1. 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

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)
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

8. 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

9. 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

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.