AZD2171 in Treating Patients With Locally Advanced Unresectable or Metastatic Liver Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying how well AZD2171 works in treating patients with locally advanced unresectable or metastatic liver cancer. AZD2171 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. Assess the progression free survival of patients with locally advanced unresectable or metastatic hepatocellular carcinoma treated with AZD2171. SECONDARY OBJECTIVES: I. Determine the toxicity of this drug in these patients. II. Determine, preliminarily, the efficacy of this drug, in terms of response rate, duration of response, and overall survival, in these patients. III. Determine the blood flow changes and vascular permeability of the tumor in patients treated with this drug. IV. Determine the pharmacokinetic profile of this drug in these patients. OUTLINE: This is a multicenter study. Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dynamic contrast-enhanced (DCE) MRI and CT perfusion scan of the liver are performed at baseline, 72 hours after the initial dose of AZD2171, and at the end of course 1. Blood samples for pharmacokinetic studies are collected periodically during study. After the completion of study treatment, patients are followed every 3 months for 1 year.

Official Title
-----------------
A Phase II Study of AZD2171 in Hepatocellular Carcinoma

Conditions
-----------------
Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

Intervention / Treatment
-----------------
* Drug: cediranib maleate
* Other: laboratory biomarker analysis
* Procedure: computed tomography
* Procedure: dynamic contrast-enhanced magnetic resonance imaging
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed hepatocellular carcinoma Locally advanced unresectable OR metastatic disease Cancer of the Liver Italian Program (CLIP) score =< 3 Symptomatic congestive heart failure Unstable angina pectoris Measurable disease, defined as >= 1 unidimensionally measurable lesion>= 20 mm by conventional techniques OR >= 10 mm by spiral CT scan Cardiac arrhythmia Measurable lesion must be outside field of prior chemoembolization No known brain metastases ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100% Life expectancy > 12 weeks Absolute neutrophil count >= 1,000/mm^3 Platelet count >= 75,000/mm^3 Hemoglobin >= 8 g/dL Bilirubin =< 3.0 mg/dL AST and ALT =< 7 times upper limit of normal Creatinine =< 2.0 mg/dL Fertile patients must use effective contraception CLIP score =< 3 Exclusion Criteria: Not pregnant or nursing Negative pregnancy test No history of allergic reactions attributed to compounds of similar chemical or biological composition to AZD2171 No chronic diarrhea or any disorder that would limit adequate absorption of AZD2171 No familial history of long QT syndrome Proteinuria =< +1 on two consecutive dipsticks taken no less than 1 week apart No other uncontrolled illness including, but not limited to, any of the following: Hypertension Ongoing or active infection No psychiatric illness or social situation that would limit study compliance Recovered from prior therapy Prior systemic chemotherapy regimens for hepatocellular carcinoma allowed More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) More than 4 weeks since prior radiotherapy, major surgery, or chemoembolization At least 30 days since prior participation in an investigational trial No other concurrent investigational agents No concurrent medication that may markedly affect renal function (e.g., vancomycin, amphotericin, or pentamidine) No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer agents or therapies No mean QTc > 470 msec (with Bazett's correction) on screening EKG (490 msec for women)

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD2171<br>Patients will receive AZD2171 (cediranib maleate) 30mg by mouth once a day. Treatment may continue for as long as benefit is shown. Patients will undergo MRI and CT scan of the liver before beginning treatment, 3 days after the first dose of AZD2171, and after finishing course one. Patients will also undergo blood collection periodically for laboratory studies. Laboratory biomarker analysis, computed tomography, dynamic contrast-enhanced magnetic resonance imaging, and pharmacological study will be performed. | Drug: cediranib maleate<br>* Given orally<br>* Other names: AZD2171;Other: laboratory biomarker analysis<br>* Peripheral blood was obtained from all patients enrolled for studies of early changes in circulating proangiogenic and proinflammatory molecules and cells. Blood samples were collected in EDTA-containing tubes before and after cediranib therapy on days 1 and 14 of cycle 1. Circulating VEGF, placental growth factor (PlGF), sVEGFR1, basic fibroblast growth factor (bFGF), interleukin (IL)-6, IL-8, transforming growth factor a ((TNF-a), gamma interferon (IFN-g) were measured using multiplex ELISA plates from Meso-Scale Discovery. Hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1), sVEGFR2, angiopoietin 2 (Ang-2), sTie2, soluble c-KIT, carbon anhydrase 9 (CAIX), and stromal cell-derived factor-1a (SDF1a) were measured using ELISA kits from R&D Systems.<br>Procedure: computed tomography<br>* computed tomography (CT) every 8 weeks to evaluate response and progression.<br>Procedure: dynamic contrast-enhanced magnetic resonance imaging<br>* Magnetic resonance imaging (MRI) every 8 weeks to evaluate response and progression.<br>* Other names: DCE-MRI;Other: pharmacological study<br>* Blood samples to characterize the steady-state PK of cediranib were drawn from a peripheral vein shortly before patients received the dose on days 8 and 15 of cycle 1 and at the following times relative to dosing on day 1 of cycle 2: 5 min and 1, 2, 4, 6, 8, and 24 hours, with the last sample collected before taking the next daily dose.<br>* Other names: pharmacological studies;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression is defined as a 20% increase in the sum of the of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions by conventional RECIST based criteria, or death, which ever comes first. This design yields at least 90% power to detect a true 3-month PFS rate of at least 69%. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Number of patients who achieve either complete or partial response based on RECIST Criteria for target lesions assessed by MRI. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 1 year | 
| Overall Survival | Overall survival will be calculated using the Kaplan-Meier method, and confidence limits for survival estimates will be calculated using the Greenwood formula. | The time from study entry until death from any cause, assessed up to 1 year |