Study Of Sunitinib Plus FOLFOX In Patients With Solid Tumors

Phase 1

Completed

• Conditions: Neoplasms; Colorectal Neoplasms
• Interventions: Drug: sunitinib + FOLFOX

• Registration Number: NCT00599924
• Lead Sponsor: Pfizer

Brief Summary

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

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

Study Timeline

• Study Start: 2005-09
• Study First Submitted: 2008-01-11
• Study First Submitted QC: 2008-01-11
• Study First Posted: 2008-01-24
• Primary Completion: 2008-11
• Study Completion: 2008-11
• Results First Submitted: 2009-11-04
• Results First Submitted QC: 2009-11-04
• Results First Posted: 2009-12-09
• Status Verified: 2015-06
• Last Update Submitted: 2015-06-22
• Last Update Posted: 2015-07-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 53

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single arm	sunitinib + FOLFOX	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

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)	up to 20 weeks	All observed or volunteered AEs and SAEs regardless of treatment group or suspected causal relationship to the investigational product(s) were reported.

Secondary Outcome Measures

Name	Time	Method
Tmax of Total Platinum	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	Oxaliplatin was metabolized to platinum and total platinum was measured.
Objective Response (OR)	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)	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.
Area Under Plasma Concentration-Time Profile From Time Zero to Twenty-Four Hours Postdose (AUC24) of Sunitinib	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	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.
Cmax of SU-012662 (Sunitinib's Metabolite)	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Tmax of Free Platinum	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	Oxaliplatin was metabolized to platinum and free platinum was measured.
Cmax of Total Platinum	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	Oxaliplatin was metabolized to platinum and total platinum was measured.
Steady State Clearance (CLss) 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	CLss was determined by total amount of drug received during infusion or duration of infusion (Ki) divided by Css.
T1/2 of Free Platinum, Total Platinum, and 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 = 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 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	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	Drug clearance (CL/F) = dose divided by area under the plasma concentration-time profile from time zero to twenty-four hours.
Terminal Phase Half-Life (t1/2) of Sunitinib	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	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).
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)	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose.	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.
T1/2 of SU-012662 (Sunitinib's Metabolite)	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	t1/2 = terminal phase half-life. t1/2 was obtained by ln2 divided by kel.
Cmax of Free Platinum	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	Oxaliplatin was metabolized to platinum and free platinum was measured.
Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUCinf) for Free Platinum	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	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.
T1/2 for Free Platinum	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 = terminal phase half-life. t1/2 was obtained by ln2 divided by kel. Oxaliplatin was metabolized to platinum and free platinum was measured.
Maximum Plasma Concentration (Cmax) of Sunitinib	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
CL/F of SU-012662 (Sunitinib's Metabolite)	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	CL/F = dose divided by area under the plasma concentration-time profile from time zero to twenty-four hours.
Area Under the Plasma Concentration-Time Profile From Time Zero to Forty-Eight Hours (AUC48) for Total Platinum	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	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.
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
Cmin of Free Platinum, Total Platinum, and 5-FU	pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Initial Area Dnder the Contrast Agent Concentration-Time Curve (IAUC) of Tumors in a Selected Group of Subjects Assessed by DCE-MRI	Cycle 3 (Day 1) and Cycle 3 (Day 8)	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.
Steady State Concentration (Css) of Fluorouracil (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	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.
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
CL/F of Free Platinum, Total Platinum, and 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	CL/F = dose divided by area under the plasma concentration-time profile from time zero to twenty-four hours.
Volume Endothelial Transfer Constant (Ktrans) of Tumors in a Selected Group of Subjects Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI)	Cycle 3 (Day 1), Cycle 3 (Day 8)	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).

Trial Locations

Locations (1)

Pfizer Investigational Site; 🇺🇸 Dallas, Texas, United States