Stomach Neoplasms
Conditions
Brief summary
The purpose of this study is to determine the safe and tolerable dose of sunitinib when given together with cisplatin and 5-fluorouracil in patients with advanced gastric cancer who have not received prior chemotherapy for their advanced cancer.
Interventions
DRUG5-fluorouracil
5- fluorouracil is given as 4000 mg/m\^2 total dose over 96 hr continuous infusion of a 21 day chemotherapy cycle. Each 21 day cycle is repeated until progression of disease or unacceptable toxicity is observed.
DRUGcisplatin
Cisplatin is given 80 mg/m\^2 through a vein on day 1 every 21 days. Each 21 day cycle is repeated until progression of disease or unacceptable toxicity is observed.
DRUGsunitinib malate
sunitinib is given orally 37.5mg /day for 14 days followed by 7 days of drug free period. Each 21 day cycle is repeated until progression of disease or unacceptable toxicity is observed.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* confirmed diagnosis of stomach cancer * advanced stomach cancer stage IV * adequate blood chemistry, blood counts and kidney function * willing to participate to study requirements and to sign an informed consent document
Exclusion criteria
* prior chemotherapy for stomach cancer in its advanced stage * excessive toxicities related to prior therapies * pregnant or breastfeeding patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First-cycle Dose Limiting Toxicities (DLTs) | Cycle 1 (Baseline to Day 21) | The incidence of DLTs assessed during the first cycle (21 days). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | Day 1 of Cycle 1 (2, 4, 6, 8, 10, and 24 hours post dose) | — |
| Area Under the Curve From Time 0 to 24 Hours Postdose [AUC (0-24)] | Day 1 of Cycle 1 (2, 4, 6, 8, 10, and 24 hours postdose) | Area under the plasma concentration versus time curve from time 0 (pre-dose) to 24 hours postdose (0-24). |
| Steady State Concentration (Css) of 5-Fluorouracil (5-FU) | Day 1 of Cycle 1 (2, 4, and 6 hours post infusion) | Steady state plasma concentration of 5-FU equals AUC(2-6) divided by 4, where AUC(2-6) is the area under the plasma concentration versus time curve from time 2 to 6 hours postdose (2-6). |
| Infusion Rate (Zero Order) (R0) of 5-FU | Day 1 of Cycle 1 (2, 4, and 6 hours post infusion) | Infusion rate of 5-FU equals total dose divided by infusion time. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Day 1 of Cycle 1 (2, 4, 6, 8, 10, and 24 hours post dose) | Tmax is the time to first occurrence of maximum observed plasma concentration (Cmax). |
| Area Under the Curve From Time 2 to 6 Hours Postdose [AUC (2-6)] of 5-FU | Day 1 of Cycle 1 (2, 4, and 6 hours post infusion) | Area under the plasma concentration versus time curve from time 2 to 6 hours postdose (2-6). |
| Number of Participants With Objective Response | Baseline, Day 21 of every even-numbered cycle up to 15 Months | Number of participants with an objective response-based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR defined as the disappearance of all target lesions. PR defined as greater than or equal to (≥) 30 percent (%) decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. |
| Duration of Response (DR) | Baseline up to Month 15 | Time from the first objective documentation of tumor response (confirmed or partial response) to first documented objective tumor progression or death due to any cause, whichever occurrs first. DR calculated as (Months) equals (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 30. |
| Progression-Free Survival (PFS) | Baseline up to Month 15 | Median time (50%) from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. PFS calculated as (Months) equals (first event date minus first dose date plus 1) divided by 30. |
| Clearance (CLss) of 5-FU | Day 1 of Cycle 1 (2, 4, and 6 hours post infusion) | Steady state total body clearance equals infusion rate (zero order) divided by steady state plasma concentration of 5-FU (R0/Css). |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU Sunitinib: 25 milligram (mg) oral capsule daily for 2 weeks (Day 1 to 14) followed by 1 week (Day 15 to 21) off treatment. Cisplatin: 80 mg per meter squared (mg/m\^2) intravenous on Day 1 of each 21-day cycle. 5-Fluorouracil (5-FU): 4000 mg/m\^2 continuous infusion for 96 hours starting Day 1 and ending Day 5 of each 21-day cycle. | 24 |
| Sunitinib (37.5 mg) in Combination With Cisplatin and 5-FU Sunitinib: 37.5 mg oral capsule daily for 2 weeks (Day 1 to 14) followed by 1 week (Day 15 to 21) off treatment. Cisplatin: 80 mg per meter squared (mg/m\^2) on Day 1 of each 21-day cycle. 5-Fluorouracil (5-FU): 4000 mg/m\^2 continuous infusion for 96 hours starting Day 1 and ending Day 5 of each 21-day cycle. | 10 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 2 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Objective progression or relapse | 11 | 5 |
| Overall Study | Other | 3 | 1 |
| Overall Study | Participant refused | 2 | 0 |
Baseline characteristics
| Characteristic | Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Sunitinib (37.5 mg) in Combination With Cisplatin and 5-FU | Total |
|---|---|---|---|
| Age Continuous | 60.1 years STANDARD_DEVIATION 12 | 56.4 years STANDARD_DEVIATION 10.4 | 59.0 years STANDARD_DEVIATION 11.5 |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 17 Participants | 6 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 24 | 10 / 10 |
| serious Total, serious adverse events | 7 / 24 | 5 / 10 |
Outcome results
Primary
Number of Participants With First-cycle Dose Limiting Toxicities (DLTs)
The incidence of DLTs assessed during the first cycle (21 days).
Time frame: Cycle 1 (Baseline to Day 21)
Population: Safety: enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Number of Participants With First-cycle Dose Limiting Toxicities (DLTs) | 1 Participants |
| Sunitinib (37.5 mg) in Combination With Cisplatin and 5-FU | Number of Participants With First-cycle Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Area Under the Curve From Time 0 to 24 Hours Postdose [AUC (0-24)]
Area under the plasma concentration versus time curve from time 0 (pre-dose) to 24 hours postdose (0-24).
Time frame: Day 1 of Cycle 1 (2, 4, 6, 8, 10, and 24 hours postdose)
Population: PK; N=the number of participants contributing to the summary statistics. AUC(0-24) of Sunitinib, SU012662, and Total Drug (Sunitinib + SU012662) calculated for at least 6 individual participants treated at the maximum tolerated dose (MTD; 25 mg Sunitinib).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Area Under the Curve From Time 0 to 24 Hours Postdose [AUC (0-24)] | Sunitinib | 249 ng*h/mL | Standard Deviation 127 |
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Area Under the Curve From Time 0 to 24 Hours Postdose [AUC (0-24)] | SU012662 (metabolite of Sunitinib) | 34.0 ng*h/mL | Standard Deviation 19.5 |
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Area Under the Curve From Time 0 to 24 Hours Postdose [AUC (0-24)] | Total Drug (Sunitinib + SU012662) | 283 ng*h/mL | Standard Deviation 144 |
Secondary
Area Under the Curve From Time 2 to 6 Hours Postdose [AUC (2-6)] of 5-FU
Area under the plasma concentration versus time curve from time 2 to 6 hours postdose (2-6).
Time frame: Day 1 of Cycle 1 (2, 4, and 6 hours post infusion)
Population: PK; N=number of participants contributing to the summary statistics. Css calculated for at least 6 individual participants treated at the MTD (25 mg Sunitinib).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Area Under the Curve From Time 2 to 6 Hours Postdose [AUC (2-6)] of 5-FU | 2372 ng*h/mL | Standard Deviation 1729 |
Secondary
Clearance (CLss) of 5-FU
Steady state total body clearance equals infusion rate (zero order) divided by steady state plasma concentration of 5-FU (R0/Css).
Time frame: Day 1 of Cycle 1 (2, 4, and 6 hours post infusion)
Population: PK; N=the number of participants contributing to the summary statistics. CLss calculated for at least 6 individual participants treated at the MTD (25 mg Sunitinib).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Clearance (CLss) of 5-FU | 161 Liters per hour | Standard Deviation 93.2 |
Secondary
Duration of Response (DR)
Time from the first objective documentation of tumor response (confirmed or partial response) to first documented objective tumor progression or death due to any cause, whichever occurrs first. DR calculated as (Months) equals (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 30.
Time frame: Baseline up to Month 15
Population: Efficacy; N=number of participants with objective response.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Duration of Response (DR) | 4.17 Months | Standard Deviation 2.28 |
| Sunitinib (37.5 mg) in Combination With Cisplatin and 5-FU | Duration of Response (DR) | 4.13 Months | Standard Deviation 0.73 |
Secondary
Infusion Rate (Zero Order) (R0) of 5-FU
Infusion rate of 5-FU equals total dose divided by infusion time.
Time frame: Day 1 of Cycle 1 (2, 4, and 6 hours post infusion)
Population: PK; N= number of participants contributing to the summary statistics. R0 calculated for at least 6 individual participants treated at the MTD (25 mg Sunitinib).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Infusion Rate (Zero Order) (R0) of 5-FU | 68.2 mg/hr | Standard Deviation 12.5 |
Secondary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Day 1 of Cycle 1 (2, 4, 6, 8, 10, and 24 hours post dose)
Population: Pharmacokinetic (PK): participants who received Sunitinib and had sufficient plasma concentration data for calculation of PK parameters; N=number of participants contributing to summary statistics. Cmax of Sunitinib, SU012662, and Total Drug (Sunitinib + SU012662) calculated for at least 6 individual participants treated at maximum tolerated dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Maximum Observed Plasma Concentration (Cmax) | Sunitinib | 16.8 nanograms per milliliter (ng/mL) | Standard Deviation 8.19 |
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Maximum Observed Plasma Concentration (Cmax) | SU012662 (metabolite of Sunitinib) | 2.24 nanograms per milliliter (ng/mL) | Standard Deviation 1.29 |
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Maximum Observed Plasma Concentration (Cmax) | Total Drug (Sunitinib + SU012662) | 19.0 nanograms per milliliter (ng/mL) | Standard Deviation 9.35 |
Secondary
Number of Participants With Objective Response
Number of participants with an objective response-based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR defined as the disappearance of all target lesions. PR defined as greater than or equal to (≥) 30 percent (%) decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Time frame: Baseline, Day 21 of every even-numbered cycle up to 15 Months
Population: Efficacy: all participants enrolled in the study who received at least 1 dose of study medication. N=number of participants with measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Number of Participants With Objective Response | 6 Participants |
| Sunitinib (37.5 mg) in Combination With Cisplatin and 5-FU | Number of Participants With Objective Response | 3 Participants |
95% CI: [13.3, 45.5]Fisher Exact
Secondary
Progression-Free Survival (PFS)
Median time (50%) from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. PFS calculated as (Months) equals (first event date minus first dose date plus 1) divided by 30.
Time frame: Baseline up to Month 15
Population: Efficacy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Progression-Free Survival (PFS) | 5.2 Months |
| Sunitinib (37.5 mg) in Combination With Cisplatin and 5-FU | Progression-Free Survival (PFS) | 6.2 Months |
Secondary
Steady State Concentration (Css) of 5-Fluorouracil (5-FU)
Steady state plasma concentration of 5-FU equals AUC(2-6) divided by 4, where AUC(2-6) is the area under the plasma concentration versus time curve from time 2 to 6 hours postdose (2-6).
Time frame: Day 1 of Cycle 1 (2, 4, and 6 hours post infusion)
Population: PK; N=number of participants contributing to the summary statistics. Css calculated for at least 6 individual participants treated at the MTD (25 mg Sunitinib).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Steady State Concentration (Css) of 5-Fluorouracil (5-FU) | 593 ng/mL | Standard Deviation 433 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Tmax is the time to first occurrence of maximum observed plasma concentration (Cmax).
Time frame: Day 1 of Cycle 1 (2, 4, 6, 8, 10, and 24 hours post dose)
Population: PK; N=the number of participants contributing to the summary statistics. Tmax of Sunitinib, SU012662, and Total Drug (Sunitinib + SU012662) calculated for at least 6 individual participants treated at the MTD (25 mg Sunitinib).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Sunitinib | 4.00 hours |
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Time to Reach Maximum Observed Plasma Concentration (Tmax) | SU012662 (metabolite of Sunitinib) | 4.00 hours |
| Sunitinib (25 mg) in Combination With Cisplatin and 5-FU | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Total Drug (Sunitinib + SU012662) | 4.00 hours |