Study Of Sunitinib Plus FOLFOX In Patients With Solid Tumors

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

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 Overview

• Status: Completed
• Conditions: Neoplasms; Colorectal Neoplasms
• Intervention / Treatment: Drug: sunitinib + FOLFOX; Drug: sunitinib + FOLFOX; Drug: sunitinib + FOLFOX; Drug: sunitinib + FOLFOX; Drug: sunitinib + FOLFOX; Drug: sunitinib + FOLFOX; Drug: sunitinib + FOLFOX

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Pfizer Investigational Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Pfizer Investigational Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Single arm; 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; 37.5 mg sunitinib + modified FOLFOX6 (Schedule 2/2); Other Names: Sunitinib malate, SUTENT, mFOLFOX6; Drug: sunitinib + FOLFOX; 50 mg sunitinib + modified FOLFOX6 (Schedule 2/2); Other Names: Sunitinib malate, SUTENT, mFOLFOX6; Drug: sunitinib + FOLFOX; 50 mg sunitinib + modified FOLFOX6 ( CRC, only Schedule 2/2); Other Names: Sunitinib malate, SUTENT, mFOLFOX6; Drug: sunitinib + FOLFOX; 37.5 mg sunitinib + modified FOLFOX6 (Schedule 4/2); Other Names: Sunitinib malate, SUTENT, mFOLFOX6; Drug: sunitinib + FOLFOX; 50 mg sunitinib + modified FOLFOX6 (Schedule 4/2); Other Names: Sunitinib malate, SUTENT, mFOLFOX6; Drug: sunitinib + FOLFOX; 37.5 mg sunitinib + modified FOLFOX6 (Continuous Dosing); Other Names: Sunitinib malate, SUTENT, mFOLFOX6; Drug: sunitinib + FOLFOX; 25 mg sunitinib + modified FOLFOX6 (Continuous Dosing); Other Names: Sunitinib malate, SUTENT, mFOLFOX6

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): November 1, 2008
• Study Completion (Actual): November 1, 2008

Study Registration Dates

• First Submitted: January 11, 2008
• First Submitted That Met QC Criteria: January 11, 2008
• First Posted (Estimate): January 24, 2008

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: June 22, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: FOLFOX; advanced solid tumors,; colorectal cancer,; sunitinib (SUTENT),
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Protein Kinase Inhibitors; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Sunitinib; Oxaliplatin; Leucovorin
• Other Study ID Numbers: A6181048