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

Study Overview
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Brief Summary
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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.

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

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: AG-013736
* Drug: AG-013736
* Drug: AG-013736
* Drug: AG-013736
* Drug: AG-013736
* Drug: AG-013736


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br> | Drug: AG-013736<br>* 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<br>|
| Experimental: Cohort 2<br> | Drug: AG-013736<br>* Axitinib continuous oral dosing (20 mg twice a day) in the fed state<br>|
| Experimental: Cohort 3<br> | Drug: AG-013736<br>* Axitinib continuous oral dosing (5 mg twice a day) in the fed state<br>|
| Experimental: Cohort 4<br> | Drug: AG-013736<br>* Axitinib continuous oral dosing (15 mg once a day) in the fed state<br>|
| Experimental: Cohort 5<br> | Drug: AG-013736<br>* Axitinib continuous oral dosing (5 mg twice a day) in the fasted state<br>|
| Experimental: Cohort 6<br> | Drug: AG-013736<br>* 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<br>|

What is the study measuring?
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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) |