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A phase I study of celecoxib and patupilone (EPO906) in patients with metastatic colorectal cancer

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

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A phase I study of celecoxib and patupilone (EPO906) in patients with metastatic colorectal cancer

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  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. Patient Characteristics (N=39)

  8. Dose Limiting Toxicities

  9. Number of patients and cycles received, DLTs and tumor response dose level

  10. Waterfall Plot

  11. Outcome – PFS, OS

  12. 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.

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