- -
INCLUSION CRITERIA:
Patients with histologically proven malignant primary gliomas who have progressive
disease after radiotherapy will be eligible for this protocol.
These include glioblastoma
multiforme (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma
(AO), anaplastic mixed oligoastrocytoma (AMO), and malignant glioma/astrocytoma NOS.
Patients must have an magnetic resonance imaging (MRI)/computed tomography (CT) scan
performed within 14 days prior to registration and on a fixed dose of steroids for at
least 5 days. If the steroid dose is increased between the date of imaging and
registration a new baseline MRI/CT is required. The same type of scan, that is, MRI or CT
must be used throughout the period of protocol treatment for tumor measurement.
Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:
Patients will be eligible four weeks after surgery if they have recovered from the
effects of surgery.
Residual disease following resection of recurrent tumor is not mandated for eligibility
into the study. To best assess the extent of residual disease post-operatively, a CT/MRI
should be done:
- - no later than 96 hours in the immediate post-operative period or.
- - at least 4 weeks post-operatively, and.
- - within 14 days of registration, and.
- - on a steroid dosage that has been stable for at least 5 days.
If the 96 hour scan is more than 14 days before registration, the scan needs to be
repeated. If the steroid dose is increased between the date of imaging and registration,
a new baseline MRI/CT is required on a stable steroid dosage for at least 5 days.
Patients must have failed prior radiation therapy.
All patients or their previously designated durable power of attorney (DPA) (if the
patient is deemed by the treating physician to be cognitively impaired or questionably
impaired in such a way that the ability of the patient to give informed consent is
questionable) must sign an informed consent indicating that they are aware of the
investigational nature of this study.
Patients must be greater than or equal to 18 years old, and must have a life expectancy
greater than 8 weeks.
Patients must have a Karnofsky performance status of greater than or equal to 60.
Patients must be at least six weeks from radiation therapy. Additionally, patients must
be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from
procarbazine, and 2 weeks from last vincristine administration. Patients must be at least
4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic
agents (e.g., interferon, tamoxifen) including investigative agents.
Patients must have adequate bone marrow function (white blood cell (WBC) greater than or
equal to 3,000/microL, absolute neutrophil count (ANC) greater than or equal to
1,500/mm(3), platelet count of greater than or equal to 100,000/mm(3), and hemoglobin
greater than or equal to 10 gm/dl), adequate liver function (aspartate aminotransferase
(AST), alanine aminotransferase (ALT) and alkaline phosphatase 2.5 less than or equal to
upper limit of normal (ULN) and bilirubin less than or equal to 1.5 times ULN), and
adequate renal function (creatinine less than or equal to 1.5 mg/dL and/or creatinine
clearance greater than or equal to 60 cc/min) before starting therapy. Patients must also
have serum potassium greater than or equal to 3.5 mg/dL, magnesium greater than or equal
to 0.75 mmol/L and calcium levels within normal levels; supplementation is allowed. In
cases where the serum calcium is below the normal range, 2 options would be available: 1)
the calcium adjusted for albumin is to be obtained and substituted for the measured serum
value. Exclusion is to then be based on the adjusted for albumin values falling below the
normal limit. 2) Determine the ionized calcium levels. Exclusion is then to be based if
these ionized calcium levels are out of normal range despite supplementation. These tests
must be performed within 14 days prior to registration. Eligibility level for hemoglobin
may be reached by transfusion.
Patients must either not be receiving steroids, or be on a stable dose of steroids for at
least five days prior to registration.
This study was designed to include women and minorities, but was not designed to measure
differences of intervention effects. Males and females will be recruited with no
preference to gender. No exclusion to this study will be based on race. Minorities will
actively be recruited to participate.
Patients must not be pregnant or nursing, and all patients (both men and women) must be
willing to practice birth control during and for 2 months after treatment with vandetanib
and/or carboplatin. Women of childbearing potential (WCBP) must have a negative serum or
urine pregnancy test. In addition, WCBP patients must agree to use adequate contraceptive
methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation;
intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner).
A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with
corrected QT interval (QTc) less than 480 msec. If a patient has a QT interval corrected
for heart rate using Bazett's) QTcB interval > 480 ms on screening ECG, the screening ECG
may be repeated twice [at least 24 hours apart] for a total of 3 ECGs. The average QTcB
from the 3 screening ECGs must be less than or equal to 480 ms in order for the patient
to be eligible for the study).
EXCLUSION CRITERIA:
Patients who, in the view of the treating physician, have significant active hepatic,
renal, or psychiatric diseases are ineligible.
Prior treatment with vandetanib.
Prior treatment with platinum-based therapy.
Patients known to have an allergic response to mannitol.
Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena
cava syndrome (SVC), New York Heart Association (NYHA) classification of heart disease
greater than or equal to 2 within 3 months before entry; or presence of cardiac disease
that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
History of arrhythmia (multifocal premature ventricular contractions PVCs), bigeminy,
trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
symptomatic or requires treatment (Common Terminology Criteria for Adverse Events (CTCAE)
grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation,
controlled on medication is not excluded.
QTc prolongation with other medications 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 (LBBB.)
QTc with Bazett's correction that is unmeasurable, or greater than or equal to 480 msec
on screening ECG. (Note: If a subject has a QTc interval greater than or equal to 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
subject to be eligible for the study. Patients who are receiving a drug that has a risk
of QTc prolongation excluded if QTc is greater than or equal to 460 msec.
Any concurrent medication that may cause QTc prolongation or induce Torsades de Pointes.
Drugs listed in Appendix E, Table 2, that in the investigators opinion cannot be
discontinued are allowed; however, must be monitored closely with additional ECGs and
laboratory assessments of electrolytes to ensure the patients safety.
Concomitant medications that are potent inducers (rifampicin, rifabutin, St. Johns Wort
and Enzyme-Inducing Anti-Epileptic Drugs (EIAEDs) of cytochrome P450 3A4 (CYP3A4)
function. EIAEDs are allowed.
Hypertension not controlled by medical therapy (systolic blood pressure greater than 160
mm Hg or diastolic blood pressure greater than 100 mm Hg)
Currently active diarrhea that may affect the ability of the patient to absorb the
vandetanib or tolerate diarrhea.
Women who are currently pregnant or breast feeding.
Patients known to have a malignancy (other than their malignant glioma) that has required
treatment in the last 12 months and/or is expected to require treatment in the next 12
months (except for non-melanoma skin cancer, carcinoma in situ in the cervix or ductal
carcinoma in situ).
Invasive procedures defined as follows:
- - Major surgical procedure, open biopsy or significant traumatic injury within 28 days
prior to Day 1 therapy.
- - Anticipation of need for major surgical procedures during the course of the study.
- - Core biopsy within 7 days prior to Day 1 (D1) therapy.
Patients should not be on anti-platelet medications (aspirin, clopidogrel, ticlopidine,
prasugel). Non-steroidal anti-inflammatory drugs should be used with caution if medically
necessary.
Restrictions.
- - Patients who are blood donors should not donate blood during the trial and for 3
months following their last dose of trial treatment.
- - Due to the experimental nature of vandetanib, all patients of childbearing potential
must be one year post-menopausal, surgically sterile, or using an acceptable method
of contraception (oral contraceptives, barrier methods in conjunction with
spermicide,
approved contraceptive implant, long-term injectable contraception, intrauterine device
or tubal ligation) during and continued after the last dose of study medication.
Contraceptive use will continue for at least two months, five half-lives, after the last
dose on study medication.
