1. What’s New In UGI Tract Cancers?
David H. Ilson, M.D., Ph.D.
Attending Physician
Memorial Sloan-Kettering Cancer Center
New York

2. Disclosure Research Support Genentech Bristol Myers Squibb / Imclone
Sanofi-Aventis
Bayer

3. Esophageal and Gastric Carcinoma US Incidence in 2013
39,590 new cases
Gastric: 21,600 (54%)
Esophagus: 17,900 (46%)
Decline in Gastric Cancer Incidence
Increase in Esophageal , GE JX, cardia adeno
OS improvement, , ,
Gastric: 16%  18%  27%
Esophageal: 5%  10%  19%
Siegel et al, CA 63: ; 2013

4. Gastric and Esophageal Cancer RNA expression signatures
Intestinal Cancer
Diffuse Cancer
GEJ Cancer
Shah M A et al. Clin Cancer Res 2011;17:
©2011 by American Association for Cancer Research

5. GEJ Cancer
Diffuse Cancer
Intestinal Cancer

6. Esoph and GEJ:
Preop therapy for
T2-3 or N+
EMR for T1a
Surgery for T1b

7. Esophageal and GEJ Adenoca: Consensus on Adjuvant Therapy
T2-3 or N+: Something more than surgery alone should be done
Preop chemo ECF, CF improves overall survival in some but not all trials
MAGIC (ECF): 13% ↑ OS at 5 yr (esophageal and GEJ 25% pts)
FFCD / FNLC (CF): 14% ↑ OS at 5 yr (esophageal and GEJ cancer, 180 pts)  same as MAGIC, no epirubicin
Cunningham NEJM 355: 11; 2006 ,Ychou J Clin Oncol 29: 1715; 2011,

8. Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy
Trials focusing purely on esophageal and GE junction cancers
Preop chemo CF failed:
MRC 0E0-2 (CF): 800 pts, adeno and squam
5 year update: 6% ↑OS
Impacted only on rate of R0 resection
U.S. INT 113 (CF): 450 pts, adeno and squam
No impact on OS or rate of R0 resection
EORTC (CF): 70 pts, adeno
No impact on OS
Allum J Clin Oncol 2009, Kelsen NEJM 1998, Schuhmacher J Clin Oncol 28: 5210; 2010

9. Preop Chemo vs Surgery Alone: 2062 patients, 10 Trials
HR favoring Chemo 0.87 (p = )
Squamous: HR (p = 0.18)
Adeno: HR 0.83 (p = 0.01)
Sjoquist Lancet Oncol 12: 681; 2011

10. Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29
Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy
Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)
Van Hagen et al NEJM 366: 2074; 2012

11. CROSS: Major Results EUS staged patients T3N0-1 75%, median age 60
74% Adenocarcinoma
93% received all courses chemotherapy
23% had > = grade 3 toxicity from pre-op therapy
Post-operative morbidity and mortality almost identical (mortality %)

12. Resection rate and resection margins
Resection rate of all randomized patients
Surgery alone CRT + surgery
186/188 (99%) 168/178 (95%)
Resection margins
R0 111/161 (69%) 148/161 (92%) p<0.002
R0 = no tumor within 1 mm of the resection margins
CROSS study

13. Overall Survival Improved with Chemo RT + Surgery
5-year survival 47% versus 34%
Median survival 49.4 versus 24 months, HR 0.66, p = 0.003)
Squamous HR 0.453
Adeno HR 0.732
Squamous path CR 49%, Adeno 23% (p = 0.008)

14. Preop Chemo RT vs Surgery Alone: 1932 patients, 13 trials
HR favoring Chemo RT 0.78 (p < )
Squamous HR 0.8 (p = 0.004)
Adeno HR 0.75 ( p = 0.02)
Sjoquist Lancet Oncol 12: 681; 2011

15. Esophageal Cancer: Preop Chemo, RT, or Both? Conclusions
Esophageal, GEJ Adeno
Preop ECF Chemo improves survival and is feasible
Preop RT + Chemo: superior OS, more path CR’s
Esophageal Squamous
RT + Chemo:
As primary therapy without surgery is preferred
Surgery after chemo RT: in selected patients
Improved local control  no improvement in survival

16. PET Scan Directed Therapy Trial Design: CALGB 80803
PET-responders: ≥ 35% SUV decrease: continue same chemo + concurrent RT (5040cGy in 180cGy fx)
T3/4 or N1 Esophageal Adenoca
PET/CT: Induction Chemo: FOLFOX6 or Carbo/Pacliotaxel
Surgical resection 6 weeks post-RT
PET Scan day 29-35
PET- nonresponders: < 35% SUV decrease: Cross over to alternate chemo + RT (5040cGy in 180cGy fx)
Hypothesis: changing chemo in PET non responding patients will improve pCR during chemo + RT

17. Optimal Surgery for Gastric Cancer?
D2 resection is the standard of care in Asia
Increasingly in the West D2 resection is considered the standard
Update of Dutch D1 vs D2 resection at 15 years supports D2:
Songun I et al Lancet Oncol 11: 439; 2010

18. Adjuvant Therapy in Gastric Cancer Improves OS
Post op RT + chemo (U.S.), less than a D1-2 resection
5FU-LV + RT, INT 116:
10% 5 yr OS, HR 0.65
Pre and post op chemo (U.K.) without RT
ECF, MAGIC:
13% 5 yr OS, HR 0.75
Post op chemo (Asia): 2 trials, 2000 pts, D2 resection, no RT
S-1 (Oral 5-FU), ACTS-GC:
13% 5 yr OS, HR 0.67 (2011 update)
Post op Cape-Oxali , CLASSIC Trial:
14% 3 yr DFS, HR 0.56
Survival improvements with all approaches similar, modest
Cunningham NEJM 355: 11; 2006 Sasako JCO 29: 4387; 2011 Bang Lancet 379: ; Macdonald NEJM 345:725; 2001

19. CLASSIC study design 8 cycles of XELOX (6 months)
R A N D O M I Z
A T I O N
Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization
No prior chemotherapy or radiotherapy
n=1035
n=520
8 cycles of XELOX (6 months)
Capecitabine: 1,000mg/m2 bid, d1–14, q3w
Oxaliplatin: 130mg/m2, d1, q3w
1:1†
Observation: No adjuvant therapy
n=515
Primary endpoint: 3-year DFS‡
Secondary endpoints: overall survival and safety profile
†Stratified by stage and country with age, sex, and nodal status as covariates
‡GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 2009
Bang Lancet 379: ; 2012 19

20. Primary endpoint (3-year DFS) met at interim analysis
1.0
0.8
74%
XELOX, n=520
0.6
60%
Observation, n=515
0.4
0.2
HR=0.56 (95% CI 0.44–0.72)
P<0.0001
0.0 6 12 18 24 30 36 42 48
Time (months)
No. left
XELOX
520
443
410
333
246
166 74 30 10
Observation
515
414
352
286
209
147 58 22 6
ITT population; DFS = disease-free survival
Median follow-up 34.4 months (range 16–51)
Bang Lancet 379: ; 2012

21. 3-year DFS by stratification factors
Category
Subgroup
HR (95% CI) n
HR estimate
All
1,035
0.58
Stage of disease
Stage II
Stage IIIA
Stage IIIB
515
377
143
0.55
0.56
0.57
Age group, years
<65
≥65
766
269
0.63
0.46
Sex
Female
Male
304
731
0.81
0.49
Nodal status N0
N1/2
103
932
0.83
0.56 2 1
0.6
0.4
0.2
ITT population

22. European / Asian Gastric Adjuvant Trials: Is RT required post op?
CRITICS Trial (NL): randomization + / - RT
Preop ECX
D1 resection
Post op chemo + / - RT
Korea ARTIST trial: chemo + / - RT (JCO 2011)
D2 resection
Post op Cape/Cis x 6 mos
+ / - Post op RT
5% increase in 3 yr DFS, N+
Repeat trial planned targeting N+ pts
TROG (Australia): Preop ECF + / - Preop RT
Esophageal and gastric, 750 pts

23. Advanced Gastric Cancer Chemotherapy: What regimen to use?
Oxali:
EOX or EOF
Cape:
ECX or EOX XP
FLO
FUFIRI
S-1 Cis
DCF
ECF
Pts
489
513
160
109
170
305
221
126
%RR
44%
45%
41%
34%
32%
54%
36%
TTP, mos
6.7
6.5
5.6
5.5
5.0
6.0
7.4
OS, mos
10.9
10.4
10.5
10.7
9.0
13.0
9.2
8.9

24. Second Line Chemo: Gastric Cancer
AGC refractory to prior FP confirmed by imaging
Age 20-75, PS 0-2, No history of CPT-11 or Taxane
RANDOMIZATION
Stratified by
Institution, PS 0-1/2, target lesion -/+
weekly Paclitaxel
80 mg/m2 d1, 8, 15 q4w
IRI
150 mg/m2 d1, 15 q4w
Ueda et al Proc ASCO 2012

25. Overall Survival IRI wPTX n 111 108 Median 8.4M 9.5M P 0.38
HR (95% CI)
1.13 ( )
Log-rank test
Probability (%)
(Months)
Number at risk
wPTX
IRI
108
111 80 75 36 29 10 2 3 1 1
FAS

26. Progression Free Survival
IRI
wPTX n
111
108
Median
2.3M
3.6M P
0.33
HR (95% CI)
1.14 ( )
3.6
Probability (%)
2.3
Log-rank test
(Months)
Number at risk
wPTX
IRI
108
111 66 46 16 18 9 8 3 6 2 2 1
FAS

27. Response Rate n CR PR SD PD NE CR+PR P wPTX 91 19 38 32 2 21% 0.24 IRI19 38 32 2
21%
0.24
IRI 88 1 11 28 45 3
14%
RECIST 1.0
Fisher’s exact test

28. Ford et al GI Symposium 2013 Kang JCO 30: 1513-1518/ 2012
Second Line Chemotherapy post Platin + 5-FU: Further support for Taxanes
Cougar Trial-02 (U.K.) (GI Symposium 2013)
168 pts with gastric and GEJ cancer
BSC vs docetaxel 75 mg/m2 every 3 weeks
OS improved from 3.6  5.2 months (HR 0.67, p = 0.01)
Responses in 7% of patients
Kang (JCO): 202 pts with gastric cancer
Docetaxel 60 mg/m2 or irinotecan 150 mg/m2 every 3 weeks vs BSC
OS improved from 3.8  5.3 months (HR 0.657, p = )
RR 10% irinotecan, 17% for docetaxel
Ford et al GI Symposium Kang JCO 30: / 2012

29. Kaplan-Meier estimates for overall survival in randomly assigned patients.
Kang J H et al. JCO 2012;30:
©2012 by American Society of Clinical Oncology

30. Molecular Targets: Gastric Cancer
KRAS mutation: < 5-10%
BRAF mutation: < 5%
EGFr over expression: %
EGFr mutation: < 5%
CMET: < 10%, IHC + 40%
HER2 over expression: %
TOGA: Trastuzumab + chemo improves OS in HER2+
Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; Yano Oncol Rep 15: 65; Gold GI CA Symp 2008 Abs 96

31. ToGA trial design
Phase III, randomized, open-label, international, multicenter study
5-FU or capecitabinea + cisplatin
(n=290)
3807 patients screened1
810 HER2-positive (22.1%)
HER2-positive advanced GC (n=584) R
5-FU or capecitabinea + cisplatin
+ trastuzumab
(n=294)
Stratification factors
advanced vs metastatic
GC vs GEJ
measurable vs non-measurable
ECOG PS 0-1 vs 2
capecitabine vs 5-FU
aChosen at investigator’s discretion GEJ, gastroesophageal junction
1Bang et al; Abstract 4556, ASCO 2009

32. Primary end point: OS Event 1.0 Median OS 13.8 11.1 0.9 Events 167 182HR
0.74
95% CI
0.60, 0.91
p value
0.0046
0.8
FC + T
0.7 FC
0.6
0.5
0.4
0.3
0.2
11.1
13.8
0.1
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
No. at risk
294
290
277
266
246
223
209
185
173
143
147
117
113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 1
T, trastuzumab

33. OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
Event
1.0
Median OS
Events HR
0.65
95% CI
0.51, 0.83
0.9
0.8
FC + T
0.7 FC
0.6
0.5
0.4
0.3
0.2
0.1
11.8
16.0
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
No. at risk
122 96
100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 1

34. Secondary end point: tumor response rate
Intent to treat
Patients (%)
p=0.0017
F+C + trastuzumab
p=0.0145
F+C
47.3%
41.8%
34.5%
32.1%
p=0.0599
5.4%
2.4% CR PR
ORR
ORR= CR + PR CR, complete response; PR, partial response

35. Secondary end point: PFS
Event
1.0
Median PFS
Events HR
0.71
95% CI
0.59, 0.85
p value
0.0002
0.9
0.8
FC + T
0.7 FC
0.6
0.5
0.4
0.3
0.2
0.1
5.5
6.7
0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time (months)
No. at risk
294
290
258
238
201
182
141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 2

36. Targeted Agents Phase III: HER2: Met Disease
LOGIC: Cape-Ox + / - Lapatinib (HER2+)
TYTAN: Paclitaxel + / - Lapatinib (HER2+)
Second Line
PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib
OS 7.6  14.0 months, HR 0.59, p =
Bang et al GI Cancers Symposium 2013 Abstract 11

37. HER 2 Directed Therapy Trials in development
First Line: Capecitabine-Cisplatin -Trastuzumab + / - Pertuzumab
Second line: Paclitaxel vs TDM-1
Second line MSKCC: Afatinib single agent

38. RTOG 1010: Phase II Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) ‘
CHEMORADIATION
SURGERY
HER-2 (+)
(FISH)
TRASTUZUMAB +
CHEMORADIATION
SURGERY +
TRASTUZUMAB (1 YR)
HER-2 (-)
(FISH)
ALTERNATIVE STUDIES
Chemoradiation: 5-FU + Oxaliplatin, RT 5040 cGy  Surgery
Maintenance trastuzumab post op
Sample Size = 130 Her-2 (+) Pts, Increase
3-Yr Survival from 30% to 50% pts to be screened

39. Targeted Agents Phase III: Met Disease
Granite: BSC vs Everolimus
Negative for OS, but improved PFS
Second Line: Paclitaxel + / - Everolimus
REAL 3: ECX + / - Panitumumab (U.K.)
Negative: Panitumumab had inferior outcomes
EXPAND: Cape-Cis + / Cetuximab (E.U.)
Negative: Cetuximab trended inferior
SCOPE-1: Cape-Cis-RT + / - Cetuximab as definitive chemo + RT, esophageal and GEJ
(U.K.) Negative trial, inferior outcomes with cetuximab
COG: BSC vs Gefitinib (U.K.): Negative trial for OS

40. R REAL3 Trial Design Arm A: EOC Arm B: mEOC-P EOC (Arm A):
Untreated advanced adenocarcinoma or undifferentiated carcinoma of the oesophagus, OGJ or stomach
EOC (Arm A):
Epirubicin 50mg/m2 IV D1
Oxaliplatin 130mg/m2 IV D1
Capecitabine 1250mg/m2/day PO in two divided doses D1-21
mEOC-P (Arm B)1:
Epirubicin 50mg/m2 IV D1
Oxaliplatin 100mg/m2 IV D1
Capecitabine 1000mg/m2/day PO in two divided doses D1-21
Panitumumab 9mg/kg IV D1
1. Okines et al, JCO 2010

41. Primary Endpoint – OS Based on 251 OS events
100
Median OS
(95% CI)
% alive at 1 year
11.3m (9.6 – 13.0)
46% (38% - 54%)
8.8m (7.7 – 9.8)
33% (26% - 41%)
HR 1.37, p = 0.013 80 60
Probability of Survival (%) 40
EOC
HR 1.37 (95% CI: 1.07 – 1.76) 20
EOC-P 6 12 18 24 30 36
Months from Randomisation
Number at risk
EOC
275 49 3
EOC-P
278 38 2
Based on 251 OS events

42. Trial Results - PFS Based on 333 PFS events
100
Median PFS
(95% CI)
% alive and progression-free at 1 year
7.4m (6.3 – 8.5)
21% (14% - 27%)
6.0m (5.5 – 6.5)
20% (14% - 26%)
HR 1.22, p = 0.068 80 60
Probability of Survival (%) 40
EOC 20
EOC-P
HR 1.22 (95% CI: 0.98 – 1.52) 6 12 18 24 30
Months from Randomisation
Number at risk
EOC
275 25 2
EOC-P
278 24
Based on 333 PFS events

43. Trial Results - RR Best Response EOC (n=238) mEOC-P (n=254) CR 5 (2%)
8 (3%) PR
95 (40%)
108 (43%) SD
51 (21%)
46 (18%) PD
19 (8%)
30 (12%)
Not evaluable
68 (29%)
62 (24%)
ORR
42%
46%
Odds Ratio for Response
1.16
(95% CI: )
p-value
0.467
Patients who had not reached 1st response assessment at time of data censoring are excluded (n=61)

44. Death due to “homelessness” (anokis)

45. Doshi et al Proc ASCO 2012

47. ECX + / - Rilotumumab in CMET High: RILOMET Trial

48. Fuchs et al GI Symposium 2013
VEGF Revisited?
AVAGAST: Cape or 5-FU + cisplatin + / - bevacizumab
PFS and RR improved
Non significant increase in OS
Ramucirumab (Fuchs, GI Symposium 2013)
Humanized antibody blocking VEGFR2
355 patients post 5-FU and platin based chemo
BSC vs Ramucirumab 8 mg/kg IV every 3 weeks
PFS improved 2.1  3.8 months (HR 0.483, p < )
OS improved 3.8  5.2 months (HR 0.776, p = )
Disease control improved from 23% to 49% (p < )
Essentially no toxicity (rare grade 3/4 hypertension 7.2%)
Fuchs et al GI Symposium 2013

49. Pancreatic Cancer and HCC US Incidence in 2013
45,220 cases, 38,460 deaths (85%)
FOLFIRINOX new standard chemotherapy for good PS pts
Gemcitabine combination therapy for good PS
Adjuvant gemcitabine + / - RT after resection
HCC and bile duct
30,640 cases, 21,670 deaths (71%)
HCC: sorafenib for metastatic disease
Cholangiocarcinoma: gemcitabine/cisplatin for metastatic disease
Siegel et al, CA 63: ; 2013

50. CONKO-001: Efficacy Results
Gemcitabine
(N= 179)
Observation
(N= 175)
P-value
Median DFS
13.4 mths
6.9 mths
< 0.001
Median OS
22.8 mths
20.2 mths
0.005
1-Year OS
72%
72.5% -
3-year OS
36.5%
19.5%
5-Year OS
21% 9%
Median f/up 53 months
Neuhaus, et al. ASCO, 2008 (LBA #4504)

51. Results ESPAC-3(v2) 1,088 pts, 17 countries 1/00- 1/07
35% R1; 72% node positive; 25% grade III
Median follow up 34.2 months
5-FU-LV
N= 551
Gemcitabine
N= 537
Log-rank
Med OS
23 mths
23.6 mths
HR= 0.94 ( )
p= 0.39
Neoptolemos, et al. JAMA, 2010

56. Resected Pancreas Cancer
US Intergroup/RTOG 0848 R A N D O M I Z E
Gemcitabine x 4 cycles
Resected Pancreas Cancer
N= 952
2nd Randomization
+/-
ChemoRT
Gemcitabine + Erlotinib x 4
Stratification
R0 vs R1 resection; T stage; N(+) vs N(-)
Primary Endpoint: Overall Survival +/- Erlotinib, +/- RT
Secondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicity
Tissue acquistion/ correlative science

57. FOLFIRINOX vs Gemcitabine
Prodige 4- ACCORD 11 R A N D O M I Z E
FOLFIRINOX
(N = 167)
Untreated Metastatic Panc Adenocarcinoma
ECOG 0-1
Gemcitabine
(N = 169)
Randomization 1: 1
Stratification
PS: 0-1 vs 2; Primary tumor location, Center
Primary Endpoint: Overall Survival
Conroy, et al. NEJM, 2011

58. FOLFIRINOX vs Gemcitabine
Overall Survival
FOLFIRINOX
Number at risk
Gemcitabine
FOLFIRINOX 1 . 7 5 2 P r o b a i l t y M n h s 3 6 9 8 4
Median 11.1 mo
Median 6.8 mo
HR = 0.57
P <
Gemcitabine
Conroy, T. NEJM, 2011

59. FOLFIRINOX vs Gemcitabine Secondary Endpoints
Gemcitabine (N = 169)
P-Value
Febrile neutropenia
5.4%
0.6%
0.009
Thrombocytopenia
9.1%
2.4%
0.008
Peripheral neuropathy 9% —
0.001
Vomiting
14.5%
4.7%
0.002
Diarrhea
12.7%
1.2%
0.0001
Filgrastim support
42.5% 5%
Overall response rate
31.6%
9.4%
Median PFS
6.4 m
3.3 m
HR = 0.47
Conroy T, et al. NEJM, 2011

60. Phase III Nab-Paclitaxel + Gemcitabine vs Gemcitabine (MPACT)
Median Overall Survival
8.5 mths
6.7 mths
HR 0.72, p=
1-Year Survival
35%
22%
Progression-Free Survival
5.5 mths
3.7 mths
Response Rate
23% 7%
Neutropenia (Gd 3-4)
38%
27%
Fatigue (Gd 3-4)
17%
Neuropathy (Gd 3-4)
<1%
Von Hoff, D. LBA #148. Gastrointestinal Cancers Symposium, 2013

61. SCALOP Trial: Unresectable Pancreatic Cancer
114 pts with locally advanced pancreatic cancer
3 months of weekly gemcitabine 
5040 cGy RT +
Gemcitabine 300 mg/m2 weekly vs
Capecitabine 830 mg/m2 bid Monday through Friday during RT
More heme (18.4% vs 0%) and non heme toxicity (26.3% vv 11.1%) for gemcitabine
OS superior with capecitabine (13.4  months (HR 0.50, p = 0.025)
Mukherjee et al GI Cancers Symposium 2013

62. CMET Targeted Therapy in HCC
Tivantinib vs Placebo in HCC (4006)
CMET TKI
107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib
160 mg tivantinib vs placebo
Cross over permitted at POD
TTP 6.0 to 6.9 weeks (HR 0.64, p = 0.04)
Effect greatest beyond 8 weeks
OS not different, given cross over ( months)
CMET IHC low, better prognosis, no benefit from tivantinib
CMET IHC high, OS 3.8 to 7.2 months (HR 0.38, p = 0.01) with tivantinib
Phase III Trial planned in CMET high pts

63. CMET Targeted Therapy in HCC
Cabozantinib vs Placebo in HCC (4007)
CMET and VEGR2 TKI, most patients failed sorafenib
107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib
100 mg cabozantinib, stable disease randomized to placebo or continuation
Cross over permitted at POD
41 treated, 22 randomized to discontinuation
PFS 4.4 mos, OS 15 mos in all pts
RR 5%, Stable disease 78%
Larger phase II trial planned

64. Continue until withdrawal, PD, or death
CALGB 80802
Eligibility
Child-Pugh A
ECOG PS: 0, 1, 2
(1:1) Randomization
(N~ )
Period 1
Period 2
Continue until withdrawal, PD, or death
6 cycles of:
Doxorubicin 60 mg/m2 IV* Day 1 in 21-day cycles
Sorafenib 400 mg po bid
Sorafenib 400 mg po bid
Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent
Approved circumstances: benefit from therapy and continues to have normal EF on MUGA