Colorectal Neoplasms, Neoplasms
Conditions
Keywords
advanced solid tumors,, colorectal cancer,, sunitinib (SUTENT),, FOLFOX
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.
Interventions
DRUGsunitinib + FOLFOX
37.5 mg sunitinib + modified FOLFOX6 (Schedule 2/2)
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 | — |
| 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. |
| Minimum Plasma Concentration (Cmin) of Sunitinib | 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 | 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. |
| 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). |
| 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) | 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 | 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. |
| 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. |
| 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) | 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). |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) Schedule 2/2 = Sunitinib administered daily for 2 weeks followed by a 2-week off period. Sunitinib was administered during every other cycle of modified FOLFOX6. | 4 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) Schedule 2/2 = Sunitinib administered daily for 2 weeks followed by a 2-week off period. Sunitinib was administered during every other cycle of modified FOLFOX6. | 9 |
| 50 mg Sunitinib + Modified FOLFOX6 (CRC Only, Schedule 2/2) CRC = colorectal cancer. Schedule 2/2 = Sunitinib administered daily for 2 weeks followed by a 2-week off period. Sunitinib was administered during every other cycle of modified FOLFOX6. | 5 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) Schedule 4/2 = Sunitinib administered daily for 4 weeks followed by a 2-week off period, overlapping with 3 cycles of modified FOLFOX6 | 12 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) Schedule 4/2 = Sunitinib administered daily for 4 weeks followed by a 2-week off period, overlapping with 3 cycles of modified FOLFOX6 | 9 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) Continuous Dosing = Sunitinib administered daily for 16 weeks. Off periods and dosage depended on toxicities observed. Sunitinib was administered with modified FOLFOX6. | 6 |
| 25 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) Continuous Dosing = Sunitinib administered daily for 16 weeks. Off periods and dosage depended on toxicities observed. Sunitinib was administered with modified FOLFOX6. | 8 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 | 0 | 0 | 2 |
| Overall Study | Death | 0 | 0 | 0 | 2 | 0 | 2 | 1 |
| Overall Study | Lack of Efficacy | 3 | 5 | 1 | 2 | 3 | 2 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 1 | 2 | 0 | 2 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | 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) | 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) |
|---|---|---|---|---|---|---|---|---|
| Age, Customized < 65 years | 37 participants | 2 participants | 6 participants | 5 participants | 7 participants | 6 participants | 6 participants | 5 participants |
| Age, Customized > = 65 years | 16 participants | 2 participants | 3 participants | 0 participants | 5 participants | 3 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 19 Participants | 1 Participants | 4 Participants | 2 Participants | 6 Participants | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 34 Participants | 3 Participants | 5 Participants | 3 Participants | 6 Participants | 8 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 9 / 9 | 5 / 5 | 12 / 12 | 9 / 9 | 6 / 6 | 8 / 8 |
| serious Total, serious adverse events | 0 / 4 | 4 / 9 | 0 / 5 | 7 / 12 | 3 / 9 | 2 / 6 | 4 / 8 |
Outcome results
Primary
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
Population: Intent to treat (ITT) = all subjects enrolled in the study that received at least one dose of study medication. Subjects who did not complete the follow-up period for dose limiting toxicity assessment because of death from progressive disease or other non-treatment related events were replaced.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 participants |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 9 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (CRC Only, Schedule 2/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 5 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (CRC Only, Schedule 2/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 7 participants |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 12 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 9 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 participants |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 participants |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| 25 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 participants |
| 25 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 8 participants |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under Plasma Concentration-Time Profile From Time Zero to Twenty-Four Hours Postdose (AUC24) of Sunitinib | Cycle 1, Day 14 | 985.43 ng*hr/mL | Standard Deviation 251.046 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under Plasma Concentration-Time Profile From Time Zero to Twenty-Four Hours Postdose (AUC24) of Sunitinib | Cycle 2, Day 1 | 948.40 ng*hr/mL | Standard Deviation 284.871 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under Plasma Concentration-Time Profile From Time Zero to Twenty-Four Hours Postdose (AUC24) of Sunitinib | Cycle 1, Day 14 | 1233.73 ng*hr/mL | Standard Deviation 322.353 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under Plasma Concentration-Time Profile From Time Zero to Twenty-Four Hours Postdose (AUC24) of Sunitinib | Cycle 2, Day 1 | 1202.50 ng*hr/mL | Standard Deviation 396.337 |
Secondary
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
Population: AUC for 5-FU was not calculated.
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Forty-Eight Hours (AUC48) for Total Platinum | Cycle 1, Day 1 | 47264.02 ng*hr/mL | Standard Deviation 10509.556 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Forty-Eight Hours (AUC48) for Total Platinum | Cycle 2, Day 1 | 56813.62 ng*hr/mL | Standard Deviation 11980.029 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Forty-Eight Hours (AUC48) for Total Platinum | Cycle 1, Day 1 | 43713.95 ng*hr/mL | Standard Deviation 5590.75 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Forty-Eight Hours (AUC48) for Total Platinum | Cycle 2, Day 1 | 51962.03 ng*hr/mL | Standard Deviation 8118.343 |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUCinf) for Free Platinum | Cycle 1, Day 1 | 7459.28 ng*hr/mL | Standard Deviation 2892.442 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUCinf) for Free Platinum | Cycle 2, Day 1 | 7942.64 ng*hr/mL | Standard Deviation 3043.567 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUCinf) for Free Platinum | Cycle 1, Day 1 | 6490.17 ng*hr/mL | Standard Deviation 1947.621 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Area Under the Plasma Concentration-Time Profile From Time Zero to Infinity (AUCinf) for Free Platinum | Cycle 2, Day 1 | 7092.65 ng*hr/mL | Standard Deviation 1906.756 |
Secondary
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.
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | AUC24 for SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 401.51 ng*hr/mL | Standard Deviation 63.164 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | AUC24 for SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 395.82 ng*hr/mL | Standard Deviation 66.618 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | AUC24 for SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 468.79 ng*hr/mL | Standard Deviation 117.108 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | AUC24 for SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 495.97 ng*hr/mL | Standard Deviation 154.314 |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Clearance (CL/F) of Sunitinib | Cycle 1, Day 14 | 41.13 L/hr | Standard Deviation 10.104 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Clearance (CL/F) of Sunitinib | Cycle 2, Day 1 | 42.40 L/hr | Standard Deviation 12.7 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Clearance (CL/F) of Sunitinib | Cycle 1, Day 14 | 44.29 L/hr | Standard Deviation 5.663 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Clearance (CL/F) of Sunitinib | Cycle 2, Day 1 | 49.44 L/hr | Standard Deviation 16.211 |
Secondary
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
Population: CL/F was not calculated for Free Platinum, Total Platinum, and 5-FU.
Secondary
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
Population: CL/F was not calculated for SU-012662.
Secondary
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
Population: Cmax of 5-FU was not calculated.
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Free Platinum | Cycle 1, Day 1 | 935.25 ng/mL | Standard Deviation 442.974 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Free Platinum | Cycle 2, Day 1 | 1043.75 ng/mL | Standard Deviation 381.656 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Free Platinum | Cycle 1, Day 1 | 634.00 ng/mL | Standard Deviation 134.05 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Free Platinum | Cycle 2, Day 1 | 789.43 ng/mL | Standard Deviation 239.65 |
Secondary
Cmax of SU-012662 (Sunitinib's Metabolite)
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 18.95 ng/mL | Standard Deviation 3.007 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 18.75 ng/mL | Standard Deviation 2.977 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 22.80 ng/mL | Standard Deviation 5.189 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 23.44 ng/mL | Standard Deviation 7.094 |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Total Platinum | Cycle 1, Day 1 | 2490.00 ng/mL | Standard Deviation 748.465 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Total Platinum | Cycle 2, Day 1 | 2905.00 ng/mL | Standard Deviation 636.684 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Total Platinum | Cycle 1, Day 1 | 2137.14 ng/mL | Standard Deviation 415.681 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmax of Total Platinum | Cycle 2, Day 1 | 2641.43 ng/mL | Standard Deviation 387.145 |
Secondary
Cmin of Free Platinum, Total Platinum, and 5-FU
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Population: Cmin was not calculated for Free Platinum, Total Platinum, and 5-FU.
Secondary
Cmin of SU-012662 (Sunitinib's Metabolite)
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmin of SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 14.45 ng/mL | Standard Deviation 3.497 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmin of SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 13.59 ng/mL | Standard Deviation 4.585 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmin of SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 15.70 ng/mL | Standard Deviation 4.365 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Cmin of SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 17.68 ng/mL | Standard Deviation 5.599 |
Secondary
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)
Population: No pharmacodynamic assessments were performed due to limited number of DCE-MRI scans collected.
Secondary
Maximum Plasma Concentration (Cmax) of Sunitinib
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Population: ITT population of subjects who had completed pharmacokinetic (PK) blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Maximum Plasma Concentration (Cmax) of Sunitinib | Cycle 1, Day 14 | 47.13 ng/mL | Standard Deviation 13.165 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Maximum Plasma Concentration (Cmax) of Sunitinib | Cycle 2, Day 1 | 44.95 ng/mL | Standard Deviation 14.272 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Maximum Plasma Concentration (Cmax) of Sunitinib | Cycle 1, Day 14 | 61.36 ng/mL | Standard Deviation 14.692 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Maximum Plasma Concentration (Cmax) of Sunitinib | Cycle 2, Day 1 | 60.24 ng/mL | Standard Deviation 13.83 |
Secondary
Minimum Plasma Concentration (Cmin) of Sunitinib
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Minimum Plasma Concentration (Cmin) of Sunitinib | Cycle 1, Day 14 | 34.95 ng/mL | Standard Deviation 10.618 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Minimum Plasma Concentration (Cmin) of Sunitinib | Cycle 2, Day 1 | 30.28 ng/mL | Standard Deviation 10.188 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Minimum Plasma Concentration (Cmin) of Sunitinib | Cycle 1, Day 14 | 38.23 ng/mL | Standard Deviation 11.629 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Minimum Plasma Concentration (Cmin) of Sunitinib | Cycle 2, Day 1 | 39.47 ng/mL | Standard Deviation 16.632 |
Secondary
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)
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Objective Response (OR) | 0 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Objective Response (OR) | 2 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (CRC Only, Schedule 2/2) | Objective Response (OR) | 0 participants |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) | Objective Response (OR) | 0 participants |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 4/2) | Objective Response (OR) | 0 participants |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) | Objective Response (OR) | 0 participants |
| 25 mg Sunitinib + Modified FOLFOX6 (Continuous Dosing) | Objective Response (OR) | 2 participants |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Clearance (CLss) of 5-FU | Cycle 1, Day 1 | 284.99 L/hr | Standard Deviation 147.808 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Clearance (CLss) of 5-FU | Cycle 2, Day 1 | 174.51 L/hr | Standard Deviation 49.445 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Clearance (CLss) of 5-FU | Cycle 1, Day 1 | 312.63 L/hr | Standard Deviation 93.563 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Clearance (CLss) of 5-FU | Cycle 2, Day 1 | 201.12 L/hr | Standard Deviation 103.534 |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Concentration (Css) of Fluorouracil (5-FU) | Cycle 1, Day 1 | 567.52 ng/mL | Standard Deviation 351.207 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Concentration (Css) of Fluorouracil (5-FU) | Cycle 2, Day 1 | 598.86 ng/mL | Standard Deviation 127.635 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Concentration (Css) of Fluorouracil (5-FU) | Cycle 1, Day 1 | 334.26 ng/mL | Standard Deviation 89.579 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Steady State Concentration (Css) of Fluorouracil (5-FU) | Cycle 2, Day 1 | 647.32 ng/mL | Standard Deviation 284.203 |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | T1/2 for Free Platinum | Cycle 1, Day 1 | 16.15 hours | Standard Deviation 3.077 |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | T1/2 for Free Platinum | Cycle 2, Day 1 | 18.55 hours | Standard Deviation 5.622 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | T1/2 for Free Platinum | Cycle 1, Day 1 | 15.60 hours | Standard Deviation 2.038 |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | T1/2 for Free Platinum | Cycle 2, Day 1 | 31.20 hours | Standard Deviation 37.925 |
Secondary
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
Population: T1/2 was not calculated for Free Platinum, Total Platinum, and 5-FU.
Secondary
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
Population: T1/2 for SU-012662 was not calculated due to short observation time.
Secondary
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
Population: T1/2 for sunitinib was not calculated due to short observation time.
Secondary
Time to Cmax (Tmax) of Sunitinib
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Time to Cmax (Tmax) of Sunitinib | Cycle 1, Day 14 | 8.00 hours |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Time to Cmax (Tmax) of Sunitinib | Cycle 2, Day 1 | 7.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Time to Cmax (Tmax) of Sunitinib | Cycle 1, Day 14 | 10.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Time to Cmax (Tmax) of Sunitinib | Cycle 2, Day 1 | 8.00 hours |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Free Platinum | Cycle 1, Day 1 | 2.00 hours |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Free Platinum | Cycle 2, Day 1 | 2.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Free Platinum | Cycle 1, Day 1 | 2.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Free Platinum | Cycle 2, Day 1 | 2.00 hours |
Secondary
Tmax of SU-012662 (Sunitinib's Metabolite)
Time frame: pre-dose, 1, 2, 4, 6, 8, 10, and 24 hours post-dose
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 8.00 hours |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 15.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of SU-012662 (Sunitinib's Metabolite) | Cycle 1, Day 14 | 10.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of SU-012662 (Sunitinib's Metabolite) | Cycle 2, Day 1 | 4.00 hours |
Secondary
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
Population: ITT population of subjects who had completed PK blood sampling for at least one day.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Total Platinum | Cycle 1, Day 1 | 2.00 hours |
| 37.5 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Total Platinum | Cycle 2, Day 1 | 2.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Total Platinum | Cycle 2, Day 1 | 2.00 hours |
| 50 mg Sunitinib + Modified FOLFOX6 (Schedule 2/2) | Tmax of Total Platinum | Cycle 1, Day 1 | 2.00 hours |
Secondary
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)
Population: No pharmacodynamic assessments were performed due to limited number of DCE-MRI scans collected.