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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. - PowerPoint PPT Presentation
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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
• 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
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).
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)
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)
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
Study Design
• Randomized phase II
• EGFR expression not required for study entry
• Initially planned for 75 pts/arm
• Statistics recalculated for 37 pts/arm
AccrualMonth # Pts Comments
Dec 22, 2003 8 Accrual held x 3 weeks per protocol
Jan 04 9 Accrual restarted Jan 15. Held to 1 per day.
Feb 04 14 Cetux and bev receive FDA approval.
March 04 15
April 04 5
May 04 8
June 04 6
July 04 5
August 04 3
Sept 04 2
Oct 04 0
Nov 04 1
Dec 04 2
Jan 05 2
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
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
Patient CharacteristicsCBI (n=41) CB (n=40) P
% male 61% 65% ns
Median Age (range)
64 (43-86)
56 (24-80)
.01
PS = 0 39 % 55 % ns
PS = 1 61 % 45 % ns
Prior oxaliplatin 85 % 90 % ns
Med. prior regimens (range)
3 (range1-6)
3 (range 1-8)
ns
Prior Pelvic RT 1 (2%) 5 (13%) ns
Toxicity: Mab-related
Cetux-Bev-Irino n=41
Cetux-Bev
n=40
Skin rash Gr 3 7 (17%) 8 (20%)
Skin rash Gr 2 25 (60%) 26 (65%)
Paronychial Gr 3 cracking
2 (5%) 2 (5%)
Allergic Rxn Gr 3 0 (0%) 0 (0%)
Headache Gr 3
(1st cetux only)
0 (0%) 2 (5%)
Toxicity: Irinotecan-Related
Cetux-Bev-Irino n=41
Cetux-Bev
n=40
Neutropenia Gr 3-4 9 (22%) 0 (0%)
Diarrhea Gr 3-4 10 (24%) 0 (0%)
Diarrhea Gr 2 12 (29%) 2 (5%)
Fatigue Gr 3 4 (10%) 0 (0%)
Fatigue Gr 2 13 (32%) 2 (5%)
Nausea Gr 3 1 (2%) 0 (0%)
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.
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).
Efficacy of CBI (n=41)
• Partial Response 15 (37%)– 95% CI 22%- 53%
• Median TTP 7.9 months– Range (1+ to 16+ months)
Efficacy of CB (n=40)
• Partial Response 8 (20%)– 95% CI 9%-36%
• Median TTP 5.6 months– Range ( 1+ to 12+ months)
Efficacy Comparison (Historical Controls)
Cetux-Irino
(historical)
Cetux-Irino + Bev P value
Resp Rate 23% 37% 0.03
TTP 4 m 7.9 m <0.01
Cetux alone
(historical)
Cetux + Bev
P value
Resp Rate 11% 20% 0.05
TTP 1.5 m 5.6 m <0.01
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.
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
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.
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)
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)
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
Acknowledgments
• Patients, their families and caregivers
• Centers – MSKCC, USC, U Chicago, NYU, Cornell, MDA
• Industry – Genentech, Imclone/BMS
• CTEP / NCI
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