CAMP with a TGD of >53 days. At Day 300, 62.5% of tumors treated with HyERB/HyCAMP had not reached 1000mm 3 . Tumor response in ERB/HyCAMP therapy was comparable to ERB/CAMP but at Day 300, 25% survival benefit was observed with ERB/HyCAMP. Comparison of the ERB/HyCAMP and ERB/CAMP treatment of the GEO tumor demonstrated increased tumor response of 37.5%. Evaluation of HyBEV combined with IFL demonstrated significantly earlier tumor response than animals treated with BEV/IFL and a 75% survival benefit. CONCLUSIONS: C ompared to the parent drug, the proprietary formulations of HyCAMP, HyERB and HyBEV used as mono- and combination therapies demonstrated improved efficacy. In the two human colon cancer xenografts used, HA formulations increased tumor response and conferred a survival benefit. These data demonstrate that HA functions as a targeted macromolecular drug transport vehicle for both therapeutic antibodies and small molecule cytotoxics thereby providing a rationale for further clinical development of HA formulated biologicals in combination with HA formulated chemotherapeutic agents.