Official Title: “A Randomized Phase II Study of Docetaxel vs. Docetaxel Plus Cisplatin vs. Docetaxel Plus S-1 as Second-line Chemotherapy After Cisplatin Plus S-1 or Capecitabine in Metastatic Gastric Cancer”

The purpose of this study is to assess efficacy and safety of docetaxel alone, docetaxel plus cisplatin, and docetaxel plus S-1 in patients with metastatic gastric cancer after failing 1st line chemotherapy with cisplatin plus S-1 or capecitabine

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Parallel Assignment, Efficacy Study

Study Primary Completion Date: November 2010

To date, the most commonly used first-line chemotherapies have been based on fluorouracil and/or cisplatin in patients with metastatic gastric cancer. Unfortunately, considerable proportions of patients with metastatic gastric cancer do not respond to first-line chemotherapy and most of the patients who do respond eventually experience disease progression. In the second-line treatment, however, standard therapies are less clearly defined.

Meanwhile, regarding re-challenge of previous failed drugs as a combination with an other newly introduced chemotherapeutic agent, there are few data. Increased expression and activity of thymidylate synthase, which is inhibited by fluoropyrimidine, is regarded to be the main reason for the development of clinical resistance to fluoropyrimidine. Since the cotreatment of docetaxel and 5-fluorouracil decreases the activity and expression of thymidylate synthase and dihydropyrimidine dehydrogenase (5-fluorouracil degradation enzyme), and increases the expression of orotate phosphoribosyl transferase, the addition of docetaxel into S-1 may recover the sensitivity to S-1 in patients previously resistant to S-1.

Several reports found that MDR-1 and MRP-1 are related to cisplatin-resistance; cisplatin induces the overexpression of MRP-1, which reduces intracellular cisplatin accumulation.

Since docetaxel suppresses the cisplatin-induced MRP-1 upregulation, the addition of docetaxel into cisplatin may recover the sensitivity to cisplatin in patients previously resistant to cisplatin.

Based on these synergism mechanisms, we speculate that the cotreatment of docetaxel and cisplatin or S-1 has better anti-tumor activity than docetaxel alone in patients resistant to cisplatin or S-1.

Intervention(s) in this Clinical Trial

• Drug: docetaxel
  • docetaxel 75 mg/m2, IV on day 1 of each 3 week cycle until progression or unacceptable toxicity develops
• Drug: docetaxel, cisplatin
  • docetaxel 60 mg/m2 and cisplatin 60 mg/m2, IV on day 1 of each 3 week cycle until progression or unacceptable toxicity develops
• Drug: docetaxel, S-1
  • docetaxel 60 mg/m2 IV on day 1 and S-1 30 mg/m2 bid PO on days 1-14 of each 3 week cycle until progression or unacceptable toxicity develops

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: docetaxel
• Experimental: doctaxel plus cisplatin
• Experimental: docetaxel plus S-1

Primary Measures

• response rate
  • Time Frame: every 2 cycles
    Safety Issue?: No

Secondary Measures

• time to progression
  • Time Frame: every 2 cycles
    Safety Issue?: No

Inclusion Criteria:

• Histologically or cytologically confirmed gastric adenocarcinoma with metastatic disease
• Age ≥18 years
• Eastern Cooperative Oncology Group performance status 0-2
• At least one measurable lesion as defined by RECIST
• Only one prior chemotherapy containing both S-1 or capecitabine and cisplatin for metastatic gastric cancer with documented progression of disease occurring during chemotherapy or within 6 months of completion of chemotherapy
• Adequate major organ function:
• ANC ≥1,500/mm3, Platelet ≥100,000/mm3, serum bilirubin ≤1.5 x upper limit of normal (ULN), AST/ALT ≤2.5 x ULN (≤5 x ULN if liver metastases are present), creatinine clearance ≥50 ml/min using the calculation formula or 24 hours urine collection
• Patients should sign a written informed consent before study entry

Exclusion Criteria:

• Prior taxane treatment
• Major surgery or radiotherapy less than 4 weeks prior to entry
• NCI CTCAE (version 3.0) adverse events ≥grade 2 except alopecia, fatigue, and weight loss
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome, or inability to take oral medication
• Patients with active gastrointestinal bleeding
• Inadequate cardiovascular function
• Serious concurrent infection or nonmalignant illness that is uncontrolled or whose control may be jeopardized by complications of study therapy
• Other malignancy within the past 3 years except adequately treated non-melanomatous skin cancer, carcinoma in situ of the cervix, or in situ of prostate cancer Gleason≤7
• Psychiatric disorder that would preclude compliance
• Patients receiving a concomitant treatment with drugs interacting with S-1 such as flucytosine, phenytoin, or allopurinol
• Female patients who are pregnant or breast feeding or adults of reproductive potential not employing effective method of birth control

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Cancer Center, Korea

Overall Clinical Trial Officials and Contacts

Sook Ryun Park, Dr. Principal Investigator Research Institute and Hospital, National Cancer Center Korea  

Overall Contact: Sook Ryun Park, Dr. 82-31-920-1609 sukryun73@hanmail.net

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00980603

Study ID Number: NCCCTS-07-296

ClinicalTrials.gov Identifier: NCT00980603

Health Authority: Korea: Food and Drug Administration