Upload
angus
View
65
Download
11
Tags:
Embed Size (px)
DESCRIPTION
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 - PowerPoint PPT Presentation
Citation preview
A phase I study of celecoxib and patupilone (EPO906) in patients with metastatic colorectal cancerSyma Iqbal, Anthony El-khoueiry, Dongyun
Yang, Sarah Cole, William Boswell, Jabi Shriki, Yan Ning, Raluca Agafitei, Xiomara
Menendez, Heinz-Josef LenzUniversity 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 CriteriaInclusion• 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 ToxicitiesDose 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 vomiting
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 CompletedMedian (range)
PR SD
PD
Ia 7 3 0 0 2 (1-4) 0 1 2
IIa 8 4 1 0 1 (1-4) 1 1 2
IIIa 9 7 1 1 4 (1-8) 0 4 3
IVa 10 8 2 1 2 (1-8) 1 5 2
Va 11 3 0 0 2 (2-4) 0 1 1
VIa 12 9 3 1 2 (1-9) 1 2 2
VIIa 13 5 1 2 2 (1-4) 0 4 0
Total 3 18 12
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.