1. for the Cancer and Leukemia Group B
A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: A preliminary analysis of CALGB 80303
Hedy Lee Kindler, Donna Niedzwiecki, Donna Hollis, Ebele Oraefo, Deborah Schrag, Herbert Hurwitz, Howard McLeod, Mary Mulcahy, Richard Schilsky, and Richard Goldberg
for the Cancer and Leukemia Group B

2. Chemotherapy for pancreatic cancer
Gemcitabine
Cornerstone of treatment
Response rates 5-10%
Median survival 5-6 months
Many gemcitabine doublets
‘Promising activity’ in phase II studies
No survival benefit in phase III trials
Phase III trial: Gemcitabine + erlotinib
Modest improvement in overall survival

3. Vascular endothelial growth factor: A key role in pancreatic cancer biology
VEGF
Over-expressed in PC
Inhibition of VEGF
Suppresses PC growth in preclinical models
High VEGF expression
Correlates with advanced stage and decreased survival

4. Gemcitabine + bevacizumab in advanced pancreatic cancer
Monoclonal antibody to VEGF
Phase II trial: Gemcitabine + bevacizumab1
52 patients with stage IV PC
Partial response rate: 21%
Median survival: 8.8 months
1-year survival: 29%
1Kindler et al, JCO 23: , 2005

5. Advanced pancreatic cancer
CALGB Trial design R A N D O M I Z E
Gemcitabine
Bevacizumab
Advanced pancreatic cancer
N=590
Gemcitabine
Placebo
Stratification:
Performance status: 0/1 vs. 2
Extent of disease: metastatic vs. locally advanced
Prior radiation: yes/no

6. Statistics
90% power to detect a 35% increase in median overall survival from 6.0 to 8.1 months (2 sided logrank  =0.05)
Toxicity monitoring for bleeding, proteinuria, HTN, and thrombosis
Five planned interim analyses for the primary endpoint of overall survival
(3 during accrual, 2 during follow-up)

7. CALGB 80303: Endpoints Primary Endpoint: Overall survival
Secondary Endpoints:
Objective response rate
Duration of response
Progression-free survival
Toxicity

8. Three companion studies to CALGB 80303
Clinical Economics/Quality of Life
Presented at ASCO 2007:
Oral Session: Patient and Survivor Care Abstract #9008 
D. Romanus, et al: Does health-related quality of life improve for pts who respond to chemotherapy? Analysis of pts with advanced pancreas cancer receiving gemcitabine on CALGB study 80303
Poster discussion: Upper GI Cancer Abstract #4524
D. Schrag, et al: A patterns-of-care study of post-progression treatment among patients with advanced pancreas cancer after gemcitabine therapy on CALGB study 80303
Angiogenesis biomarker study
Pharmacogenomic predictors of outcome
Will be reported at a later date

9. Eligibility-1
Histologically/cytologically confirmed unresectable pancreatic adenocarcinoma
No prior chemotherapy for metastatic disease
> 4 weeks from adjuvant chemo or radiation
No prior gemcitabine, bevacizumab, or other VEGF inhibitor
ECOG PS 0-2
Adequate hematologic, hepatic, renal function, <1+ proteinuria

10. Eligibility-2 No documented invasion of adjacent organs
No recent invasive surgical procedures
Surgery >28 days, FNA >7 days
No significant bleeding episodes in prior 6 months, no esophageal varices
Anticoagulants permitted, on a stable therapeutic dose
No clinically significant cardiovascular disease
Written informed consent

11. CT scans: obtained every 2 cycles
CALGB 80303: Treatment R A N D O M I Z T
Gemcitabine mg/m2 D 1, 8, 15
Bevacizumab 10 mg/kg D 1, 15
Gemcitabine mg/m² D 1, 8, 15
Placebo D 1, 15
1 cycle = 28 days
CT scans: obtained every 2 cycles

12. CALGB 80303: Trial progress Activated: June 30, 2004
Enrollment completed: April 14, 2006
Final accrual: 602 patients
Contributors: CALGB, ECOG, CTSU
Study unblinded: June 26, 2006
Current analysis database frozen: May 7, 2007
Number of events (deaths) observed: 500
(>100% of the total expected deaths at
planned final analysis)

13. Release of study data on CALGB 80303
Based on a protocol-specified interim analysis, with 64% of information on overall survival, the CALGB Data Safety Monitoring Board released study data in June 2006 because a futility boundary was crossed
The DSMB felt that it was unlikely that there would be significant differences in overall survival between treatment arms with further follow-up
All patients on treatment were unblinded and notified of these results
Patients thought to benefit from bevacizumab could continue it with informed consent

14. Patient characteristics
Gemcitabine
Bevacizumab
N=302
Placebo
N=300
Median age (years)
63.8
65.0
Male
Female
58%
42%
51%
49%
Performance status 1 2
36%
53%
11%
39%
52% 9%
Locally advanced
Metastatic
15%
85%
16%
84%
Prior radiation

15. Total mg/m2 Gemcitabine received
CALGB 80303: Dose Delivery GB GP P
Mean # cycles
delivered
3.9
3.2
0.02
Total mg/m2 Gemcitabine received
9577
8633
0.15

16. CALGB 80303: Grade ¾ toxicity
N=277 GP
N=263 P
Neutropenia
33%
29%
0.35
Anemia 5% 8%
0.22
Thrombocytopenia
12%
1.0
CVA 2%
GI Bleeding 3%
0.58
Hypertension
0.0013
Visceral perforation
0.4% 0%
Proteinuria 1%
0.01
Venous thrombosis 9%

17. CALGB 80303: Objective Response
Gemcitabine
Bevacizumab
Placebo
Complete
Response 1% 2%
Partial
10% 8%
Stable
Disease
36%
31%
Disease control:
CR + PR + SD
47%
40%

18. Progression-free survival
CALGB 80303: Survival GB GP P HR
Median
overall
survival
(95% CI)
5.8
months
(5.0, 6.7)
6.1
(5.0, 7.1)
0.78
1.03
Progression-free survival
4.9
(4.4, 5.8)
4.7
(3.9, 5.8)
0.99
1.0
1-yr survival
18%
(14, 23)
20%
(16, 26)

19. CALGB 80303: Progression-Free Survival by Treatment Arm
Bevacizumab 4.9 mo
Placebo mo
HR = 1.00
P =
HR=1.00
p=0.99

20. CALGB 80303: Overall Survival by Treatment Arm
Bevacizumab 5.8 mo Placebo mo
HR = 1.03
P =

21. CALGB 80303: Overall Survival by Disease Stage
Metastatic mo
Locally advanced mo
HR = 1.4
P =

22. CALGB 80303: Overall Survival by Performance Status
PS 0: mo
PS 1: mo
PS 2: mo
P =
p=0.0001

23. Patient characteristics in phase II and III trials of gemcitabine + bevacizumabGB
N=302 GP
N=300
Phase II GB N=52
Median age
63.8
65.0
63.0
Male
58%
51%
52% PS 1 2
36%
53%
11%
39% 9%
60%
38% 2%
Metastatic
85%
84%
100%
Adjuvant tx
23%
Previous
thrombosis
permitted
excluded

24. CALGB 80303: Conclusions
The addition of bevacizumab to gemcitabine does not improve survival in patients with advanced pancreatic cancer
The distribution of patients with good prognostic factors likely accounts for differences between CALGB and the prior phase II trial, and confirms the need for randomized trials in this disease
It is anticipated that the companion studies of angiogenesis biomarkers, pharmacogenomics,
and clinical economics/quality of life will provide additional insights into the biology and clinical management of advanced pancreatic cancer

25. Acknowledgments The patients who participated in this study
CALGB Statistical Center and Central Office:
Donna Niedzwiecki, Donna Hollis, Ebele
Oraefo, Susan Sutherland, Sarah Duggan
National Cancer Institute:
Margaret Mooney, Helen Chen
Genentech:
Eric Hedrick, Robert Mass
The many CALGB, ECOG, and CTSU investigators, nurses, and data managers
who enrolled and took care of the patients
on this trial