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A Phase I Dose Escalation Study of Vandetanib (ZACTIMA, ZD6474) With Hypofractionated Stereotactic Radiotherapy in Patients With Recurrent Malignant Gliomas

Phase 1
18 Years
Not Enrolling
Malignant Gliomas

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Trial Information

A Phase I Dose Escalation Study of Vandetanib (ZACTIMA, ZD6474) With Hypofractionated Stereotactic Radiotherapy in Patients With Recurrent Malignant Gliomas

Screening Prior to receiving any treatment, tests will be performed to determine overall
medical condition. This will include blood tests, questions about medical history, and
physical and neurological exams.

MRI scan of the brain, electrocardiogram (ECG) and chest X-ray will be performed as baseline
studies if they have not been performed in the last 28 days.

Women of child-bearing potential will also have a serum pregnancy test within 2 days before
taking the study drug.

During treatment If all of the study criteria are met and subject is enrolled in the study,
you will start taking the study drug at least 7 days before radiation therapy. You will take
the study drug once a day by mouth. You should take the study drug at about the same time
each day. If you forget to take a dose, take the missed dose as soon as you remember, as
long as it is at least 12 hours before the next dose is due. If it is less than 12 hours
until the next dose, do not take the dose you have missed. If you throw up within 30
minutes after you take the study drug, you should take another dose, and use medicine to
stop or relieve your vomiting per your doctor's instruction. You will continue to take the
study drug for a total duration of one year. The study will be stopped if your disease
progresses or there is excessive toxicity. Your participation in the study will be for one
year. However, we will continue to follow your disease status, general health and possible
treatment-related side effects after one year and for as long as possible.

This is a Phase I study. These types of studies usually include a small number of subjects
and are often called dose-escalation studies. Subjects in the first dose group will be
receiving a small dose of the study drug. If no unacceptable side effects are observed in
these subjects, the next group of subjects will receive the next higher dose of study drug.
The study drug doses planned are as follows:

Dose Level Drug dose Level 1 100 mg once a day Level 2 200 mg once a day Level 3 300 mg once
a day

You will be assigned to one of three levels depending on when you enter the study.

You will also receive radiation therapy. The radiation dose is the same for all patients.
Radiation therapy will begin at least 7 days after you begin taking the study drug. The
radiation therapy will be once a day for 3 consecutive days. A special plastic mask will be
made for you and used to hold your head still during each radiation treatment.

Tests and procedures will be performed throughout your treatment to determine how your
cancer is responding and to monitor you for safety purposes. The tests and procedures will
be scheduled for you. The following tests and procedures will be performed:

- Physical examination, neurological examination, and ECG, right before, and in the
first, second, fourth, eighth and twelfth week of drug treatment; then once every three

- Brain MRI and quality of life questionnaires at one month and three month after
radiation therapy, then once every three months.

- Chest X-ray as your doctor determines.

Follow-up You will also have follow-up visits with your doctor once a month for the first 6
months, then once every three months. You may also see your doctor anytime as needed.

Duration You will be on this study for up to 12 months.

Inclusion Criteria:

- Patients with histopathologically confirmed malignant gliomas that recurred after
surgical resection and conventional radiation therapy

- Tumor is not located in the eloquent part of the brain and not touching the
brainstem, optic chiasm or optic nerve so that these critical structures will not
receive full dose of re-irradiation

- Recurrent tumor is not surgically resectable or patient is not medically operable

- Age > 18 years.

- Radiographical evidence of local recurrence on brain MRI, with or without
histopathological confirmation.

- Estimated survival of at least 3 months

- Zubrod Performance Scale of 0-2

- Hgb greater than 10 gm/dl, absolute neutrophil count greater than 1500/ul, platelets
greater than 100,000/ul, blood urea nitrogen (BUN) less than 25 mg/dl, Bilirubin less
than 2.0 mg/dl, serum glutamate pyruvate transaminase (SGPT) or serum glutamate
oxaloacetate transaminase (SGOT) less than 2 x normal range

- Less than or equal to 3 recurrent tumors, and combined largest diameter of all tumors
less than or equal to 6 cm

- Single recurrent tumor less than or equal to 6 cm in the largest diameter

Exclusion Criteria:

- Prior therapy with any anti-Epidermal growth factor receptor(EGFR) and/or anti-VEGFR

- Recurrent tumor greater than 6 cm in the largest diameter

- Recurrent tumor located in the brainstem.

- Prior radiation therapy to the brain within 2 months.

- Evidence of severe or uncontrolled systemic disease or any concurrent condition (such
as severe cognitive impairment)

- pregnant and breast-feeding women will be excluded

- Treated on any other clinical protocols or with a non-approved or investigational
drug within 30 days before Day 1 of study treatment.

- Any evidence of clinically active interstitial lung disease (patients with chronic
stable radiographic changes who are asymptomatic need not be excluded)

- Clinically significant cardiac event

- History of arrhythmia. Atrial fibrillation, controlled on medication is not

- Previous history of corrected electrocardiogram QT interval (QTc)prolongation as a
result from other medication that required discontinuation of that medication.

- Congenital long QT syndrome, or 1st 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. If a patient has QTc 480 msec on
screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The
average QTc from the three screening ECGs must be less than 480 msec in order for the
patient to be eligible for the study.

- Concomitant medication that may cause QTc prolongation, induce Torsades de Pointes or
induce cytochrome P450 3A4 (CYP3A4) function Hypertension not controlled by medical
therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure
greater than 100 mm Hg)

- Active diarrhea that may affect the ability of the patient to absorb the VANDETANIB.

- Major surgery within 4 weeks, or incompletely healed surgical incision before
starting study therapy

- Clinical and/or radiographic evidence of bleeding in the recurrent brain tumor.

- Patients currently on enzyme inducing anticonvulsants. However, patients are eligible
if the enzyme inducing anticonvulsants can be discontinued or switched to non- enzyme
inducing anticonvulsants one week before study entry. Non-enzyme inducing
anticonvulsants cannot be those which may cause QTc prolongation, induce Torsades de
Pointes or induce CYP3A4 function

- Laboratory results:

- Serum bilirubin greater than 1.5 x the upper limit of reference range (ULRR)

- Serum creatinine greater than 1.5 x ULRR or creatinine clearance less than 50
mL/minute (calculated by Cockcroft-Gault formula)

- Potassium, less than 4.0 mmol/L despite supplementation; serum calcium (ionized
or adjusted for albumin,) or magnesium out of normal range despite

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than
2.5 X ULRR

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence of acute and delayed ≥ grade 3 Central nervous system (CNS) toxicity by Common Terminology Criteria (CTC) v.3.

Outcome Time Frame:

12 months.

Safety Issue:


Principal Investigator

Changhu Chen, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado, Denver


United States: Food and Drug Administration

Study ID:



Start Date:

March 2007

Completion Date:

January 2011

Related Keywords:

  • Malignant Gliomas
  • malignant
  • gliomas
  • Glioma



University of Colorado Health Science Center Aurora, Colorado  80010-0510