TPU-S1303

Taiho Oncology, Inc.

202 Carnegie Center, Suite 100, Princeton, United States, 08540

Takekazu Aoyama, Taiho Oncology, Inc., 1 6097505300, aoyama@taihopui.com

Takekazu Aoyama, Taiho Oncology, Inc., 1 6097505300, aoyama@taihopui.com

No

No

No

Final

23 Jan 2015

Yes

07 Mar 2014

Yes

15 Aug 2014

Yes

To compare the following endpoints for the S-1/cisplatin regimen (experimental arm) with the 5-FU/cisplatin regimen control arm) in patients with metastatic diffuse gastric cancer: - overall survival (OS)

This study was conducted and informed consent was obtained according to the ethical principles that have their origins in the Declaration of Helsinki and its amendments, and in accordance with Title 21 CFR 312.50 through 312.70, the International Conference on Harmonisation (ICH) Tripartite Guidelines for Good Clinical Practice, and local and national laws and regulations relevant to the use of investigational therapeutic agents. Patients were monitored for safety from the time of signed informed consent form through 30 days after the last dose of study medication or until the start of new antitumor therapy, whichever was earlier. Adverse events were coded using the Medical Dictionary for Regulatory Activities Dictionary (MedDRA), Version 14.0, and were categorized by system organ class (SOC) and preferred term (PT). Treatment-related SAEs that occurred after the 30-day follow-up. Patients were followed for survival status every 8 weeks until death or until 2 years after the last patient was randomized in the study. During follow-up, CT scans were performed every 8 weeks until the occurrence of radiologic progression or the start of a new antitumor therapy.

14 Apr 2011

No

Yes

United States: 32

Mexico: 7

Argentina: 2

Brazil: 18

Croatia: 2

Ukraine: 117

Russian Federation: 71

Israel: 1

South Africa: 3

Poland: 5

Portugal: 2

Romania: 12

Spain: 35

United Kingdom: 5

Belgium: 1

Bulgaria: 7

Estonia: 10

Germany: 3

Hungary: 9

Italy: 19

361

110

0

0

0

0

0

0

292

54

15

Baseline Period

Not applicable

S-1

L01BC53

Tegafur/gimeracil/oteracil

Capsule, hard

Oral use

S-1 is an immediate release dosage form contained in hard gelatin capsules in which tegafur (FT), gimeracil (CDHP), and oteracil as monopotassium salt (Oxo) are combined at a molar ratio of 1:0.4:1. S-1 25 mg/m² was administered orally twice daily (BID) every 12 hours from Day 1 through Day 21 followed by a 7 day rest period on Days 22 to 28. This regimen was repeated every 28 days. S-1 was administered 1 hour before or 1 hour after a meal with a glass of water. Lot numbers were: 15-mg capsules, 0183, 2188, and 8G86; 20-mg capsules, 9E81, 1I91, and 13L8820.

Cisplatin

Cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloridoplatinum(II) (CDDP)

Solution for infusion

Intravenous use

Cisplatin used in the study was the commercially available product. Cisplatin 75 mg/m2 was administered intravenously (IV) as a 1- to 3-hour infusion on Day 1 following the morning dose of S-1. This regimen was repeated every 28 days for a maximum of 8 cycles.

5-FU

L01BC02

Fluorouracil

Solution for injection

Intravenous use

The 5-FU used in the study was the commercially available product. 5-FU 800 mg/m2/24 hours was administered intravenously (IV) by continuous infusion over 120 hours (on Days 1 through 5) followed by a 16-day rest period on Days 6 through 21. This regimen was repeated every 3 weeks.

Cisplatin

Cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloridoplatinum(II) (CDDP)

Solution for injection

Intravenous use

Cisplatin used in the study was the commercially available product. Cisplatin 80 mg/m2 was administered intravenously (IV) as a 1- to 3-hour infusion on Day 1 prior to the start of the 5-FU infusion on Day 1 for a maximum of 8 cycles. This regimen was repeated every 21 days.

Treatment Period

Randomised - controlled

Yes

S-1

L01BC53

Tegafur/gimeracil/oteracil

Capsule, hard

Oral use

S-1 is an immediate release dosage form contained in hard gelatin capsules in which tegafur (FT), gimeracil (CDHP), and oteracil as monopotassium salt (Oxo) are combined at a molar ratio of 1:0.4:1. S-1 25 mg/m² was administered orally twice daily (BID) every 12 hours from Day 1 through Day 21 followed by a 7 day rest period on Days 22 to 28. This regimen was repeated every 28 days. S-1 was administered 1 hour before or 1 hour after a meal with a glass of water. Lot numbers were: 15-mg capsules, 0183, 2188, and 8G86; 20-mg capsules, 9E81, 1I91, and 13L8820.

Cisplatin

Cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloridoplatinum(II) (CDDP)

Solution for infusion

Intravenous use

Cisplatin used in the study was the commercially available product. Cisplatin 75 mg/m2 was administered intravenously (IV) as a 1- to 3-hour infusion on Day 1 following the morning dose of S-1. This regimen was repeated every 28 days for a maximum of 8 cycles.

5-FU

L01BC02

Fluorouracil

Solution for injection

Intravenous use

The 5-FU used in the study was the commercially available product. 5-FU 800 mg/m2/24 hours was administered intravenously (IV) by continuous infusion over 120 hours (on Days 1 through 5) followed by a 16-day rest period on Days 6 through 21. This regimen was repeated every 3 weeks.

Cisplatin

Cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloridoplatinum(II) (CDDP)

Solution for injection

Intravenous use

Cisplatin used in the study was the commercially available product. Cisplatin 80 mg/m2 was administered intravenously (IV) as a 1- to 3-hour infusion on Day 1 prior to the start of the 5-FU infusion on Day 1 for a maximum of 8 cycles. This regimen was repeated every 21 days.

End of Treatment Period

Not applicable

Yes

No investigational medicinal product assigned in this arm

No investigational medicinal product assigned in this arm

Baseline

Intention to treat (ITT)

ITT population - Total patients who were randomized

Intention to treat (ITT) - S-1/Cisplatin

Intention to treat (ITT) population in the S-1/Cisplatin experimental group

Intention to treat (ITT) - 5-FU/Cisplatin

Intention to treat (ITT) population in the 5-FU/Cisplatin control group

Baseline

S-1/Cisplatin (experimental arm)

5-FU/Cisplatin (control arm)

S-1/Cisplatin (experimental arm)

5-FU/Cisplatin (control arm)

Intention to treat (ITT)

ITT population - Total patients who were randomized

Intention to treat (ITT) - S-1/Cisplatin

Intention to treat (ITT) population in the S-1/Cisplatin experimental group

Intention to treat (ITT) - 5-FU/Cisplatin

Intention to treat (ITT) population in the 5-FU/Cisplatin control group

Overall Survival (OS) was the primary endpoint of this study and was defined as the time from the day of randomization to the date of death for the Intent-to-treat (ITT) population. Patients who did not die as of the OS cut-off date were censored at the date last known to be alive. The difference in OS between the 2 treatment groups was assessed using the unstratified log-rank test (Score statistic from PHREG and ties=Breslow). Survival for each group was summarized using Kaplan Meier curves and was further characterized in terms of the median and survival probability at 3, 6, 9 and 12 months, along with the corresponding 2-sided 95% confidence intervals for the estimates. Confidence intervals (CIs) for median survival were based upon the methods of Brookmeyer and Crowley. The influence of stratification factors and other baseline characteristics was assessed using the stratified log-rank test and Cox’s regression approach.

Primary

The time from randomization to the date of death for the Intent-to-treat (ITT) population.

The difference in OS between the 2 treatment groups was assessed using the unstratified log-rank test (Score statistic from PHREG and ties=Breslow). Survival for each group was summarized using Kaplan Meier curves and was further characterized in terms of the median and survival probability at 3, 6, 9 and 12 months, along with the corresponding 2-sided 95% confidence intervals for the estimates. Confidence intervals (CIs) for median survival were based upon the methods of Brookmeyer and Crowley

S-1/Cisplatin (experimental arm) v 5-FU/Cisplatin (control arm)

361

Pre-specified

0.99

2-sided

Standard deviation

Progression-free survival was defined as the time from date of randomization until date of radiological disease progression or death due to any cause. Patients who were alive with no disease progression were censored at the date of the last tumor assessment. Patients who received new anticancer therapy before disease progression were censored at the date of the last evaluable tumor assessment before new anticancer therapy was initiated.

Secondary

Progression-free survival was defined as the time from date of randomization until date of radiological disease progression or death due to any cause.

Progression-Free Survival (PFS) were analyzed using the same methods as for the primary endpoint - Overall Survival (OS).

S-1/Cisplatin (experimental arm) v 5-FU/Cisplatin (control arm)

361

Pre-specified

0.86

2-sided

Standard deviation

Time to treatment failure was defined as the time from date of randomization until date of disease progression (clinical or radiologic), or permanent discontinuation of study treatment (S-1 or 5-FU), or death due to any cause. Patients who were still on study treatment at the time of the analysis were censored at the last date the patient was known to be on treatment.

Secondary

Time to treatment failure was defined as the time from date of randomization until date of disease progression (clinical or radiologic), or permanent discontinuation of study treatment (S-1 or 5-FU), or death due to any cause.

Time to treatment failure (TTF) was analyzed using the same methods as for the primary endpoint Overall Survival (OS).

S-1/Cisplatin (experimental arm) v 5-FU/Cisplatin (control arm)

361

Pre-specified

0.84

2-sided

Standard deviation

Patients were monitored for safety from the time of signed informed consent form through 30 days after the last dose of study medication or until the start of new antitumor therapy, whichever was earlier.

Adverse events were coded using the Medical Dictionary for Regulatory Activities Dictionary (MedDRA), Version 14.0, and were categorized by system organ class (SOC) and preferred term (PT).

14

S-1/Cisplatin (As Treated Population)

5-FU/Cisplatin (As Treated Population)