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
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
Background:

 -  Growth of new blood vessels (angiogenesis) provides many tumors, including brain tumors,
 with needed nutrients and oxygen for cancer cells to survive. One possible treatment for
 different kinds of cancer involves treatment with drugs that slow or stop angiogenesis
 and prevent further tumor growth.

 -  Vandetanib is an oral medication known to block angiogenesis and has shown significant
 antitumor activity in laboratory and animal studies. Vandetanib appears to be well
 tolerated by patients at specific daily doses.

 -  Carboplatin is a drug that interrupts division of cancer cells and has been shown to be
 a useful drug in treatment of tumors known as gliomas. It is a useful drug for treating
 brain tumors, but researchers are interested in gathering more information about how it
 works as a treatment for patients who have not responded to initial surgery, radiation,
 or chemotherapy.

 Objective:

 - To determine the safety and effectiveness of vandetanib and carboplatin, given together or
 sequentially, against recurrent high-grade gliomas.

 Eligibility:

 - Adults diagnosed with a malignant glioma who have received standard treatments that no
 longer appear to be effective.

 Design:

 -  Patients will be assigned to one of two groups. Group 1 patients (combination group)
 will receive oral vandetanib for 28 days and intravenous (IV) carboplatin (once at the
 beginning of the 28-day cycle). Group 2 patients (sequential group) will receive IV
 carboplatin alone (once at the beginning of the 28-day cycle) and then oral vandetanib
 (300 mg daily) for 28 days if the tumor grows or the patient develops unacceptable
 carboplatin toxicity.

 -  Treatment will continue in 28-day cycles for 1 year for both groups.

 -  Patients will undergo a number of tests and procedures during the treatment cycle,
 including physical examinations, routine laboratory tests, electrocardiograms, and
 magnetic resonance imaging (MRI) scans

 -  At the end of 1 year of treatment, patients will be reevaluated for possible
 continuation of drug therapy.
Background:

 In vivo experiments have documented the ability of vandetanib (ZD6474) to inhibit tumor
 growth in various preclinical tumor models. Given the pronounced neovasculature associated
 with malignant gliomas, and abundant published data demonstrating the dependence of glioma
 growth on the maintenance and proliferation of this neovasculature, vandetanib represents a
 potentially promising new therapeutic approach to these otherwise refractory tumors. Phase II
 data of vandetanib for recurrent glioblastomas conducted at the National Institutes of Health
 showed promising activity but responses were usually short-lasting.

 Carboplatin has shown activity as monotherapy in the treatment of recurrent malignant gliomas
 in adults and preclinical data generated at Dr. Fines' laboratory demonstrate additive
 anti-glioma activity with vandetanib. The safety profile of carboplatin and the preclinical
 and clinical data supports its use in combination with vandetanib in patients with malignant
 gliomas.

 Vandetanib is also an epidermal growth factor receptor (EGFR) inhibitor and it has been
 demonstrated that the presence of the EGFRvIII mutant and/or the presence of an intact
 phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and non-phosphorylated protein
 kinase B (AKT) predict for a higher likelihood of response to the EGFR inhibitors Tarceva and
 Iressa.

 Objectives:

 To establish data regarding the anti-tumor activity of vandetanib in combination with
 carboplatin and single agent carboplatin and to collect information regarding the spectrum of
 toxicities.

 To determine if the presence of the EGFRvIII mutant and/or the presence of an intact PTEN and
 non-phosphorylated AKT predict for a higher likelihood of response to vandetanib.

 Eligibility:

 Patients with histologically proven malignant glioma are eligible for this study.

 Design:

 Patients will be randomized (1:1) to one of two groups. Patients in group one will be treated
 with vandetanib (300 mg daily for patients not on enzyme inducing anti-epileptic drugs
 (EIAEDs) and 400 mg daily for patients on EIAEDs) and with carboplatin (area under the
 concentration-time curve at steady-state [area under curve (AUC)], 6mg/mL x min) once every
 4-week cycle (combination group). Patients in group two will receive carboplatin alone (AUC
 6mg/mL x min) once every 4-week cycle. Patients who develop tumor progression or unacceptable
 toxicity on carboplatin alone (group 2) can then receive single agent vandetanib (300 mg
 daily for patients not on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg daily for
 patients on EIAEDs) in 4-week cycles (sequential group). A total of 128 evaluable patients
 will be analyzed. The total accrual ceiling will allow for 74 patients to be enrolled in the
 glioblastoma multiforme (GBM) stratum and 74 patients in the anaplastic gliomas (AG) stratum
 (total 148) to factor in replacing those patients who come off treatment prior to cycle 1.
-  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.