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
18 Years
N/A
Both
Gastric Cancer
Trial Information
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
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.
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
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
response rate
Outcome Time Frame:
every 2 cycles
Safety Issue:
No
Principal Investigator
Sook Ryun Park, Dr.
Investigator Role:
Principal Investigator
Investigator Affiliation:
Research Institute and Hospital, National Cancer Center Korea
Authority:
Korea: Food and Drug Administration
Study ID:
NCCCTS-07-296
NCT ID:
NCT00980603
Start Date:
November 2008
Completion Date:
May 2011
Related Keywords:
- Gastric Cancer
- gastric cancer
- metastatic
- docetaxel
- cisplatin
- S-1
- Stomach Neoplasms
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