Study Of Sunitinib Plus FOLFOX In Patients With Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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Study Design: Treatment, Single Group Assignment (7 cohorts), Open Label, Non-Randomized, Safety Study.

Official Title
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Phase I Study Of SU011248 In Combination With Oxaliplatin, Leucovorin, And 5-Fluorouracil In Patients With Advanced Solid Malignancies

Conditions
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Colorectal Neoplasms, Neoplasms

Intervention / Treatment
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* Drug: sunitinib + FOLFOX
* Drug: sunitinib + FOLFOX
* Drug: sunitinib + FOLFOX
* Drug: sunitinib + FOLFOX
* Drug: sunitinib + FOLFOX
* Drug: sunitinib + FOLFOX
* Drug: sunitinib + FOLFOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced solid tumor malignancy (during expansion at the maximum tolerated dose, entry will be limited to patients wtih adenocarcinoma of the colon or rectum) Eastern Cooperative Oncology Group (ECOG) 0 or 1 Exclusion Criteria: Prior treatment with more than 6 cycles of traditional alkylating agent-based chemotherapy regimens Prior treatment with more than 2 cycles of carboplating-based chemotherapy regimens For colorectal cancer patients in the expanded cohorts, prior treatment with more than 2 systemic chemotherapy regimens in the metastatic setting

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>SU011248 [sunitinib] in combination with FOLFOX; FOLFOX is a chemotherapy regimen that combines oxaliplatin and leucovorin with bolus and infusion 5-FU. The modified FOLFOX 6 (mFOLFOX6) regimen is one of several different regimens of FOLFOX used in clinic, according to different dosages of the 4 drugs. mFOLFOX6 was administered every 2 weeks on Days 1 and 2 of each cycle. 25, 37.5 and 50 mg/day, oral, administered on an outpatient basis in three different dosing regimens: schedule 2/2 (2 weeks on, 2 weeks off), schedule 4/2 (4 weeks on, 2 weeks off), and continuous daily dosing (every day); FOLFOX will be administered every 2 weeks, using the modified FOLFOX 6 (mFOLFOX6) regimen, consisting of: oxaliplatin 85 mg/m2 + leucovorin 400 mg/m2 as a 2-hr IV infusion; 5-FU 400 mg/m2 IV bolus, followed by - 5-FU 2400 mg/m2 as a 46-hr IV infusion | Drug: sunitinib + FOLFOX<br>* 37.5 mg sunitinib + modified FOLFOX6 (Schedule 2/2)<br>* Other names: Sunitinib malate, SUTENT, mFOLFOX6;Drug: sunitinib + FOLFOX<br>* 50 mg sunitinib + modified FOLFOX6 (Schedule 2/2)<br>* Other names: Sunitinib malate, SUTENT, mFOLFOX6;Drug: sunitinib + FOLFOX<br>* 50 mg sunitinib + modified FOLFOX6 ( CRC, only Schedule 2/2)<br>* Other names: Sunitinib malate, SUTENT, mFOLFOX6;Drug: sunitinib + FOLFOX<br>* 37.5 mg sunitinib + modified FOLFOX6 (Schedule 4/2)<br>* Other names: Sunitinib malate, SUTENT, mFOLFOX6;Drug: sunitinib + FOLFOX<br>* 50 mg sunitinib + modified FOLFOX6 (Schedule 4/2)<br>* Other names: Sunitinib malate, SUTENT, mFOLFOX6;Drug: sunitinib + FOLFOX<br>* 37.5 mg sunitinib + modified FOLFOX6 (Continuous Dosing)<br>* Other names: Sunitinib malate, SUTENT, mFOLFOX6;Drug: sunitinib + FOLFOX<br>* 25 mg sunitinib + modified FOLFOX6 (Continuous Dosing)<br>* Other names: Sunitinib malate, SUTENT, mFOLFOX6;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 |  | pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose | 
| Time to Cmax (Tmax) of Sunitinib |  | pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose | 
| Minimum Plasma Concentration (Cmin) of Sunitinib |  | 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. | pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose | 
| 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. | 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). | pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose | 
| Cmax of SU-012662 (Sunitinib's Metabolite) |  | pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose | 
| Tmax of SU-012662 (Sunitinib's Metabolite) |  | pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose | 
| Cmin of SU-012662 (Sunitinib's Metabolite) |  | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 |  | 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 |  | 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. | 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. | 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 |  | 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). | 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. | Cycle 3 (Day 1) and Cycle 3 (Day 8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced solid tumors,, colorectal cancer,, sunitinib (SUTENT),, FOLFOX