Study With AG-013736 Combined With Chemotherapy And Bevacizumab In Patients With Metastatic Colorectal Cancer

A Randomized Phase 2 Study Of The Anti-Angiogenesis Agent AG-013736 In Combinations With Chemotherapy And Bevacizumab In Patients With Metastatic Colorectal Cancer Preceded By A Phase 1 Portion

To determine the safety and efficacy of AG-013736 in combination with other standard of care medication in patients with first line metastatic colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Neoplasms
• Intervention / Treatment: Drug: bevacizumab; Drug: AG-013726; Drug: AG-013736 (axitinib)

• Study Type: Interventional
• Enrollment (Actual): 187
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Daphne, Alabama, United States, 36526
      • Pfizer Investigational Site
    • Huntsville, Alabama, United States, 35801
      • Pfizer Investigational Site
    • Huntsville, Alabama, United States, 35805
      • Pfizer Investigational Site
    • Mobile, Alabama, United States, 36608
      • Pfizer Investigational Site
  • California
    • Antioch, California, United States, 94531
      • Pfizer Investigational Site
    • Colton, California, United States, 92324
      • Pfizer Investigational Site
    • Corona, California, United States, 92879
      • Pfizer Investigational Site
    • Gilroy, California, United States, 95020
      • Pfizer Investigational Site
    • Glendora, California, United States, 91741
      • Pfizer Investigational Site
    • La Jolla, California, United States, 92037
      • Pfizer Investigational Site
    • La Jolla, California, United States, 92093
      • Pfizer Investigational Site
    • LaJolla, California, United States, 92093
      • Pfizer Investigational Site
    • Pasadena, California, United States, 91105
      • Pfizer Investigational Site
    • Pleasant Hill, California, United States, 94523
      • Pfizer Investigational Site
    • Pomona, California, United States, 91767
      • Pfizer Investigational Site
    • Rancho Cucamonga, California, United States, 91730
      • Pfizer Investigational Site
    • Rancho Mirage, California, United States, 92270
      • Pfizer Investigational Site
    • Redlands, California, United States, 92374
      • Pfizer Investigational Site
    • San Diego, California, United States, 92103
      • Pfizer Investigational Site
    • San Diego, California, United States, 92121
      • Pfizer Investigational Site
    • San Leandro, California, United States, 94578
      • Pfizer Investigational Site
    • West Covina, California, United States, 91790
      • Pfizer Investigational Site
  • Colorado
    • Auroa, Colorado, United States, 80012
      • Pfizer Investigational Site
    • Boulder, Colorado, United States, 80303
      • Pfizer Investigational Site
    • Colorado Springs, Colorado, United States, 80909
      • Pfizer Investigational Site
    • Denver, Colorado, United States, 80220
      • Pfizer Investigational Site
    • Denver, Colorado, United States, 80218
      • Pfizer Investigational Site
    • Lakewood, Colorado, United States, 80228
      • Pfizer Investigational Site
    • Littleton, Colorado, United States, 80120-4413
      • Pfizer Investigational Site
    • Lone Tree, Colorado, United States, 80124
      • Pfizer Investigational Site
    • Longmont, Colorado, United States, 80501
      • Pfizer Investigational Site
    • Parker, Colorado, United States, 80138
      • Pfizer Investigational Site
    • Thornton, Colorado, United States, 80260
      • Pfizer Investigational Site
  • Florida
    • Ocala, Florida, United States, 34471
      • Pfizer Investigational Site
    • Stuart, Florida, United States, 34994
      • Pfizer Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Pfizer Investigational Site
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Pfizer Investigational Site
    • Indianapolis, Indiana, United States, 46237
      • Pfizer Investigational Site
    • Jeffersonville, Indiana, United States, 47130
      • Pfizer Investigational Site
    • Muncie, Indiana, United States, 47303
      • Pfizer Investigational Site
  • Kansas
    • Kansas City, Kansas, United States, 66112
      • Pfizer Investigational Site
    • Overland Park, Kansas, United States, 66210
      • Pfizer Investigational Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Pfizer Investigational Site
    • Louisville, Kentucky, United States, 40217
      • Pfizer Investigational Site
    • Louisville, Kentucky, United States, 40241
      • Pfizer Investigational Site
    • Louisville, Kentucky, United States, 40207
      • Pfizer Investigational Site
    • Shelbyville, Kentucky, United States, 40065
      • Pfizer Investigational Site
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Pfizer Investigational Site
  • Michigan
    • Brownstone, Michigan, United States, 48183
      • Pfizer Investigational Site
    • Dearborn, Michigan, United States, 48126
      • Pfizer Investigational Site
    • Detroit, Michigan, United States, 48202
      • Pfizer Investigational Site
    • West Bloomfield, Michigan, United States, 48322
      • Pfizer Investigational Site
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Pfizer Investigational Site
    • Kansas City, Missouri, United States, 64131
      • Pfizer Investigational Site
    • Kansas City, Missouri, United States, 64154
      • Pfizer Investigational Site
    • Lee's Summit, Missouri, United States, 64064
      • Pfizer Investigational Site
    • St. Louis, Missouri, United States, 63110
      • Pfizer Investigational Site
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • Pfizer Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Pfizer Investigational Site
  • New Jersey
    • Summit, New Jersey, United States, 07902
      • Pfizer Investigational Site
  • New York
    • Albany, New York, United States, 12206
      • Pfizer Investigational Site
    • Albany, New York, United States, 12208
      • Pfizer Investigational Site
    • Amsterdam, New York, United States, 12010
      • Pfizer Investigational Site
    • Hudson, New York, United States, 12534
      • Pfizer Investigational Site
    • Latham, New York, United States, 12110-0610
      • Pfizer Investigational Site
    • Rexford, New York, United States, 12148
      • Pfizer Investigational Site
    • Troy, New York, United States, 12180
      • Pfizer Investigational Site
  • North Carolina
    • Kernersville, North Carolina, United States, 27284
      • Pfizer Investigational Site
    • Lexington, North Carolina, United States, 27295
      • Pfizer Investigational Site
    • Mount Airy, North Carolina, United States, 27030
      • Pfizer Investigational Site
    • North Wilkesboro, North Carolina, United States, 28659
      • Pfizer Investigational Site
    • Pollocksville, North Carolina, United States, 28573
      • Pfizer Investigational Site
    • Winston Salem, North Carolina, United States, 27103
      • Pfizer Investigational Site
  • Oregon
    • Oregon City, Oregon, United States, 97045
      • Pfizer Investigational Site
    • Portland, Oregon, United States, 97213
      • Pfizer Investigational Site
    • Portland, Oregon, United States, 97225
      • Pfizer Investigational Site
    • Portland, Oregon, United States, 97227
      • Pfizer Investigational Site
    • Tualatin, Oregon, United States, 97062
      • Pfizer Investigational Site
  • Pennsylvania
    • West Reading, Pennsylvania, United States, 19611
      • Pfizer Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Pfizer Investigational Site
    • Easley, South Carolina, United States, 29640
      • Pfizer Investigational Site
    • Greenville, South Carolina, United States, 29615
      • Pfizer Investigational Site
    • Greenville, South Carolina, United States, 29605
      • Pfizer Investigational Site
    • Seneca, South Carolina, United States, 29672
      • Pfizer Investigational Site
    • Spartanburg, South Carolina, United States, 29307
      • Pfizer Investigational Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Pfizer Investigational Site
    • Franklin, Tennessee, United States, 37067
      • Pfizer Investigational Site
    • Gallatin, Tennessee, United States, 37066
      • Pfizer Investigational Site
    • Hermitage, Tennessee, United States, 37076
      • Pfizer Investigational Site
    • Lebanon, Tennessee, United States, 37087
      • Pfizer Investigational Site
    • Nashville, Tennessee, United States, 37203
      • Pfizer Investigational Site
    • Nashville, Tennessee, United States, 37205
      • Pfizer Investigational Site
    • Nashville, Tennessee, United States, 37207
      • Pfizer Investigational Site
    • Nashville, Tennessee, United States, 37211
      • Pfizer Investigational Site
    • Smyrna, Tennessee, United States, 37167
      • Pfizer Investigational Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Pfizer Investigational Site
    • Dallas, Texas, United States, 75390
      • Pfizer Investigational Site
    • Dallas, Texas, United States, 75235
      • Pfizer Investigational Site
    • Dallas, Texas, United States, 75237
      • Pfizer Investigational Site
    • Fort Worth, Texas, United States, 76177
      • Pfizer Investigational Site
    • Houston, Texas, United States, 77090
      • Pfizer Investigational Site
    • Tyler, Texas, United States, 75702
      • Pfizer Investigational Site
  • Utah
    • Ogden, Utah, United States, 84403-3274
      • Pfizer Investigational Site
  • Washington
    • Everett, Washington, United States, 98201
      • Pfizer Investigational Site
    • Kennewick, Washington, United States, 99336
      • Pfizer Investigational Site
    • Vancouver, Washington, United States, 98684
      • Pfizer Investigational Site
    • Vancouver, Washington, United States, 98686
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• (Phase 1) Patients with any solid/GI tumor who have had no more than 1 previous chemotherapy for greater than 3 months prior to enrollment
• (Phase 2) Patients with locally advanced or metastatic colorectal cancer (CRC) previously untreated with any systemic therapy.
• Patients treated with adjuvant chemotherapy (with radiation) will be eligible if last treatment was > 12 months prior to enrollment,
• Patients must have measurable disease by RECIST and if any history of hypertension, it must be controlled with medication.

Exclusion Criteria:

• Prior system therapy for advanced CRC (Ph 2 portion only)
• Prior treatment with anti-angiogenesis agent such as bevacizumab or VEGF inhibitors.
• Prior irradiation of greater than 25% of bone marrow (whole pelvis = 25%)
• Prior radiation, major surgery, or investigational agent within 4 weeks of study entry except palliative radiotherapy to non-target, metastatic lesions. Minor surgeries should be completed > 2 weeks of enrollment and be fully recovered from any procedure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: B; bevacizumab 5 mg/kg every 2 weeks + FOLFOX	Drug: bevacizumab; bevacizumab 5 mg/kg every 2 weeks
Experimental: C; AG-013726 5 mg bid+ bevacizumab 2 mg/kg every 2 weeks + FOLFOX	Drug: AG-013726; AG-013726 5 mg bid every 2 weeks
Experimental: A; AG-013736 5 mg bid starting dose + FOLFOX	Drug: AG-013736 (axitinib); AG-013736 5 mg bid starting dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Objective Response: Phase 2	Percentage of participants with objective response (OR) based assessment of confirmed complete response(CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all lesions and no appearance of new lesions. Confirmed PR defined as >=30 percent (%) decrease in sum of the longest dimensions (LD) of the target lesions taking as reference the baseline sum LD , without progression of nontarget lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response.	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Axitinib: Phase 1	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Pharmacokinetic (PK) parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUClast for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.	Predose, 1, 2, 2.5, 4, 6 and 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Axitinib: Phase 1	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUC (t - ∞] for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Maximum Observed Plasma Concentration (Cmax) For Axitinib: Phase 1	PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3.Cmax for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Minimum Observed Plasma Trough Concentration (Cmin) For Axitinib: Phase 1		Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Apparent Oral Clearance (CL/F) For Axitinib: Phase 1	Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. CL/F for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Plasma Decay Half-Life (t1/2) For Axitinib: Phase 1	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. t1/2 for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Oxaliplatin: Phase 1	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUClast for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Oxaliplatin: Phase 1	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Maximum Observed Plasma Concentration (Cmax) For Oxaliplatin: Phase 1	PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. Cmax for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Minimum Observed Plasma Trough Concentration (Cmin) For Oxaliplatin: Phase 1		Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Clearance (CL) For Oxaliplatin: Phase 1	CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. CL for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Plasma Decay Half-Life (t1/2) For Oxaliplatin: Phase 1	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. t1/2 for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For 5-Fluorouracil: Phase 1	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUClast for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For 5-Fluorouracil: Phase 1	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Maximum Observed Plasma Concentration (Cmax) For 5-Fluorouracil: Phase 1	PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. Cmax for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Minimum Observed Plasma Trough Concentration (Cmin) For 5-Fluorouracil: Phase 1		Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Clearance (CL) For 5-Fluorouracil: Phase 1	CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. CL for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Plasma Decay Half-Life (t1/2) For 5-Fluorouracil: Phase 1	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. t1/2 for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Irinotecan: Phase 1	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). AUClast for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Irinotecan: Phase 1	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞) for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Maximum Observed Plasma Concentration (Cmax) For Irinotecan: Phase 1	Cmax for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Minimum Observed Plasma Trough Concentration (Cmin) For Irinotecan: Phase 1		Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Clearance (CL) For Irinotecan: Phase 1	CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Plasma Decay Half-Life (t1/2) For Irinotecan: Phase 1	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. t1/2 for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Bevacizumab: Phase 1	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUClast for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Bevacizumab: Phase 1	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Maximum Observed Plasma Concentration (Cmax) For Bevacizumab: Phase 1	PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. Cmax for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Minimum Observed Plasma Trough Concentration (Cmin) For Bevacizumab: Phase 1		Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Clearance (CL) For Bevacizumab: Phase 1	CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. CL for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Plasma Decay Half-Life (t1/2) For Bevacizumab: Phase 1	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. t1/2 for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Duration of Response (DR): Phase 2	Time in days from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1. DR was calculated for the subgroup of participants with a confirmed objective tumor response. CR: disappearance of all lesions and no appearance of new lesions. PR: >=30% decrease in sum of LD of target lesions taking as reference the baseline sum LD, without progression of nontarget lesions and no appearance of new lesions. Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)
Progression-Free Survival (PFS): Phase 2	Time in days from date of randomization to first documentation of objective tumor progression or death due to any cause. PFS was calculated as first event date minus the date of first dose of study medication plus 1. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was "Death"). Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)
Time to Treatment Failure (TTF): Phase 2	TTF is defined as the time from the randomization to the date of the first documentation of PD, symptomatic deterioration, death due to any cause, or treatment discontinuation due to adverse event, refusal or other reasons. Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)
Overall Survival (OS): Phase 2	Time in days from randomization date to date of death due to any cause. OS was calculated as the death date minus the date of first dose of study medication plus 1. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).	Every 3 months after discontinuation of study treatment until death due to any cause or 1 year after randomization of the last participant
Change From Baseline in M.D. Anderson Symptom Assessment Inventory - Diarrhea (MDASI-D) Symptom Severity and Interference Subscale Scores at Day 1 of Cycle 2 Through Day 1 Cycle 42 and Follow-up: Phase 2	PROs included assessment of symptom severity and interference which were measured using M.D. Anderson Symptom Assessment Inventory-Diarrhea (MDASI-D), 20-item questionnaire which assesses the severity of 14 symptoms over the past 24 hours, as well as symptoms interference with 6 areas of function (e.g., walking, work, mood), when the symptom was "at its worst". Each item is scored from 0 to 10, with '0' indicating that the symptom was either not present or did not interfere with their activities, and '10' indicating that the symptom was "as bad as you can imagine" or "interfered completely" with their life. The 2 subscales, symptom severity score and symptom interference score were average of respective items and ranged from 0 to 10, higher score indicating greater severity or interference of symptoms.	Cycle 1 Day 1 (baseline), every 2 weeks for the first 2 months (Cycle 2 Day 1 [C2D1], Cycle 3 Day 1, and Cycle 4 Day 1) then monthly thereafter starting Cycle 6 Day 1, and 28 days after the last dose

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Hoh CK, Burris HA 3rd, Bendell JC, Tarazi J, Rosbrook B, Kim S, Infante JR, Reid TR. Intermittent dosing of axitinib combined with chemotherapy is supported by (18)FLT-PET in gastrointestinal tumours. Br J Cancer. 2014 Feb 18;110(4):875-81. doi: 10.1038/bjc.2013.806. Epub 2014 Jan 14.
• Infante JR, Reid TR, Cohn AL, Edenfield WJ, Cescon TP, Hamm JT, Malik IA, Rado TA, McGee PJ, Richards DA, Tarazi J, Rosbrook B, Kim S, Cartwright TH. Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study. Cancer. 2013 Jul 15;119(14):2555-63. doi: 10.1002/cncr.28112. Epub 2013 Apr 19.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: April 13, 2007
• First Submitted That Met QC Criteria: April 13, 2007
• First Posted (Estimate): April 16, 2007

Study Record Updates

• Last Update Posted (Estimate): December 6, 2013
• Last Update Submitted That Met QC Criteria: November 7, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: GI neoplasms (phase 1)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Bevacizumab; Axitinib
• Other Study ID Numbers: A4061020