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Phase III Trial of 3-weekly vs. 5-weekly Schedule of S-1 Plus Cisplatin Combination Chemotherapy for First Line Treatment of Advanced Gastric Cancer.

Phase 3
18 Years
74 Years
Open (Enrolling)
Advanced Gastric Cancer

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Trial Information

Phase III Trial of 3-weekly vs. 5-weekly Schedule of S-1 Plus Cisplatin Combination Chemotherapy for First Line Treatment of Advanced Gastric Cancer.

The primary endpoint of this study is Progression Free Survival (PFS). It is defined as the
time from the date of randomization to the time of disease progression as assessed by the
investigators, or death due to any cause. The primary goal of this study is to compare two
different schedules of S-1 plus cisplatin combination treatments (3-weekly regimen vs.
5-weekly regimen) for advanced gastric cancer with respect to the PFS based on the hybrid
design where we can test superiority and non-inferiority in the same trial (Reference:
Journal of Clinical Oncology 25: 5019-5023, 2007, Boris Freidlin, et el). First, the
non-inferiority hypothesis will be tested based on the non-inferiority margin 1.15. If the
inferiority cannot be rejected(meaning non-inferiority is proven) then the superiority will
be tested. If the superiority test is positive, then superiority is concluded; otherwise
non-inferiority without superiority will be concluded.

The sample size was calculated from the following consideration:

For non-inferiority test: non-inferiority margin 1.15, 10 percent reduction of hazard ratio,
power 80 percent, alpha 0.025, accrual period 36 months, follow-up period 12 months, and the
expected median PFS of 6 months for 5 weekly regimen were assumed. Based on the above
considerations, total of 560 patients will be need. With 10 percent follow-up loss, we need
622 patients.

For superiority test: the median PFS for 5-weekly regimen is expected to be 6 months and 7.5
months for 3-weekly regimen. With sample size of 560 patients calculated above, for
detecting 1.5 months difference in the median PFS between the two groups , we will have 81
percent of power, one-sided 5 percent type I error. Using the log rank test assuming
exponential underlying distribution, accrual period of 36 months, minimum of 12 months
follow-up after the last enrolment, 516 events will be needed to show the superiority of 3
week cycle.

Inclusion Criteria:

- Histologically documented metastatic or recurrent gastric adenocarcinoma including
adenocarcinoma of the gastro-esophageal junction

- Age 18 to 74 years old

- Performance status (ECOG scale) 0-2

- No significant problems for oral intake and drug administration

- At least one measurable or evaluable disease defined by RECIST

- Adequate bone marrow function (ANC ≥ 1,500/uL, Platelet ≥ 100,000/ uL, Hb ≥ 9.0 g/dl)

- Adequate renal function: serum creatinine ≤ UNL (if serum creatinine > UNL,
creatinine clearance should be ≥ 60 mL/min)

- Adequate hepatic function (Total bilirubin < 2 x UNL and AST/ALT levels < 3 x UNL
without liver metastasis,total bilirubin < 3x ULN and AST/ALT levels < 5 x UNL with
liver metastasis)

- Prior systemic therapy (for instance, cytotoxic chemotherapy or active/passive
immunotherapy) is allowed if at least 6 months has elapsed between completion of
adjuvant/neoadjuvant therapy and enrolment into the study) and cisplatin was not used

- Patients should sign a written informed consent before study entry

Exclusion Criteria:

- Tumor type other than adenocarcinoma

- Previously exposed to any fluropymidine within 6 months before the study

- Previously exposed to Platinum therapy regardless of its period and/or duration

- Microscopic residual disease only after noncurative gastrectomy with R1 resection
(resection margin positive)

- Second primary malignancy (except in situ carcinoma of the cervix or adequately
treated basal cell carcinoma of the skin or prior malignancy treated more than 5
years ago without recurrence)

- Prior radiotherapy was administered to target lesions selected for this study, or
radiotherapy to the non-target lesions has been completed within 4 weeks before

- Presence of CNS metastasis

- Major surgery within 4 weeks before initiation of study treatment or lack of complete
recovery from the effects of major surgery (patient received curative operation or
RFA for metastatic disease)

- Serious illness or medical conditions:

- Congestive heart failure (NYHA class III or IV)

- Unstable angina or myocardial infarction within the past 12 months

- Significant arrhythmias requiring medication and conduction abnormality such as
over 2nd degree AV block

- Uncontrolled hypertension

- Hepatic cirrhosis (≥ Child class B)

- Interstitial pneumonia

- Pulmonary adenomatosis

- Psychiatric disorder that may interfere with protocol compliance

- Unstable diabetes mellitus

- Uncontrolled ascites or pleural effusion

- Active infection

- Receiving a concomitant treatment interacting with S-1 or cisplatin:

- Flucytosine (a fluorinated pyrimidine antifungal agent)

- Antivirals such as sorivudine, ramivudine, brivudine or other chemically related
agents, warfarin, phenprocoumon, phenytoin, allopurinol

- Pregnant or lactating woman

- Women of child bearing potential not using a contraceptive method

- Sexually active fertile men not using effective birth control during medication of
study drug and up to 6 months after completion of study drug if their partners are
women of child-bearing potential

- Any patients judged by the investigator to be unfit to participate in the study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

progression-free survival

Outcome Time Frame:

accrual of patients for 36 months, followup of the last patient for 12 months

Safety Issue:


Principal Investigator

Yoon-Koo Kang, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Asan Medical Center, Seoul, Korea


Korea: Food and Drug Administration

Study ID:




Start Date:

January 2009

Completion Date:

December 2013

Related Keywords:

  • Advanced Gastric Cancer
  • Stomach Neoplasms