This study determined the maximum tolerated dose and safety of SU011248 (sunitinib malate, SUTENT) in combination with FOLFOX \[Leucovorin + Fluorouracil (5-FU) + Oxaliplatin\]. Three different dosing regimens with starting doses of sunitinib at 37.5 mg/day (Schedule 2/2, Schedule 4/2, and Continuous Dosing) were tested in patients with advanced solid tumors, including colorectal cancer.
Study Design: Treatment, Single Group Assignment (7 cohorts), Open Label, Non-Randomized, Safety Study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
53
37.5 mg sunitinib + modified FOLFOX6 (Schedule 2/2)
50 mg sunitinib + modified FOLFOX6 (Schedule 2/2)
50 mg sunitinib + modified FOLFOX6 ( CRC, only Schedule 2/2)
Pfizer Investigational Site
Aurora, Colorado, United States
Pfizer Investigational Site
Nashville, Tennessee, United States
Pfizer Investigational Site
Dallas, Texas, United States
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.
Time frame: up to 20 weeks
Objective Response (OR)
From the start of treatment until disease progression/recurrence. OR=confirmed Complete Response (CR) or confirmed Partial Response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR = disappearance of all target lesions. CR was confirmed if it persisted on repeat imaging study ≥ 4 weeks after initial documentation of response. PR = ≥ 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. PR was confirmed if it persisted on repeat imaging study ≥ 4 weeks after initial documentation of response.
Time frame: From start of treatment until Day 8 of Cycles 4 and 8 (2/2 Schedule), Day 8 of Cycles 3 and 6 (4/2 Schedule), and Day 1 of Cycles 3 and 7 (Continuous Dosing)
Maximum Plasma Concentration (Cmax) of Sunitinib
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Time to Cmax (Tmax) of Sunitinib
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Minimum Plasma Concentration (Cmin) of Sunitinib
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Clearance (CL/F) of Sunitinib
Drug clearance (CL/F) = dose divided by area under the plasma concentration-time profile from time zero to twenty-four hours.
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
37.5 mg sunitinib + modified FOLFOX6 (Schedule 4/2)
50 mg sunitinib + modified FOLFOX6 (Schedule 4/2)
37.5 mg sunitinib + modified FOLFOX6 (Continuous Dosing)
25 mg sunitinib + modified FOLFOX6 (Continuous Dosing)
Area Under Plasma Concentration-Time Profile From Time Zero to Twenty-Four Hours Postdose (AUC24) of Sunitinib
AUC24 = Area under the plasma concentration-time profile from time zero (pre-dose) to twenty-four hours. AUC24 was obtained by the Linear/Log trapezoidal method.
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Terminal Phase Half-Life (t1/2) of Sunitinib
t1/2 = terminal phase half-life. t1/2 was obtained by natural log of 2 (ln2) divided by the rate constant for terminal phase (kel).
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Cmax of SU-012662 (Sunitinib's Metabolite)
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Tmax of SU-012662 (Sunitinib's Metabolite)
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Cmin of SU-012662 (Sunitinib's Metabolite)
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
AUC24 for SU-012662 (Sunitinib's Metabolite)
AUC24 = Area under the plasma concentration-time profile from time zero (pre-dose) to twenty-four hours. AUC24 was obtained by the Linear/Log trapezoidal method.
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose.
CL/F of SU-012662 (Sunitinib's Metabolite)
CL/F = dose divided by area under the plasma concentration-time profile from time zero to twenty-four hours.
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
T1/2 of SU-012662 (Sunitinib's Metabolite)
t1/2 = terminal phase half-life. t1/2 was obtained by ln2 divided by kel.
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Cmax of Free Platinum
Oxaliplatin was metabolized to platinum and free platinum was measured.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Tmax of Free Platinum
Oxaliplatin was metabolized to platinum and free platinum was measured.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUCinf) for Free Platinum
Oxaliplatin was metabolized to platinum and free platinum was measured. AUCinf = Area under the plasma concentration-time profile from time zero (pre-dose) to infinity. AUCinf was obtained by the Linear/Log trapezoidal method.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
T1/2 for Free Platinum
t1/2 = terminal phase half-life. t1/2 was obtained by ln2 divided by kel. Oxaliplatin was metabolized to platinum and free platinum was measured.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Cmax of Total Platinum
Oxaliplatin was metabolized to platinum and total platinum was measured.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Tmax of Total Platinum
Oxaliplatin was metabolized to platinum and total platinum was measured.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Area Under the Plasma Concentration-Time Profile From Time Zero to Forty-Eight Hours (AUC48) for Total Platinum
Oxaliplatin was metabolized to platinum and total platinum was measured. AUC48 = Area under the plasma concentration-time profile from time zero (pre-dose) to forty-eight hours. AUC48 was obtained by the Linear/Log trapezoidal method.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Steady State Concentration (Css) of Fluorouracil (5-FU)
Steady state is reached when the amount of drug getting into the system per unit time is equal to the amount of drug cleared from the system.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Steady State Clearance (CLss) of 5-FU
CLss was determined by total amount of drug received during infusion or duration of infusion (Ki) divided by Css.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Area Under the Curve (AUC) of 5-FU
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Cmax of 5-FU
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
T1/2 of Free Platinum, Total Platinum, and 5-FU
t1/2 = terminal phase half-life. t1/2 was obtained by ln2 divided by kel. Oxaliplatin was metabolized to platinum and free and total platinum were measured.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
CL/F of Free Platinum, Total Platinum, and 5-FU
CL/F = dose divided by area under the plasma concentration-time profile from time zero to twenty-four hours.
Time frame: pre-dose, 1h, 2h, 2 h 5 min, 2h 15 min, 2h 30 min, 2h 45 min, 4h, 6h, 8h, 10h, 24h, and 48h post-dose
Cmin of Free Platinum, Total Platinum, and 5-FU
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Volume Endothelial Transfer Constant (Ktrans) of Tumors in a Selected Group of Subjects Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI)
Volume endothelial Ktrans was estimated by fitting the tissue contrast agent time course to the Kety equation (Tofts model for analysis of DCE-MRI data).
Time frame: Cycle 3 (Day 1), Cycle 3 (Day 8)
Initial Area Dnder the Contrast Agent Concentration-Time Curve (IAUC) of Tumors in a Selected Group of Subjects Assessed by DCE-MRI
IAUC: The initial area under the curve was estimated by integrating the area under the contrast agent concentration time course for the first 90 seconds after bolus arrival in the tumor.
Time frame: Cycle 3 (Day 1) and Cycle 3 (Day 8)