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