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A Randomised, Double-blind, Parallel Group, Multi-centre, Phase II Study to Assess the Efficacy and Safety of Best Support Care (BSC) Plus ZD6474(Vandetanib) 300 mg, BSC Plus ZD6474(Vandetanib) 100 mg, and BSC Plus Placebo in Patients With Inoperable Hepatocellular Carcinoma (HCC)

Phase 2
20 Years
Not Enrolling
Carcinoma, Hepatocellular

Thank you

Trial Information

A Randomised, Double-blind, Parallel Group, Multi-centre, Phase II Study to Assess the Efficacy and Safety of Best Support Care (BSC) Plus ZD6474(Vandetanib) 300 mg, BSC Plus ZD6474(Vandetanib) 100 mg, and BSC Plus Placebo in Patients With Inoperable Hepatocellular Carcinoma (HCC)

Inclusion Criteria:

- Able to understand and provide informed consent

- Histologically diagnosed HCC, OR clinically diagnosed HCC for patients with
difficulty in obtaining histological diagnosis. A clinically diagnosed HCC should
fulfil ALL the criteria below.

- Chronic hepatitis B or C and/or evidence of liver cirrhosis

- Presence of hepatic tumour(s) with image findings (sonography, CT scan, or MRI
scan) compatible with HCC, and no evidence of other gastrointestinal tumours

- A persistent elevation of serum a-fetoprotein level >= 400 ng/ml without any
evidence of an existing a-fetoprotein-secreting germ cell tumour

- Locally advanced (for example, portal vein invasion, multiple nodules, or nodules in
both lobes) or metastatic HCC with at least one measurable lesion by RECIST criteria
that meets ANY the criteria below:

- HCC not suitable to receive local therapy, including surgical resection,
percutaneous ethanol injection (PEI), or transarterial chemo-embolization (TACE)

- Disease recurred or was refractory to previous local therapy

- Patients refused local therapy

- At least one measurable lesion by RECIST criteria. Tumour lesions treated previously
with local radiotherapy, percutaneous ethanol injection, radiofrequency ablation, or
transarterial embolization are NOT considered measurable.

- If they completed percutaneous ethanol injection, radiofrequency ablation,
transarterial embolization, or cryotherapy at least 4 weeks prior to enrollment,
patients must have subsequent progression or recurrence with at least one new
measurable lesion that has not been treated with any local procedure.

- Karnofsky performance status >= 70

- Life expectancy >= 2 months

- Child-Pugh class A liver function

- Adequate bone marrow reserve, defined as white blood cell count >= 3,000/ml, and
platelet count >= 75,000/ml

- Liver transaminases (AST and ALT) <= 5 times upper normal limits (UNLs); serum
bilirubin <= 1.5 times UNL <= 2 mg/dL

- Serum creatinine <= 1.5 times UNL

- Negative pregnancy test for women of childbearing potential. Patients of
childbearing age as well as his/her partner must use effective contraception during
the study period unless they are surgically sterile or one year post-menopausal

Exclusion Criteria:

- Receiving concurrent anti-cancer therapy for HCC, which includes local therapy,
chemotherapy, or other experimental therapy

- Prior systemic cytotoxic chemotherapy

- Prior transarterial chemo-embolization (TACE) or hepatic arterial infusion (HAI),
with any of the following conditions for those patients who have any target lesions
in the liver:

- More than 5 TACE or HAI sessions undergone prior to enrollment

- The cumulative doses of doxorubicin > 120 mg/m2, mitomycin-C > 24 mg/m2,
cisplatin > 120 mg/m2, or 5-fluorouracil > 2400 mg/m2

- Details of the TACE or HAI regimens are not available in the chart

- (Note: The number of sessions of prior TACE or HAI will not be limited for patients
who have no target lesion in the liver).

- Local treatment including radiotherapy (except palliative radiotherapy), percutaneous
ethanol injection, radiofrequency ablation, transarterial embolization, or
cryotherapy completed within 4 weeks prior to enrollment

- Prior therapy targeting VEGF or EGF signalling pathways, including but not limited to
bevacizumab, cetuximab, gefitinib, erlotinib, or sorafenib.

- Prior thalidomide therapy is not allowed but for patients who stop thalidomide due to
intolerability and meet either one of following condition can be included:

- Patients who took thalidomide for no more than <= 3 days before enrolment

- Patients who took thalidomide for > 3 days but <= 14 days and are confirmed
clinically not responding to thalidomide. 14 days washout period is needed
before enrolment.

- Laboratory results:

- Serum potassium less than 4.0 mmol/L despite supplementation

- Serum calcium (ionized or adjusted for albumin) or magnesium out of their normal
ranges despite supplementation

- Esophagogastroduodenoscopy reveals lesions that are considered high risk of
gastrointestinal bleeding

- Brain or leptomeningeal metastases

- History of HCC tumour rupture

- History of upper gastrointestinal bleeding within 1 year

- Current or recent (within 10 days prior to enrollment) users of full-dose oral or
parenteral anti-coagulants

- Surgical procedures, open biopsy, or significant traumatic injury within 28 days
prior to enrollment. Fine-needle aspiration, core biopsy, and central venous line
placement must be done at least 7 days prior to enrollment. Incompletely healed
surgical incision prior to enrollment.

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the investigator's opinion makes it undesirable for the patient to participate in
the study or which would jeopardize compliance with the protocol.

- Clinically significant cardiac event such as myocardial infarction; New York Heart
Association classification of heart disease > 2 within 3 months before entry; or
other cardiac disease that, in the opinion of the investigator, increases the risk of
ventricular arrhythmia.

- History of arrhythmia (multifocal premature ventricular contractions, bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation), which is
symptomatic, requires treatment (CTCAE grade 3), or asymptomatic sustained
ventricular tachycardia. Atrial fibrillation, if controlled on medication, will not
be excluded.

- Previous history of QTc prolongation as a result of therapy with other medication
that required discontinuation of that medication.

- Congenital long QT syndrome, or first-degree relative with unexplained sudden death
under 40 years of age

- Presence of left bundle branch block

- QTc with Bazett's correction that is unmeasurable, or >= 480 msec on screening ECG

- Use of any concomitant medication that are generally accepted by authorities to have
a risk of causing Torsades de Pointes within 2 weeks before enrollment (use of the
concomitant medication that may be associated with Torsades de Pointes but lack
substantial evidence of causing Torsades de Pointes is allowed, but the screening QTc
must be less then 460 msec, and an additional ECG is required within the first 24
hours after the first dose of study medication is required).

- Use of any concomitant medication that induce CYP3A4 activity within 2 weeks before

- Use of interferon within 3 months before enrollment

- Hypertension not well controlled by medical therapy (systolic blood pressure greater
than 160 mmHg or diastolic blood pressure greater than 100 mmHg)

- Currently active diarrhea that may affect the ability of the patient to absorb the
ZD6474 or diarrhea due to intolerability

- Current pregnancy or breast-feeding

- Other previous or current malignancies within the last 5 years, with the exception of
adequately treated cervical carcinoma in situ and basal cell or squamous cell
carcinoma of the skin

- Receipt of any investigational agents within 30 days prior to commencing protocol

- Any unresolved toxicity greater than CTC grade 2 from previous anti-cancer therapy

- Known hypersensitivity to ZD6474 or any of its excipients

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Tumour Stabilisation Rate

Outcome Description:

Tumour stabilisation rate calculated as percentage of patients with best objective tumour response (Complete Response, Partial Response or Stable Disease) for >=16 weeks based on Response Evaluation Criteria in Solid Tumours (RECIST). Complete Response - Disappearance of all target lesions; Partial Response - >=30% decrease in the sum of longest diameter of target lesions; Progressive Disease - >=20% increase in the sum of longest diameter of target lesions; Stable Disease - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome Time Frame:

After 16 weeks of treatment.

Safety Issue:


Principal Investigator

Ann-Lii Cheng, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Director of Medical Oncology, Department of Oncology, National Taiwan University Hospital


Taiwan: Department of Health

Study ID:




Start Date:

July 2007

Completion Date:

June 2009

Related Keywords:

  • Carcinoma, Hepatocellular
  • Hepatocellular carcinoma
  • Advanced solid, malignant tumour
  • Carcinoma
  • Carcinoma, Hepatocellular