A Study of Vascular Endothelial Growth Factor (VEGF) Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer

Study Overview
=================
Brief Summary
-----------------
The major purpose of this study is to determine if a new drug called pazopanib decreases lymphedema in subjects previously treated for cancer. Lymphedema, or swelling of the arm, is a result of damage to the lymphatic vessels in the arm during surgery and/or radiation. The damaged vessels can not adequately drain fluid from the arm, resulting in increased pressure and swelling. Pazopanib has not previously been studied as a treatment for lymphedema.

Detailed Description
-----------------
Pazopanib inhibits the growth of blood vessels in tumors by inhibiting a protein called vascular endothelial growth factor (commonly called VEGF). Pazopanib is not currently approved by the US Food and Drug Administration (FDA) and therefore considered an experimental medication. High levels of VEGF cause blood vessels to leak fluid, increasing the pressure in tumors similar to the increased pressure in lymphedema. Previous studies have found that treatment with pazopanib decreases the fluid pressure in tumors. That is why we think pazopanib might be an effective treatment for lymphedema.

Official Title
-----------------
A Phase II Study of VEGF Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer

Conditions
-----------------
Lymphedema

Intervention / Treatment
-----------------
* Drug: Pazopanib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have unilateral lymphedema of the ipsilateral arm attributed to prior surgical treatment or radiation therapy for cancer that is severe enough to warrant therapy in the opinion of the patient and treating physician. All patients must have greater than a 3 cm total difference in arm circumference between the affected and unaffected arm measured at five defined points (see protocol). Be at least 18 years of age Have adequate organ function as specified in the protocol. Agree to use effective contraceptive methods during the course of the study if the patient has child-producing potential Have an ECOG performance status of 0 or 1 Exclusion Criteria: Pregnant, lactating, or unwilling to use appropriate birth control Active infection Patients may not have clinically significant cardiovascular disease including myocardial infarction within 6 months prior to initiation of therapy, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, grade II or greater peripheral vascular disease, uncontrolled hypertension defined as SBP>160 or DBP>90. Patients may not have any prior history of cerebrovascular disease including TIA or stroke. Locally recurrent or metastatic disease Concurrent therapeutic anticoagulation or any history of DVT or PE. Major surgery within 4 weeks of starting protocol therapy (non-operative biopsy or placement of a vascular access device is not considered major surgery) Radiation therapy or chemotherapy within the past 6 weeks or currently undergoing radiation therapy or chemotherapy (Concurrent adjuvant hormonal therapy is allowed.) Altered the physical therapy regimen within the past month Indwelling venous device in the ipsilateral arm Bilateral lymphedema Concomitant requirement for medication classified as substrates for the CYP450 enzymes and listed as prohibited in the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pazopanib Treatment<br>Pazopanib 800 mg orally once each day (maximum total duration of treatment = 24 weeks) | Drug: Pazopanib<br>* Pazopanib will be administered at a starting dose of 800 mg orally once each day.<br>* Other names: GW786034;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Volume Ipsilateral Lymphedema in Arm | The primary endpoint will be change in excess arm volume (affected arm volume minus unaffected arm volume) compared to baseline. This will be done at Cycle 2 (29 days) and Cycle 6 (174 days). | Baseline through Cycle 6, Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Interstitial Fluid Pressure (ECF Volume) in the Arm | Interstitial fluid pressure was reported at 24 hours. This is the difference in the last-first reading, affected arm. To assess the degree of improvement in arm edema as measured by changes in interstitial fluid pressure (ECF volume using an automated device lymphometer) | First 24 hours after drug was administered | 
| Change in Impedance or ECF Volume in the Arm | Arm impedance was reported at two baseline readings and for Cycle 2, Day 1. To assess the degree of improvement in arm edema as measured by changes in arm impedance (ECF volume using an automated device lymphometer). Data reported is the ratio of the impedance in the affected versus unaffected arm | Baseline, and Cycle 2, Day 1 | 
| Number of Patients With Trt Related Grade 2+ AEs | This is the number of patients who had greater than or equal to Grade 2 Adverse Events related to treatment. This also includes the number of patients who had treatment related Grade 2 or greater Adverse Events that lasted more than 2 weeks (14 days) and excluded events of hypertension (labeled as 'special'). | End of Treatment | 
| Clinical Benefit as Assessed by Quality of Life Questionnaire (FACT-B+4 Lymphedema Questions) | The quality of life questionnaire (FACT-B+4 lymphedema questions) was given at various timepoints during the study. The values for the subscales are given for baseline, Cycle 1:Day 1, Cycle 2:Day 1, and Cycle 6:Day 1. Physical Well-Being (PWB; sum of 7 items, point range 0-28) Social /Family Well-Being (SWB, sum of 7-items, point range 0-28) Emotional Well-Being (EWB; sum of 6-items, point range 0-24) Functional Well-Being (FWB; sum of 7-items, point range 0-28) Additional Concerns (BCS; sum of 9-items, point range 0-36) Arm subscale (AS; sum of 5-items, point range 0-20) -- This was not collected in Cycle 1 or 2. Fact-B+4 score=Sum of PWB, SWB, EWB, FWB, BCS, AS, point range 0-164 Trial Outcome Index=Sum of PWB, FWB, BCS, point range 0-92 Fact-G score=sum of PWB, SWB, EWB, FWB, point range 0-108 Fact-B score=sum of PWB, SWB, EWB, FWB, BCS, point range 0-144 Note: The higher the score, the better the outcome | Baseline through Cycle 6, Day 1 |