Gastric Cancer
Conditions
Keywords
Gastric Cancer
Brief summary
This is an open-label, international, two-arm, parallel, randomized, Phase 3 study evaluating the efficacy and safety of S-1/cisplatin versus 5-FU/cisplatin in patients with advanced gastric cancer previously untreated with chemotherapy for advanced disease. Patients will be randomly assigned (1:1) to S-1/cisplatin (experimental arm) or 5-FU/cisplatin (control arm). Patients will be stratified by number of metastatic sites (one vs. more than one), locally advanced or metastatic disease, prior adjuvant therapy (yes or no), measurable or non-measurable disease, and center.
Interventions
DRUGS-1/Cisplatin
In Arm A, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth (NPO 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with approximately 8 ounces of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour IV infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin.
DRUG5-FU/cisplatin
In Arm B, 5-FU 1000 mg/m2/24 hours was administered CIV on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin.
Sponsors
Quintiles, Inc.
Taiho Oncology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study: * Has given written informed consent * Has histologically confirmed, unresectable, locally advanced (Stage IV) or metastatic gastric cancer, including adenocarcinoma of the gastro-esophageal junction * Has measurable or evaluable but non-measurable disease, defined as follows: * Measurable Disease - Patients with measurable disease as defined by RECIST criteria, i.e., the presence of at least one measurable lesion. A measurable lesion is one that can be accurately measured in at least one dimension with the longest diameter \>\_ 20 mm using conventional techniques or \>\_ 10 mm using spiral Computed Tomography (CT)scan. Locally recurrent disease (other than primary) is accepted if there is at least one measurable lesion (i.e. peritoneal mass, lymph node, etc.) * Evaluable but Non-measurable Disease - Patients with all lesions below the limits defined above for measureable disease (i.e., longest diameter \< 20 mm with conventional techniques or \< 10 mm with spiral CT) excluding those patients with only a primary lesion and/or with only non-evaluable cancer such as bone metastases, ascites, pleural or pericardia effusions, lymphangitic carcinomatosis of the skin or lung, previously irradiated lesions not in progression, or peritoneal carcinomatosis \< 10 mm in diameter with conventional imaging techniques. * No prior palliative chemotherapy is permitted. Adjuvant and /or neo-adjuvant chemotherapy is permitted if more than 12 months have elapsed between the end of adjuvant or neo-adjuvant therapy and first recurrence. This does not qualify as 1st line therapy. * Is able to take medications orally * Is \>\_ 18 years of age * Is at least 3 weeks from prior major surgery * Is at least 4 weeks from prior radiotherapy * Has a ECOG performance status 0 to 1 * Has adequate organ function as defined by the following criteria: * AST (SGOT) and ALT (SGPT) \<\_ 2.5 x ULN; if liver function abnormalities are due to underlying liver metastasis, AST (SGOT) and ALT (SGPT) \<\_ 5 x ULN * Total serum bilirubin of \<\_ 1.5 x ULN * Absolute granulocyte count of \>\_ 1,500/mm (i.e. \>\_ 1.5 x 10/L by International Units (IU) * Platelet count \>\_ 100,000/mm (IU: \>\_ 100 x 10/L * Hemoglobin value of \>\_ 9.0 g/dL * Calculated creatinine clearance \>\_ 60 mL/min (Cockcroft-Gault formula) * Is willing and able to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
Exclusion criteria
Exclude a patient from this study if he/she does not fulfill the inclusion criteria, or if any of the following conditions are observed: * Has had a treatment with any of the following within the specified timeframe prior to study drug administration: * Any prior palliative chemotherapy or any previous therapy for malignancy, including any chemotherapy, immunotherapy, biologic or hormonal therapy, within the past 5 years. * Adjuvant or neo-adjuvant therapy within the past 12 months * Concurrent treatment with any investigational anti-cancer agent * Prior cisplatin as neo-adjuvant and /or adjuvant chemotherapy with cumulative dose \> 300 mg/m * \> 25% of marrow-bearing bone radiated * Concurrent treatment with an investigational agent or within 30 days from randomization * Concurrent enrollment in another clinical study * Has a serious illness or medical condition(s) including, but not limited to the following: * Known brain or leptomeningeal metastases * Uncontrolled ascites requiring drainage at least twice a week * Other malignancies within the past 5 years, except adequately treated carcinoma-in-situ of the cervix or non-melanoma skin cancer * Myocardial infarction within the last 6 months, severe/unstable angina, congestive heart failure New York Heart Association (NYHA) class III or IV * Chronic nausea, vomiting or diarrhea * Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS-related illness * Psychiatric disorder that may interfere with consent and/or protocol compliance * Known neuropathy, Grade 2 or higher * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgement of the Investigator would make the patient inappropriate for entry into this study * Is receiving concomitant treatment with drugs interacting with S-1. The following drugs are prohibited because there may be an interaction with S-1: * Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole (may enhance S-1 activity) * Allopurinol (may diminish S-1 activity * Phenytoin (S-1 may enhance phenytoin activity) * Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 activity) * Is receiving concomitant treatment with drugs interacting with 5-FU: * Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole(may enhance 5-FU activity) * Allopurinol (may diminish 5-FU activity) * Phenytoin (5-FU may enhance phenytoin activity) * Is receiving concomitant treatment with drugs interacting with cisplatin: * Phenytoin (cisplatin may diminish phenytoin activity) * Aminoglycosides (should be avoided within 8 days after cisplatin administration) * Ethyol (may diminish cisplatin activity * Is a pregnant or lactating female * Has known hypersensitivity to 5-FU or cisplatin * Patients with reproductive potential who refuse to use an adequate means of contraception (including male patients)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Survival | The cutoff date for survival analysis was 07 March 2008 (12 months after last patient randomized). | Survival was defined as the time from the date of randomization to the time of death (from any cause) for each patient. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Data cutoff was 07 March 2008 (12 months after last patient randomized). | The proportion of patients with objective evidence of complete response (CR) or partial response (PR) based on tumor response assessments. Per the Response Evaluation Criteria in Solid tumors (RECIST), CR was defined as the disappearance of all target lesions for at least 4 weeks, and PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions. |
| Duration of Response (DR) | Data cutoff was 07 March 2008 (12 months after last patient was randomized). | Duration of response was defined as the time from date of first confirmed response (CR or PR) to date of first progressive disease (PD) or death. Per the RECIST criteria, definitions were as follows: CR was the disappearance of all target lesions for at least 4 weeks, PR was at least a 30% decrease in the sum of the longest diameter of target lesions, and PD was at least a 20% increase in the sum of the longest diameter of target lesions. |
| Progression-free Survival (PFS) | From date of randomization until date of first documented PD, date of death, or until data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first. | The time from randomization to date of first documented PD or date of death, whichever occurred first. |
| Time to Treatment Failure (TTF) | From date of randomization until date of permanent discontinuation of S-1 or 5-FU, first documented PD, death, or data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first. | The time from randomization to date of permanent discontinuation of S-1 or 5-FU, first documented PD, or death, whichever occurred first. |
Countries
Canada, United States
Participant flow
Recruitment details
This multicenter study was conducted between May 18, 2005 and March 7, 2008 in 24 countries including the United States. Study centers were also located in Canada, Eastern and Western Europe, South America, Australia, and ex-Soviet Union block of nations.
Participants by arm
| Arm | Count |
|---|---|
| S-1/Cisplatin In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1.
Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment. | 521 |
| 5-FU/Cisplatin In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles. | 508 |
| Total | 1,029 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Disease progression | 1 | 1 |
| Overall Study | Intercurrent illness | 0 | 1 |
| Overall Study | Investigator judgment | 0 | 1 |
| Overall Study | Randomization error/patient ineligible | 1 | 6 |
| Overall Study | Withdrew Consent | 1 | 5 |
Baseline characteristics
| Characteristic | S-1/Cisplatin | 5-FU/Cisplatin | Total |
|---|---|---|---|
| Age, Continuous Baseline Measure Data (descriptive stats, median) | 59.0 Years | 59.0 Years | 59.0 Years |
| Anatomical Location of Primary Lesion Gastroesophageal junction | 82 Participants | 88 Participants | 170 Participants |
| Anatomical Location of Primary Lesion Stomach | 438 Participants | 417 Participants | 855 Participants |
| Anatomical Location of Primary Lesion Stomach and gastroesophageal junction | 1 Participants | 3 Participants | 4 Participants |
| Body surface area (BSA) Categories </=1.29 m2 | 4 Participants | 5 Participants | 9 Participants |
| Body surface area (BSA) Categories 1.30-1.49 m2 | 46 Participants | 44 Participants | 90 Participants |
| Body surface area (BSA) Categories 1.50-1.69 m2 | 118 Participants | 147 Participants | 265 Participants |
| Body surface area (BSA) Categories 1.70-1.89 m2 | 208 Participants | 181 Participants | 389 Participants |
| Body surface area (BSA) Categories 1.90-2.09 m2 | 114 Participants | 93 Participants | 207 Participants |
| Body surface area (BSA) Categories 2.10-2.29 m2 | 29 Participants | 34 Participants | 63 Participants |
| Body surface area (BSA) Categories >/=2.30 m2 | 2 Participants | 4 Participants | 6 Participants |
| Disease Measurability Measureable disease | 499 Participants | 485 Participants | 984 Participants |
| Disease Measurability No disease present | 1 Participants | 0 Participants | 1 Participants |
| Disease Measurability Nonevaluable disease | 0 Participants | 1 Participants | 1 Participants |
| Disease Measurability Non-measurable disease | 21 Participants | 22 Participants | 43 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 226 Participants | 200 Participants | 426 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 295 Participants | 308 Participants | 603 Participants |
| Extent of Disease 1 metastatic site | 157 Participants | 161 Participants | 318 Participants |
| Extent of Disease >/=2 metastatic sites | 340 Participants | 327 Participants | 667 Participants |
| Extent of Disease Locally advanced | 23 Participants | 20 Participants | 43 Participants |
| Extent of Disease Not assessed | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 6 Participants | 10 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 61 Participants | 53 Participants | 114 Participants |
| Race (NIH/OMB) White | 447 Participants | 438 Participants | 885 Participants |
| Sex: Female, Male Female | 139 Participants | 161 Participants | 300 Participants |
| Sex: Female, Male Male | 382 Participants | 347 Participants | 729 Participants |
| Tissue Type Adenocarcinoma NOS | 87 Participants | 87 Participants | 174 Participants |
| Tissue Type Moderately-differentiated | 105 Participants | 91 Participants | 196 Participants |
| Tissue Type Mucinous adenocarcinoma | 28 Participants | 32 Participants | 60 Participants |
| Tissue Type Other | 97 Participants | 94 Participants | 191 Participants |
| Tissue Type Other types | 2 Participants | 4 Participants | 6 Participants |
| Tissue Type Papillary adenocarcinoma | 15 Participants | 15 Participants | 30 Participants |
| Tissue Type Poorly differentiated adenocarcinoma | 210 Participants | 189 Participants | 399 Participants |
| Tissue Type Poorly differentiated cancer | 7 Participants | 2 Participants | 9 Participants |
| Tissue Type Signet-ring cell carcinoma | 75 Participants | 95 Participants | 170 Participants |
| Tissue Type Tubular adenocarcinoma | 132 Participants | 113 Participants | 245 Participants |
| Tissue Type Unknown | 7 Participants | 5 Participants | 12 Participants |
| Tissue Type Unknown/not specified | 1 Participants | 1 Participants | 2 Participants |
| Tissue Type Well-differentiated | 20 Participants | 17 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 514 / 521 | 504 / 508 |
| serious Total, serious adverse events | 257 / 521 | 248 / 508 |
Outcome results
Primary
Median Survival
Survival was defined as the time from the date of randomization to the time of death (from any cause) for each patient.
Time frame: The cutoff date for survival analysis was 07 March 2008 (12 months after last patient randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| S-1/Cisplatin | Median Survival | 8.6 Months |
| 5-FU/Cisplatin | Median Survival | 7.9 Months |
p-value: 0.198395% CI: [0.8, 1.05]Log Rank
Secondary
Duration of Response (DR)
Duration of response was defined as the time from date of first confirmed response (CR or PR) to date of first progressive disease (PD) or death. Per the RECIST criteria, definitions were as follows: CR was the disappearance of all target lesions for at least 4 weeks, PR was at least a 30% decrease in the sum of the longest diameter of target lesions, and PD was at least a 20% increase in the sum of the longest diameter of target lesions.
Time frame: Data cutoff was 07 March 2008 (12 months after last patient was randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| S-1/Cisplatin | Duration of Response (DR) | 6.5 Months |
| 5-FU/Cisplatin | Duration of Response (DR) | 5.8 Months |
p-value: 0.080895% CI: [0.57, 1.03]Log Rank
Secondary
Overall Response Rate (ORR)
The proportion of patients with objective evidence of complete response (CR) or partial response (PR) based on tumor response assessments. Per the Response Evaluation Criteria in Solid tumors (RECIST), CR was defined as the disappearance of all target lesions for at least 4 weeks, and PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions.
Time frame: Data cutoff was 07 March 2008 (12 months after last patient randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| S-1/Cisplatin | Overall Response Rate (ORR) | 29.1 Percentage of patients in each group |
| 5-FU/Cisplatin | Overall Response Rate (ORR) | 31.9 Percentage of patients in each group |
p-value: 0.3952Fisher Exact
Secondary
Progression-free Survival (PFS)
The time from randomization to date of first documented PD or date of death, whichever occurred first.
Time frame: From date of randomization until date of first documented PD, date of death, or until data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| S-1/Cisplatin | Progression-free Survival (PFS) | 4.8 Months |
| 5-FU/Cisplatin | Progression-free Survival (PFS) | 5.5 Months |
p-value: 0.915895% CI: [0.86, 1.14]Log Rank
Secondary
Time to Treatment Failure (TTF)
The time from randomization to date of permanent discontinuation of S-1 or 5-FU, first documented PD, or death, whichever occurred first.
Time frame: From date of randomization until date of permanent discontinuation of S-1 or 5-FU, first documented PD, death, or data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| S-1/Cisplatin | Time to Treatment Failure (TTF) | 3.8 Months |
| 5-FU/Cisplatin | Time to Treatment Failure (TTF) | 3.8 Months |
p-value: 0.03295% CI: [0.77, 0.99]Log Rank