1. and the NSABP Investigators
Initial Safety Report of NSABP C-08, A Randomized Phase III Study of Modified FOLFOX 6 With or Without Bevacizumab in the Adjuvant Treatment of Patients With Stage II/III Colon Cancer
Carmen Allegra, Greg Yothers, Saima Sharif, Michael O’Connell, Norman Wolmark
and the NSABP Investigators

2. I have no relevant industry relationships to disclose.
Disclosure Statement
I have no relevant industry relationships to disclose.

3. Stage II or III Colon Cancer Number of Positive Lymph Nodes
NSABP C-08 Schema
Stage II or III Colon Cancer
Stratification
Number of Positive Lymph Nodes
Randomization
mFOLFOX6
mFOLFOX6 +
Bevacizumab
Disease-free survival: primary endpoint

4. mFOLFOX6 Regimen Leucovorin 400 mg/m2 IV 5-FU 400 mg/m2 IV
5-FU 2400 mg/m2 over 46 hrs
Oxaliplatin 85 mg/m2 IV
Bevacizumab (Arm 2) 5mg/kg
Repeat every 2 wks X 12 doses (chemo) doses (bev)

5. C-08 Patient Recruitment Timeline
Opened: Sept ’04
Closed: Oct ’06
Total Accrual: Pts
Average monthly accrual: 110 Pts

6. C-08 Patient Demographics
31 March 2008
FOLFOX
FOLFOX + Bev
Randomized
1356
1354
Mean time on study (mo)
Age < 60 (%)
58.3
58.2
Male (%)
49.8
49.9
Stage II (%)
24.9
Stage III (1-3) (%)
45.4
45.5
Stage III (4+) (%)
29.7
29.6
28.5

7. C-08 Selected Inclusion/Exclusion Criteria
Stage II or III colon adenocarcinoma
Randomization between day 29 & 50 post-op
ECOG PS 0 or 1
Exclusion
Any history of CVA or TIA
Any symptomatic PVD
History of ATE within 12 months

8. Doses of Therapy Administered Restricted to Pts without DFS Event
mFOLFOX6 mFOLFOX6+Bev p
Oxali ≥ 10 of % % <0.01
5-FU ≥ 10 of % % <0.01
Bev ≥ 21 of %

9. Cumulative Dose Oxali (mg/m2) Restricted to Pts without DFS Event
Median Dose Delivered
mFF6= 850 mg/m2
mFF6+Bev= 880 mg/m2 p =
Median Dose Intensity
mFF6= mg/m2/wk
mFF6+Bev= 41.6 mg/m2/wk
p = 0.13
Percent of Patients

10. Duration of Bev (5 mg/kg q2wks) Restricted to Pts without DFS Event
Percent of Bev Patients
Median Duration 11.5 months
Months

11. Duration of Bev and 5-FU Restricted to Pts without DFS Event
Bev Duration
5-FU Duration (both arms)
Percent of Patients
Months

12. Treatment Associated Mortality (%) Excluding death after relapse or second primary
within 6 months of randomization
mFOLFOX
mFOLFOX6 + bev
p=1.0
within 18 months of randomization
mFOLFOX
mFOLFOX6 + bev 1.35
p=1.0

13. Maximum Grade of AE by Treatment First 18 months after Randomization
p =
Percent of Patients

14. Chemotherapy Associated Toxicities (Grade 3+) (%)
mFOLFOX6
mFOLFOX6+bev
Venous Thrombosis 8 9
Neutropenia 33 30
Febrile neutropenia 1
Fatigue 7
Diarrhea 10 11
Dehydration 4 5
Sensory Neuropathy 14 16
(33 Gr 2)
p<0.01;Gr2+
(29 Gr 2)

15. Toxicities Associated with Bevacizumab in Advanced Disease Studies Not Significantly Different in C-08 (%)
mFOLFOX6
mFOLFOX6+bev
Cardiac Ischemia
0.76
1.51
CNS Ischemia
0.38
0.45
Peripheral
Arterial Ischemia
0.23
GI Perforation
0.15
0.3
Hemorrhage
1.9

16. Toxicities (Grade 3+) Significantly Reduced with Bevacizumab (%)
mFOLFOX6
mFOLFOX6 + Bev
p-value
Thrombocytopenia
3.4
1.4
<0.001
Allergic Reaction
4.7
3.1
0.03

17. Toxicities (Grade 3+) Significantly Increased with Bevacizumab (%)
mFOLFOX6
+ Bev
p-value
Hypertension
1.8 12
(5 pts Gr 4)
<0.0001
Any Pain
6.3
11.1
Proteinuria
0.8
2.7
<0.001
Wound Complications
0.3
1.7
(all Gr 3)

18. Bevacizumab Arm -Wound Complications-
23 cases (1.7%) on bevacizumab arm
All Grade 3
All but one resulted in surgical intervention
Half resulted in bevacizumab discontinuation
14 pts had symptomatic abdominal inc. hernias
1 dehiscence/abscess
Median time to occurrence – 5 mos
9 pts had inf port dehiscence and/or infect/inflam
Median time to occurrence – 2 mos

19. Pain (Grade 3+) Chest Pain 1 2.3 <0.01 Joint Pain 2.1 0.04
mFOLFOX6
(%)
+ Bev (%)
p-value
Chest Pain 1
2.3
<0.01
Joint Pain
2.1
0.04
Muscle Pain
1.2
2.4
0.03

20. Significantly Different Toxicities (Grade 3+) After Chemotherapy Completion
mFOLFOX6
(%)
+ Bev (%)
p-value
Wound Complication
0.3
1.1
0.01
Hypertension
0.7
5.9
<0.0001
Sensory Neuropathy
(Grade 2+)
26.1
32.4
<0.001
Depression
1.3
2.9
<0.01
Dizziness
1.6
0.04
Proteinuria
0.2
Pain - Any
2.1
4.7

21. Maximum Grade of AE by Age Decade (All Patients)
Percent of Patients

22. C-08 Summary
The overall safety of adding bevacizumab to mFOLFOX6 in the colon cancer adjuvant setting is acceptable in the selected population of patients eligible for C-08 with a mean time on study of 28.5 mos; however, the use of bevacizumab in the colon adjuvant setting cannot currently be recommended in the absence of efficacy data
The cumulative dose & dose-intensity of mFOLFOX6 was not decreased by the addition of bevacizumab
No increase in ATE, hemorrhage, GI perforations or death from any cause as a result of the addition of bevacizumab to mFOLFOX6

23. C-08 Summary
Other complications seen at increased frequency (HTN, wound complications, proteinuria & pain) are important but manageable
Sensory neuropathy grade 2+ was increased with bev but may be secondary to an increased cumulative dose of oxaliplatin
Long term follow-up to detect any potential increase in delayed side effects associated with bevacizumab continues

24. Special Thanks to our NSABP Investigators and to All of the Patients Who Participated in the Conduct of C-08