Phase II Study of Best Support Care (BSC) Plus ZD6474(Vandetanib) in Patients With Inoperable Hepatocellular Carcinoma (HCC)
Condition: Carcinoma, Hepatocellular
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Vandetanib; Vandetanib; Best Supportive Care
Intervention description: ZD6474 300mg; ZD6474 100 mg; Placebo + Best Supportive Care
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 67.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Hepatocellular carcinoma; Advanced solid, malignant tumour

Summary:

      This is a multi-centre, phase II study to assess the efficacy and safety of ZD6474 in
      patients with Child-Pugh class A, inoperable HCC. This study comprises 2 phases, the primary
      treatment phase and the secondary treatment phase. The primary treatment phase is a
      randomised, double-blind, parallel-group phase II study to assess the efficacy and safety of
      ZD6474 300 mg plus best support care (BSC), ZD6474 100 mg plus BSC, and placebo plus BSC. The
      secondary treatment phase is an open-label expanded access program of ZD6474. In the primary
      treatment phase, patients will be randomised in a 1:1:1 ratio to receive ZD6474 300 mg plus
      BSC, ZD6474 100 mg plus BSC, or placebo plus BSC, respectively. Randomisation will be
      stratified on the basis of Cancer of the Liver Italian Programme (CLIP) tumour staging (CLIP
      score 0-2 versus 3-4). The primary treatment will continue until objective disease
      progression, according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, or
      until patients meet any other withdrawal or discontinuation criteria.The primary endpoint is
      tumour stabilisation rate, and the secondary endpoints are objective response rate,
      progression-free survival, and overall survival. The purpose of the secondary treatment phase
      is to expand the access of ZD6474 so that every patient who is enrolled into this study can
      have the chance to receive the active medicine.Once an individual patient has progressive
      disease in the primary treatment phase, the blind will be broken for this patient. If this
      patient is in the ZD6474 100 mg arm or placebo arm, the patient will be offered the secondary
      treatment with ZD6474 300 mg per day. If this patient is randomised to the ZD6474 300 mg arm,
      the study medication will be discontinued unless the patient wishes to remain the treatment,
      and the patient is to be followed up for survival.
    

Eligibility criteria:

        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
             enrollment

          -  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
             treatment

          -  Any unresolved toxicity greater than CTC grade 2 from previous anti-cancer therapy

          -  Known hypersensitivity to ZD6474 or any of its excipients