Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
Conditions
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.
Interventions
DRUGcediranib maleate
Given orally
OTHERlaboratory 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.
PROCEDUREcomputed tomography
computed tomography (CT) every 8 weeks to evaluate response and progression.
PROCEDUREdynamic contrast-enhanced magnetic resonance imaging
Magnetic resonance imaging (MRI) every 8 weeks to evaluate response and progression.
OTHERpharmacological 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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 3 months | 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%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Up to 1 year | 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 |
| Overall Survival | The time from study entry until death from any cause, assessed up to 1 year | Overall survival will be calculated using the Kaplan-Meier method, and confidence limits for survival estimates will be calculated using the Greenwood formula. |
Countries
United States
Participant flow
Recruitment details
The study enrolled the targeted 17 patients for the first stage between May 2009 and January 2010. Patients were recruited in the outpatient clinics.
Participants by arm
| Arm | Count |
|---|---|
| Singe Arm Open Label Study With AZD2171 at 30 mg Daily Patients will receive AZD2171 (cediranib maleate) 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.
cediranib maleate: Given orally
laboratory biomarker analysis
computed tomography
dynamic contrast-enhanced magnetic resonance imaging
pharmacological study | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Singe Arm Open Label Study With AZD2171 at 30 mg Daily |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 66 years |
| Cancer Of Liver Italian Program (CLIP) | 2 units on a scale |
| Eastern Cooperative Oncology Group | 1 units on a scale |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 5 / 17 |
Outcome results
Primary
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%.
Time frame: 3 months
Population: The number of patients who were progression free at 3 months was determined. 13 of 17 patients (77%) were progression free at 3 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Singe Arm Open Label Study With AZD2171 at 30 mg Daily | Progression-free Survival | 77 percentage of participants |
Secondary
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.
Time frame: The time from study entry until death from any cause, assessed up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Singe Arm Open Label Study With AZD2171 at 30 mg Daily | Overall Survival | 11.7 months |
Secondary
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
Time frame: Up to 1 year
Population: Patients receiving AZD2171 (cediranib maleate)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Singe Arm Open Label Study With AZD2171 at 30 mg Daily | Response Rate | 0 participants with confirmed response |
Post Hoc
Discontinued Treatment Due to SAE
Participants that discontinued treatment due to a Serious Adverse Event (SAE)
Time frame: May 2009 through January 2010
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Singe Arm Open Label Study With AZD2171 at 30 mg Daily | Discontinued Treatment Due to SAE | 0 Participants |