University of Southern California, Norris Comprehensive Cancer Center A phase I study of celecoxib and patupilone (EPO906) in patients with metastatic colorectal cancer Syma Iqbal, Anthony El-khoueiry, Dongyun Yang, Sarah Cole, William Boswell, Jabi Shriki, Yan Ning, Raluca Agafitei, Xiomara Menendez, Heinz-Josef Lenz University of Southern California, Norris Comprehensive Cancer Center

Introduction Patupilone (EPO906) is an epothilone that induces polymerization of tubulin dimers into stable microtubules leading to cell cycle arrest and apoptosis. In vivo, EPO906 is an inhibitor of cells that display a multidrug-resistant phenotoype due to overexpression of the P-gycoprotein efflux pump. Preclinical data reveal regression in colon cancer models resistant to 5-FU. The dose limiting toxicity (DLT) of EPO906 has been diarrhea in previous studies. Preclinical data suggest an increase in COX-2 expression with EPO906 and reduction in diarrhea when EPO906 is combined with celebrex. A phase I study of EPO906 in combination with celebrex for patients with advanced/metastatic colorectal cancer.

Objectives The primary objective of this study was to determine of the maximum tolerated dose (MTD) of EPO906 + celecoxib. Secondary objectives were progression free survival (PFS), response rate and overall survival. Further, preliminary biomarkers were assessed for correlation with outcome and toxicity

Eligibility Criteria Inclusion Patients with metastatic colorectal cancer who had failed 5-FU, CPT-11 and Oxaliplatin based therapy SWOG PS 0-1 Adequate organ function ANC >1000, platelet, >100K Total bilirubin <2 x ULN, AST/ALT <5X ULN in pts with liver metastasis Creatinine <1.25 X ULN Exclusion Pts on therapeutic coumadin Any peripheral neuropathy >grade 1 Patients taking full dose NSAIDS

Treatment Plan The dose of celecoxib was fixed at 400 mg bid with EPO906 7 mg/m2 dose escalated to a maximum dose of 13mg/m2 in 1 mg/m2 increments Pts received celecoxib for one week prior to first dose of EPO906. Patients kept a diarrhea diary and were counseled about optimal management of diarrhea.

Statistics A standard 3+3 design If dose limiting toxicity ( DLT) at least possibly attributable to either celecoxib or EPO906 was observed in 1/3 patients, then 3 more (for a total 6) were treated at that dose level. If no additional toxicity was observed, the dose was escalated in the next 3 patients. As soon as 2 DLT’s were observed, dose escalation was stopped. MTD is the highest dose in which none or one patient experienced DLT attributable to drugs.

Patient Characteristics (N=39) Age 58 (35-84) Males 16 Females 23 # of previous treatments for metastatic disease Median (range) 4(1-9) 1-3 18 4-6 17 7-9 4 SWOG PS 0 24 1 15

Dose Limiting Toxicities Dose Level EPO 906 Dose DLTs IIIa 9 mg/m2 Grade 3 diarrhea and vomiting IVa 10 mg/m2 Grade 3 nausea VIa 12 mg/m2 Grade 3 diarrhea VIIa 13 mg/m2 Grade 3 diarrhea and anorexia

Number of patients and cycles received, DLTs and tumor response dose level Toxicity N of cycles Tumor response Dose Level EPO 906 Dose level mg/m2 N Not evaluable for DLT DLT Completed Median (range) PR SD PD Ia 7 3 2 (1-4) 1 2 IIa 8 4 1 (1-4) IIIa 9 4 (1-8) IVa 10 2 (1-8) 5 Va 11 2 (2-4) VIa 12 2 (1-9) VIIa 13 Total 18

Waterfall Plot

Outcome – PFS, OS

Conclusions The combination of EPO906 and celecoxib is well tolerated with promising activity in heavily pretreated advanced CRC pts. The MTD is 12 m/m2, higher than what has been previously reported, suggesting a benefit from the addition of celecoxib and aggressive diarrhea management. A phase II study of this combination in pts with advanced colorectal cancer has begun accrual.