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

A Phase II Study of AZD2171 in Hepatocellular Carcinoma

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

Study Overview

• Status: Terminated
• Conditions: Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Adult Primary Hepatocellular Carcinoma
• Intervention / Treatment: Drug: cediranib maleate; Other: laboratory biomarker analysis; Procedure: computed tomography; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Other: pharmacological study

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center

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:

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: AZD2171; 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; Given orally; Other Names: AZD2171; Other: laboratory biomarker analysis; 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.; Procedure: computed tomography; computed tomography (CT) every 8 weeks to evaluate response and progression.; Procedure: dynamic contrast-enhanced magnetic resonance imaging; Magnetic resonance imaging (MRI) every 8 weeks to evaluate response and progression.; Other Names: DCE-MRI; Other: pharmacological study; 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.; 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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Andrew Zhu, Massachusetts General Hospital

Publications and helpful links

General Publications

• Zhu AX, Ancukiewicz M, Supko JG, Sahani DV, Blaszkowsky LS, Meyerhardt JA, Abrams TA, McCleary NJ, Bhargava P, Muzikansky A, Sheehan S, Regan E, Vasudev E, Knowles M, Fuchs CS, Ryan DP, Jain RK, Duda DG. Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study. Clin Cancer Res. 2013 Mar 15;19(6):1557-66. doi: 10.1158/1078-0432.CCR-12-3041. Epub 2013 Jan 29.

Helpful Links

• pubmed article

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: January 25, 2007
• First Submitted That Met QC Criteria: January 25, 2007
• First Posted (Estimate): January 29, 2007

Study Record Updates

• Last Update Posted (Estimate): October 31, 2016
• Last Update Submitted That Met QC Criteria: September 13, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Cediranib
• Other Study ID Numbers: NCI-2009-00130; 05-311 (Other Identifier: DFHCC IRB); N02CO12400 (Other Grant/Funding Number: US NIH Grant/Contract Award Number); CDR0000526405 (Registry Identifier: PDQ (Physician Data Query))