1 / 25

LB Saltz, HJ Lenz, H Kindler, H Hochster, S Wadler, P Hoff, N Kemeny, E Hollywood, M Gonen,

Randomized Phase II Trial of Cetuximab/Bevacizumab/Irinotecan versus Cetuximab/Bevacizumab in Irinotecan-Refractory Colorectal Cancer. LB Saltz, HJ Lenz, H Kindler, H Hochster, S Wadler, P Hoff, N Kemeny, E Hollywood, M Gonen, S Wetherbee, H Chen. Objectives.

neila
Download Presentation

LB Saltz, HJ Lenz, H Kindler, H Hochster, S Wadler, P Hoff, N Kemeny, E Hollywood, M Gonen,

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Randomized Phase II Trial of Cetuximab/Bevacizumab/Irinotecan versus Cetuximab/Bevacizumab in Irinotecan-Refractory Colorectal Cancer LB Saltz, HJ Lenz, H Kindler, H Hochster, S Wadler, P Hoff, N Kemeny, E Hollywood, M Gonen, S Wetherbee, H Chen

  2. Objectives • To evaluate the safety and efficacy of concurrent administration of cetux + bev, with and without irinotecan, in irinotecan-refractory colorectal cancer. • Secondary objective: assessment of TTP and RR in each arm, with exploratory comparison between arms

  3. Background • Cetuximab: human-murine chimeric monoclonal antibody that targets the ligand binding site of the epidermal growth factor receptor (EGFR). • Bevacizumab: humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF).

  4. Cetuximab in CPT-11-Refractory CRC • Cetux + Irino: • 23% RR (ASCO 2001, Saltz et al) • 23% RR (ASCO 2003, Cunnigham et al) • Cetux alone • 9% RR (ASCO 2002, Saltz et al) • 11% RR (ASCO 2003, Cunningham et al) • 12% RR (ASCO 2004, Lenz et al)

  5. Bevacizumab in CRC • Improved RR, TTP, OS with 1st line IFL • (ASCO 2003, Hurwitz et al) • 1% RR with 5FU/LV in refractory CRC • (ASCO 2004 Chen et al) • Improved OS with 2nd line FOLFOX • (ASCO GI 2005, Giantonio et al)

  6. Entry Criteria • Measurable metastatic colorectal cancer. • Prior tumor growth on irinotecan or irinotecan-containing regimen. • As judged by the treating investigator • Rise in CEA alone not acceptable • May not have discontinued irinotecan for tox only • Any number of prior regimens acceptable. • ECOG 0-1. • Normal renal, hepatic, and bone marrow function. • No prior anti-EGFR or anti-VEGF therapy

  7. Study Design • Randomized phase II • EGFR expression not required for study entry • Initially planned for 75 pts/arm • Statistics recalculated for 37 pts/arm

  8. Accrual

  9. Treatment Plan • Arm A (CBI) • Cetuximab, 400 mg/m2 loading dose, then 250 mg/m2 weekly • Bevacizumab 5 mg/kg every other week • Irinotecan at same dose and schedule as last given prior to study entry • Arm A (CB) • Cetuximab, 400 mg/m2 loading dose, then 250 mg/m2 weekly • Bevacizumab 5 mg/kg every other week

  10. Treatment Plan • Cetuximab +/- irintoecan given day 1, and bevacizumab given day 2, week 1 only. • Seen for office visit at least every other week. • Evaluated by CT or MRI every 6 weeks. • Toxicity graded on CTCAE 3.0

  11. Patient Characteristics

  12. Toxicity: Mab-related

  13. Toxicity: Irinotecan-Related

  14. Adverse events: GI (n=74) • Lower GI Bleed: (Pt with carcinomatosis explored for lower GI bleed. Found necrotic tumor eroding into small bowel – felt to be POD) • Rectal Fistula: (Pt developed rectal fistula in setting of carcinomatosis and POD) • UGI bleed. (Endoscopy revealed non-perforating duodenal ulcer) • Enterococcal Endocarditis: Pt admitted with HGB =6, creat =5. W/u revealed enterococcal sepsis with echo showing severe TR and AI with cardiac vegetation. Pt expired in hospital.

  15. Adverse Events:Arterial Thrombotic (n=74) • CNS lacunar infarct: (MRI showed right frontal lobe lacunar infarct. Also showed many chronic lacunar infarcts and chronic microvascular ischemic changes). • MI: (Pt with hx of diabetes, HTN, anemia, and neuropathy, experienced MI on week 22 of treatment. Admitted to local hospital for 10 days. Discharged, then died at home 6 days later, from presumed further cardiac event.) • Chest pain: (Atypical chest pain 80 minutes into 1st bev infusion. Enzymes and ECG’s negative for MI. No chest pain with subsequent treatments. Later admitted with new chest pain, had new a-fib and UE-DVT).

  16. Efficacy of CBI (n=41) • Partial Response 15 (37%) • 95% CI 22%- 53% • Median TTP 7.9 months • Range (1+ to 16+ months)

  17. Efficacy of CB (n=40) • Partial Response 8 (20%) • 95% CI 9%-36% • Median TTP 5.6 months • Range ( 1+ to 12+ months)

  18. Efficacy Comparison (Historical Controls)

  19. Pending Scientific Correlates(Tissue and blood collected) • Cetuximab PK with and without Bev • Bevacizumab PK • Tissue (archived) for PCR • UGT1A1, topo 1, ERCC-1, XRCC-1, p53, GSTP1, p21, p27 VEGF, E-cadherin, TP, COX-2, TGFβ, EGFR • Germ line polymorphisims (peripheral blood) • UGT1A1, XPD, XRCC-1, XRCC-3, ERCC-1, GST-P1 VEGF, TGFβ, COX-2, EGFR • Plasma for VEGF levels • at baseline, 6, 12, and 18 weeks.

  20. Conclusions • Concurrent adminstration of cetuximab and bevacizumab is feasible. • Toxicities are as would be predicted from the individual agents, without clear indication of synergistic toxicity

  21. Conclusions • Compared with historical controls, bevacizumab appears to add to the efficacy of cetuximab and cetuximab/irinotecan in irinotecan-refractory, bevacizumab-naïve colorectal cancer patients. • The usefulness of bevacizumab with cetuximab in patients with prior bevacizumab exposure remains unknown. Studies to address this question are in development.

  22. BOND STUDIES • BOND 1 cetux-irino vs cetux • BOND 2 cetux-bev-irino vs cetux-bev (in bev-naïve patients) • BOND 3 cetux-bev-irino vs cetux-bev (in bev-refractory patients)

  23. BOND STUDIES • BOND 1 cetux-irino vs cetux • BOND 2 cetux-bev-irino vs cetux-bev (in bev-naïve patients) • BOND 2.5 cetux-bev-irino (single arm phase II) (in bev-refractory patients) • BOND 3 cetux-bev-irino vs cetux-bev (in bev-refractory patients)

  24. Planned GI Intergroup CRC Study(Alan Venook and Charles Blanke, PI’s) • Investigator’s choice: FOLFOX vs FOLFIRI • Then randomize to add: • Cetuximab • Bevacizumab • Cetuximab + Bevacizumab

  25. Acknowledgments • Patients, their families and caregivers • Centers – MSKCC, USC, U Chicago, NYU, Cornell, MDA • Industry – Genentech, Imclone/BMS • CTEP / NCI

More Related