First In Human, Phase 1 Study of AG013736 In Patients With Solid Tumors

Phase I, Open-Label, Multicenter, Dose-Escalation Study Of The Tyrosine Kinase Inhibitor Of VEGFR-2, AG013736, In Patients With Advanced Solid Tumors

The purpose of the study was to characterize the safety of investigational agent AG-013736, in patients with solid tumors in this First In Human trial.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: AG-013736; Drug: AG-013736; Drug: AG-013736; Drug: AG-013736; Drug: AG-013736; Drug: AG-013736

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • Pfizer Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • Pfizer Investigational Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • 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:

• Patients with cytologically or histologically confirmed solid tumor(s) and with at least one measurable disease site
• Patients with adequate bone marrow, liver and kidney function
• Patients with life expectancy of at least 12 weeks

Exclusion Criteria:

• Patients who have received chemotherapy, immunotherapy, radiotherapy or any investigational agent within 4 weeks of study entry
• Patients with have had a major surgical procedure within 4 weeks of study entry

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1	Drug: AG-013736; Axitinib continuous oral dosing (10 mg once a day, 10 mg twice a day, 20 mg twice a day or 30 mg twice day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (20 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (15 mg once a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fasted state; Drug: AG-013736; Axitinib continuous oral dosing (2 mg twice a day on the first day of dosing, followed by 5 mg twice a day) in the fasted state
Experimental: Cohort 2	Drug: AG-013736; Axitinib continuous oral dosing (10 mg once a day, 10 mg twice a day, 20 mg twice a day or 30 mg twice day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (20 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (15 mg once a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fasted state; Drug: AG-013736; Axitinib continuous oral dosing (2 mg twice a day on the first day of dosing, followed by 5 mg twice a day) in the fasted state
Experimental: Cohort 3	Drug: AG-013736; Axitinib continuous oral dosing (10 mg once a day, 10 mg twice a day, 20 mg twice a day or 30 mg twice day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (20 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (15 mg once a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fasted state; Drug: AG-013736; Axitinib continuous oral dosing (2 mg twice a day on the first day of dosing, followed by 5 mg twice a day) in the fasted state
Experimental: Cohort 4	Drug: AG-013736; Axitinib continuous oral dosing (10 mg once a day, 10 mg twice a day, 20 mg twice a day or 30 mg twice day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (20 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (15 mg once a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fasted state; Drug: AG-013736; Axitinib continuous oral dosing (2 mg twice a day on the first day of dosing, followed by 5 mg twice a day) in the fasted state
Experimental: Cohort 5	Drug: AG-013736; Axitinib continuous oral dosing (10 mg once a day, 10 mg twice a day, 20 mg twice a day or 30 mg twice day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (20 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (15 mg once a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fasted state; Drug: AG-013736; Axitinib continuous oral dosing (2 mg twice a day on the first day of dosing, followed by 5 mg twice a day) in the fasted state
Experimental: Cohort 6	Drug: AG-013736; Axitinib continuous oral dosing (10 mg once a day, 10 mg twice a day, 20 mg twice a day or 30 mg twice day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (20 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (15 mg once a day) in the fed state; Drug: AG-013736; Axitinib continuous oral dosing (5 mg twice a day) in the fasted state; Drug: AG-013736; Axitinib continuous oral dosing (2 mg twice a day on the first day of dosing, followed by 5 mg twice a day) in the fasted state

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	MTD is defined as the dose level at which "no more than 1 of 6 participants experience dose-limiting toxicity (DLT) following de-escalation from the maximum administered dose (MAD)." DLT includes grade (Gr) 2 or greater gastrointestinal toxicities, Gr 3 anemia, nonhematological toxicities (excluding nausea, vomiting, and diarrhea) or Gr 4 neutropenia, thrombocytopenia and inability to resume axitinib (AG-013736) dosing within 14 days of stopping due to treatment related toxicity.	Baseline up to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax)		Pre-dose, 0.5, 1, 2, 4, 8, and 12 hours (hrs) post-dose on Day (D) 1 and 15 of Cycle (C) 1 and Day 29 (Day 1 of Cycle 2); pre-dose on Day 43 (Day 15 of Cycle 2) and Day 57 (Day 1 of Cycle 3)
Time to Reach Maximum Observed Plasma Concentration (Tmax)		Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 1 and 15 of Cycle 1 and Day 29 (Day 1 of Cycle 2); pre-dose on Day 43 (Day 15 of Cycle 2) and Day 57 (Day 1 of Cycle 3)
Area Under the Curve From Time Zero to 12 Hours [AUC (0-12)]	AUC (0-12)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-12).	Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 1 and 15 of Cycle 1 and Day 29 (Day 1 of Cycle 2); pre-dose on Day 43 (Day 15 of Cycle 2) and Day 57 (Day 1 of Cycle 3)
Apparent Oral Clearance (CL/F)	Clearance 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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 1 and 15 of Cycle 1 and Day 29 (Day 1 of Cycle 2); pre-dose on Day 43 (Day 15 of Cycle 2) and Day 57 (Day 1 of Cycle 3)
Plasma Decay Half-Life (t1/2)	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 1 and 15 of Cycle 1 and Day 29 (Day 1 of Cycle 2); pre-dose on Day 43 (Day 15 of Cycle 2) and Day 57 (Day 1 of Cycle 3)
Maximum Observed Plasma Concentration (Cmax) in Fed State Versus Overnight Fasting		Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 29 (Day 1 of Cycle 2) and Day 30 (Day 2 of Cycle 2)
Time to Reach Maximum Observed Plasma Concentration (Tmax) in Fed State Versus Overnight Fasting		Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 29 (Day 1 of Cycle 2) and Day 30 (Day 2 of Cycle 2)
Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] in Fed State Versus Overnight Fasting	AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24).	Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 29 (Day 1 of Cycle 2) and Day 30 (Day 2 of Cycle 2)
Apparent Oral Clearance (CL/F) in Fed State Versus Overnight Fasting	Clearance 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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 29 (Day 1 of Cycle 2) and Day 30 (Day 2 of Cycle 2)
Plasma Decay Half-Life (t1/2) in Fed State Versus Overnight Fasting	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Pre-dose, 0.5, 1, 2, 4, 8, and 12 hrs post-dose on Day 29 (Day 1 of Cycle 2) and Day 30 (Day 2 of Cycle 2)

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: November 1, 2002
• Primary Completion (Actual): July 1, 2004
• Study Completion (Actual): August 1, 2004

Study Registration Dates

• First Submitted: November 2, 2011
• First Submitted That Met QC Criteria: November 7, 2011
• First Posted (Estimate): November 10, 2011

Study Record Updates

• Last Update Posted (Estimate): March 26, 2012
• Last Update Submitted That Met QC Criteria: February 25, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Axitinib
• Other Study ID Numbers: AG013736-001; A4060010