Irinotecan-based regimens in combination with therapeutic antibodies formulated with hyaluronan (HA): a pre-clinical evaluation
Authors: Gary Brownlee, Jeanette Falzon, Minh Pho, Christopher Vearing, Alice Laycock, Samara Bennett, Lisa Donnet, Pete Gibbs, Tracey Brown
Journal: Cancer Research (2007)

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 1000mm3 )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 1000mm3. 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: Compared 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.