1. Randomized phase III study of irinotecan (IRI) versus weekly paclitaxel (wPTX) for advanced gastric cancer (AGC) refractory to combination chemotherapy (CT) of fluoropyrimidine plus platinum (FP): WJOG4007 trial
Ueda S, Hironaka S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y,
Morita S, Okamoto I, Boku N, Hyodo I,
Gastrointestinal Group of West Japan Oncology Group
Thank you, chairmans. On behalf of West Japan Oncology Group, I thank ASCO scientific committee for giving us a great opportunity to present our randomized phase III study of irinotecan versus weekly paclitaxel for advanced gastric cancer refractory to combination chemotherapy of fluoropyrimidine plus platinum.

2. Background
A combination chemotherapy (CT) of fluoropyrimidine and platinum (FP) has been regarded as the standard first-line treatment for AGC
Two randomized phase III trials1,2 showed a survival benefit of second-line CT (docetaxel or irinotecan (IRI) ) compared with best supportive care
However, no standard regimen has been established
In Japan, wPTX3,4 has been used more commonly than docetaxel and IRI5 based on its tolerability
Combination chemotherapy of Fluoropryrimidine and platinum has been regarded as the standard first-line treatment for advanced gastric cancer. Two randomized III trials showed a survival benefit of second-line chemotherapy compared with best supportive care, no standard regimen has been established. In Japan, weekly paclitaxel has been used more commonly than docetaxel and CPT-11 because of its tolerability
1 Thuss-Patience PC, Eur J Cancer 2011, 2 Kang JH, J Clin Oncol 2012, 3 Arai, Proc ASCO 2003,
4 Hironaka, Gastric Cancer 2006, 5 Futatsuki Gan to Kagaku Ryoho 1994

3. Study Scheme 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 -/+
Patients with advanced gastric cancer refractory to prior FP were randomly assigned into weekly paclitaxel or irinotecan group. Stratification factors were institution, performance status and target lesion. Paclitaxel 80mg/m2 was administered weekly for consecutive three weeks with one-week rest. And irinotecan 150mg/m2 was administered bi-weekly.
weekly Paclitaxel
80 mg/m2 d1, 8, 15 q4w
IRI
150 mg/m2 d1, 15 q4w

4. Endpoints and Statistical Considerations
Primary endpoint: Overall survival (OS)
Secondary endpoints: Response Rate (RR)
Progression Free Survival (PFS)
Toxicity
Proportion of third-line CT
Statistical Consideration
Assumed median OS:
wPTX 5 months : reference
IRI 7.5 months : investigational (Superiority)
2-sided alpha 5% and power 80%
No planned interim analysis
220 pts were required.
Primary endpoint was overall survival and secondary endpoints were response rate, progression free survival, toxicity and the rate of third-line chemotherapy.
Sample size was calculated based on the assumption that median survival time was 5 months for weekly paclitaxel and 7.5 months for irinotecan with 2-sided alpha of 5% and power of 80%.
Interim analysis was not planned.
Thus, projected sample size was 220 patients.

5. Eligibility Criteria
Histologically proven unresectable or recurrent gastric adenocarcinoma
Refractory to prior combination CT with FP confirmed by imaging during treatment or within 1 month after last CT
No prior CT with taxanes or IRI
Age range years
PS (ECOG) of 0-2
Preserved organ functions
Measurable or evaluable lesions
No severe peritoneal dissemination
Written informed consent
This is eligibility criteria. Refractory to prior combination chemotherapy with FP by imaging, and no prior chemotherapy with taxanes or irinotecan.

6. Full Analysis Set (FAS) Safety Analysis Set (SAS)
CONSORT Diagram
Randomization
223 pts
Assigned wPTX
111 pts
Assigned IRI
112 pts
108 pts
(3 pts excluded)
Full Analysis Set (FAS)
111 pts
(1 pt excluded)
108 pts
(3 pts excluded)
Safety Analysis Set (SAS)
110 pts
(2 pts excluded)
106 pts
(5 pts excluded)
Per Protocol Set (PPS)
110 pts
(2 pts excluded)

7. Patient Characteristics 1
wPTX
(n=108)
IRI
(n=111) P
Age
Median (range)
64.5 (37-75)
65 (38-75)
0.72
Gender
Male
Female 84 24 87
1.00 PS
0-1 2
104 4
107
Gastrectomy + - 37 71 39 72
0.58
Prior CT
S-1+CDDP
Cape+CDDP
S-1+Oxa 92 13 3
102 8 1
0.30
This is patient characteristics patients were assigned to weekly paclitaxel arm and 111 patients were assigned to irinotecan arm. The baseline patient characteristics were well-balanced between the arms. Majority of enrolled patients were performance status PS0-1. S-1 plus cisplatin therapy was predominantly used for first-line treatment in both treatment groups compared with capecitabine plus cisplatin.
Fisher’s exact test
FAS

8. Patient Characteristics 2
wPTX
(n=108)
IRI
(n=111) P
Target lesion + - 91 17 88 23
1.00
Histology*
Intestinal
Diffuse 54 57
0.97
Peritoneal mets 28 80 83
No. of metastatic sites
<1
2< 51 64 47
0.59
* Lauren classification
Fisher’s exact test
FAS

9. Overall Survival IRI wPTX n 111 108 Median 8.4M 9.5M P 0.38
HR (95% CI)
1.13 ( )
Log-rank test
Probability (%)
This is overall survival. There was no significant difference between two arms.
Median survival time was 9.5 months for weekly paclitaxel and 8.4 months for irinotecan.
Hazard ratio was 1.13 and p-value was 0.38.
(Months)
Number at risk
wPTX
IRI
108
111 80 75 36 29 10 2 3 1 1
FAS

10. 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
This is progression free survival. There was no significant difference between two arms.
Median progression free survival was 3.6 months for weekly paclitaxel and 2.3 months for irinotecan.
Hazard ratio was 1.14 and p-value was
(Months)
Number at risk
wPTX
IRI
108
111 66 46 16 18 9 8 3 6 2 2 1
FAS

11. 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

12. Hematological Toxicities (%Grade 3<)
wPTX
(n=108)
IRI
(n=110) P
Leukocytes
20.4
19.1
0.87
Neutrophils
28.7
39.1
0.12
Hemoglobin
21.3
30.0
0.16
Platelets
0.9
1.8
1.00
This is Hematological toxicities.
They were generally mild and tolerable in both arms. There was no significant difference between both arms.
CTCAE 3.0
Fisher’s exact test
SAS

13. Non-Hematological Toxicities (%Grade 3<)
wPTX
(n=108)
IRI
(n=110) P
Nausea
1.9
4.5
0.45
Vomiting
2.8
0.9
0.37
Anorexia
7.4
17.3
0.04
Diarrhea
0.21
Hyponatremia
3.7
15.5
0.005
Neuropathy (Sens.)
0.003
Febrile Neutropenia
9.1
0.08
Treatment Related Death
3.6
1.00
This is non-Hematological toxicities.
Grade 3 or 4 anorexia and hyponatremia were more frequent in irinotecan arm, whereas sensory neuropathy was observed in only paclitaxel arm.
Other non-hematological toxicities were generally mild and tolerable.
CTCAE 3.0
Fisher’s exact test
SAS

14. Reasons for Treatment Discontinuation
wPTX
(n=106)
IRI
(n=110)
Total
(n=216)
Disease Progression 93
( 88%) 96
( 87%)
189
Adverse Event 6
( 6%) 10
( 9%) 16
Withdraw 5
( 5%) 2
( 2%) 7
Death 1
( 1%)
Other
This is reasons for treatment discontinuation.
Most of patients discontinued study due to disease progression in both arms.
PPS

15. Post-Study Chemotherapy (3rd line)
wPTX
(n=108)
IRI
(n=111) P
Received 3rd line CT 97
(90%) 80
(72%)
0.001
CPT-11 containing 81
(75%) 5
( 5%)
Taxane containing 8
( 7%) 67
(60%)
Others
Fisher’s exact test
FAS

16. Summary
Median OS was 9.5 months for wPTX and 8.4 months for IRI (HR 1.13, P=0.38)
Median PFS was 3.6 months for wPTX and 2.3 months for IRI (HR 1.14, P=0.33)
RR was 21% for wPTX and 14% for IRI (P=0.24)
Toxicities were tolerable in both arms
90% of pts with wPTX and 72% with IRI received post- study CT (P=0.001)
This is the summary of this trial.

17. Conclusion
WJOG4007 trial failed to demonstrate the superiority of IRI to wPTX in OS
wPTX can be adopted as a control arm of future phase III trials of second-line CT for AGC
In conclusion; The WJOG4007 trial failed to demonstrate the superiority of CPT-11 to wPTX in overall survival.
Thus, weekly paclitaxel can be adopted as a control arm of future phase III trials of second-line chemotherapy for advanced gastric cancer.

18. Acknowledgement
We would like to express special thanks to all participating patients,
Data and Safety Monitoring Committee, Audit Committee of WJOG, and
WJOG Data Center (Ms Hirai Y, Mrs. Nonogaki K, Ms. Ozumi N and Dr. Nakamura S)
37 Participating Institutions
Oita University Hosp.
Osaka Medical college
Osaka National Hosp.
Osaka Red Cross Hosp.
Ryugasaki Saiseikai Hosp.
Saitama Cancer Center
Shikoku Cancer Center
Shizuoka Cancer Center
Shizuoka General Hosp.
St. Marianna University School of Medicine Hosp.
Teikyo University Hosp.
Tochigi Cancer Center
Tohoku University Hosp.
Tokai University Hosp.
Tsukuba University Hosp.
Tsuyama Chuo Hosp.
Yamagata Prefectural Central Hosp.
Yokohama City Hosp.
Aichi Cancer Center
Chiba Cancer Center
Ibaraki Prefectural Central Hosp.
Fujita Health University Hosp.
Hiroshima Prefectural Hosp.
Hyogo Cancer Center
Jichi Medical University
Kenseikai Dongo Hosp.
Kinki University
KKR　Sapporo Medical Center Tonan hospital
Kobe University Hosp.
Kochi Health Sciences Center
Kouseiren Takaoka Hosp.
Kushiro City General Hosp.
Kyushu Cancer Center
Kyushu University Hosp.
Narita Red Cross Hosp.
Niigata Cancer Center
Osaka City General Hosp.
Osaka Medical Center for Cancer and Cardiovascular Disease
We would like to express special thanks to all participating patients and WJOG staff.
Thank you for your attention.