A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas

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.