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BICC-C Study

BICC-C Study. A Randomized, Multi-Center Phase III Trial of Irinotecan in Combination with Three Different Methods of Administration of Fluoropyrimidine with Celecoxib versus Placebo as First-line Treatment for Patients with Metastatic Colorectal Cancer

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BICC-C Study

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  1. BICC-C Study A Randomized, Multi-Center Phase III Trial of Irinotecan in Combination with Three Different Methods of Administration of Fluoropyrimidine with Celecoxib versus Placebo as First-line Treatment for Patients with Metastatic Colorectal Cancer Charles Fuchs (Principal Investigator) John Marshall (Co-Principal Investigator) Edith Mitchell (US), Rafal Wierzbicki (Canada), Vinod Ganju (Australia), Mark Jeffery (New Zealand), Joseph Schulz (US), Donald Richards (US), and the BICC-C Study Working Group (>100 study sites)

  2. Background • In previous studies of metastatic CRC (mCRC): • Both infusional & bolus regimens of 5-FU with LV and irinotecan confer superior efficacy when compared to 5-FU and LV alone • Few studies have compared a combination using infusional 5-FU to the same combination with bolus 5-FU • Single-agent capecitabine offers equivalent efficacy to bolus 5-FU and LV in the adjuvant and metastatic setting • Few studies have compared combinations using infusional 5-FU & irinotecan to the same combination with capecitabine

  3. Background • Cyclooxygenase-2 (COX-2) is up regulated in colorectal adenoma and adenocarcinomas • In phase III trials, celecoxib reduces the incidence of colorectal adenomas • In mouse xenografts of human CRC, celecoxib inhibits angiogenic factors and induces apoptosis and tumor regression • In xenografts, celecoxib appears to increase chemotherapy activity and reduce chemotherapy toxicity

  4. Original Study Design FOLFIRI Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1) 5-FU: 400 mg/m2 (bolus) (D1) 5-FU: 2400 mg/m2 (46-h infusion) (D1) q2wks R A N D O M I Z A T I O N R A N D O M I Z A T I O N Celecoxib 400 mg bid 1st-line mCRC N = 1000 mIFL Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8) LV: 20 mg/m2 (D1, 8) q3wks Placebo CapeIRI Irinotecan: 250 mg/m2 (D1) Capecitabine: 1000 mg/m2 bid (D1-14) q3wks Stratification : Age (< 70 vs > 70) PS (0 vs 1) Low dose aspirin use (< 325 mg every day): yes vs no

  5. Timeline of Study Events Period 2Add Bevacizumab 1st Patient Enrolled May 2004 Period 11st Patient Enrolled Feb 2003 2002 2003 2004 2006 2005

  6. Period 1: Treatment Regimens FOLFIRI R A N D O M I Z A T I O N R A N D O M I Z A T I O N Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1) 5-FU: 400 mg/m2 (bolus) (D1) 5-FU: 2400 mg/m2 (46-h infusion) (D1) q2wks Celecoxib 400 mg bid 1st-line mCRC N = 430 2/03–4/04 mIFL Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8) LV: 20 mg/m2 (D1, 8) q3wks Placebo CapeIRI Irinotecan: 250 mg/m2 (D1) Capecitabine: 1000 mg/m2 bid (D1-14) q3wks Stratification : Age (< 70 vs > 70) PS (0 vs 1) Low dose aspirin use (< 325mg every day): yes vs no

  7. Period 2: Treatment Regimens FOLFIRI Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1) 5-FU: 400 mg/m2 (bolus) (D1) 5-FU: 2400 mg/m2 (46-h infusion) (D1) q2wks R A N D O M I Z A T I O N R A N D O M I Z A T I O N Celecoxib 400 mg bid 1st-line mCRC N = 117 5/04–12/04 + 5 mg/kg bevacizumab q 2wks mIFL Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8) LV: 20 mg/m2 (D1, 8) q3wks Placebo + 7.5 mg/kg bevacizumab q 3wks CapeIRI Irinotecan: 250 mg/m2 (D1) Capecitabine: 1000 mg/m2 bid (D1-14) q3wks Stratification: Age, PS, Low dose aspirin use

  8. Period 2Enrollment Closed Dec 2004 ASCO Presentation Clinical Cut-off: Mar 1, 2006 Database Lock: May 10, 2006 ASCO Abstract Clinical Cut-off: Aug 1, 2005 Database Lock: Dec 20, 2005 Timeline of Study Events Period 2Add Bevacizumab 1st Patient Enrolled May 2004 Period 11st Patient Enrolled Feb 2003 2002 2003 2004 2006 2005

  9. Eligibility Criteria • Metastatic colorectal cancer (mCRC) • Measurable disease (RECIST) • No prior chemotherapy for mCRC • Adjuvant therapy >12 months • Age >18 years • ECOG Performance Status <1 • Adequate hematologic, hepatic, and renal function

  10. Study Endpoints • Primary endpoint • Progression free survival (PFS) for FOLFIRI vs mIFL • Secondary endpoints • PFS, overall survival (OS), response rate, & safety for • FOLFIRI vs mIFL vs CapeIRI • Celecoxib vs placebo • FOLFIRI + bevacizumab vs mIFL + bevacizumab

  11. Period 1: Patients Characteristics

  12. Period 1: Tumor Response (ITT)

  13. Period 1: Progression Free Survival (ITT)* Clinical Data Cut-Off: August 1st, 2005 1.0 0.9 0.8 0.7 0.6 Proportion of Progression Free Survival 0.5 0.4 0.3 0.2 FOLFIRI mIFL 0.1 CapeIRI 0 0 10 20 30 Time (months) *Pre-defined analysis; Data in ASCO 2006 abstract

  14. FOLFIRI mIFL CapeIRI Period 1: Progression Free Survival (ITT) Clinical Data Cut-Off: May 1st, 2007 Proportion of Subjects Who Did Not Progress 0 10 20 30 40 Time to Progression (months)

  15. FOLFIRI mIFL CapeIRI Period 1: Overall Survival(ITT)Clinical Data Cut-Off: May 1st, 2007 1 0.9 0.8 0.7 0.6 Proportion of Patients Who Survived 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 Survival Time (months)

  16. Period 1: Common Grade 3-4 Adverse Events

  17. Period 1: Reasons for Study Discontinuation

  18. PERIOD 2 DATA Addition of Bevacizumab Arm A: FOLFIRI + bevacizumab (n = 57) Arm B: mIFL + bevacizumab (n = 60)

  19. Period 2: Patients Characteristics

  20. Period 2: Progression Free Survival (ITT)Clinical Data Cut-Off: May 1st, 2007 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Did Not Progress 0.5 0.4 0.3 FOLFIRI + Bevacizumab mIFL + Bevacizumab 0.2 0.1 0 0 10 20 30 Time to Progression (months)

  21. Period 2: Overall Survival (ITT)Clinical Data Cut-Off: May 1st 2007 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Survived 0.5 0.4 0.3 FOLFIRI + Bevacizumab mIFL + Bevacizumab 0.2 0.1 0 0 10 20 30 40 Survival Time (months)

  22. Period 2: Common Grade 3-4 Adverse Events

  23. Analysis of Celecoxib vs Placebo Period 1 Celecoxib (n = 213) Placebo (n = 217)

  24. Celecoxib vs Placebo - Period 1: Patients Characteristics

  25. Celecoxib vs Placebo - Period 1: PFS (ITT)Clinical Data Cut-Off: May 1st 2007 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Did Not Progress 0.5 0.4 0.3 0.2 Celecoxib 0.1 Placebo 0 0 10 20 30 40 Time to Progression (months)

  26. Celecoxib vs Placebo - Period 1: OS (ITT)Clinical Data Cut-Off: May 1st 2007 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Survived 0.5 0.4 0.3 0.2 Celecoxib 0.1 Placebo 0 0 10 20 30 40 50 Survival Time (months)

  27. Celecoxib vs Placebo - Period 1:Common Grade 3-4 Adverse Events

  28. Conclusions Period 1 • First line FOLFIRI significantly improves PFS when compared with mIFL or CapeIRI • Trend in overall survival favors FOLFIRI • Toxicity profile generally favors FOLFIRI Period 2 • First line FOLFIRI + bevacizumab significantly improves OS compared with mIFL + bevacizumab • Both regimens were tolerable Celecoxib • Celecoxib neither improved efficacy nor reduced chemotherapy toxicity

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