Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

ZD6474 in Treating Patients With Recurrent or Progressive Gliomas

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Active	18 and over	NCI	NCI-06-C-0063 NCI-P6680, NCT00293566

Special Category: NCI Web site featured trial, NIH Clinical Center trial

Objectives

Phase I

1. Establish the maximum tolerated dose of ZD6474 in patients with recurrent high-grade gliomas or progressive low-grade gliomas taking enzyme-inducing anti-epileptic drugs (EIAEDs).
2. Obtain preliminary information regarding the spectrum of toxicities of this drug in these patients.
3. Determine the pharmacokinetics of this drug in these patients.
4. Obtain preliminary information regarding potential anti-tumor activity of this drug in these patients.

Phase II

1. Establish data regarding the anti-tumor activity of this drug in patients with recurrent high-grade gliomas not taking EIAEDs.
2. Obtain preliminary information regarding the spectrum of toxicities of this drug in patients with recurrent high-grade gliomas not taking EIAEDs.

Entry Criteria

Disease Characteristics:

• Histologically proven primary malignant high-grade* glioma, including the following types:
  • Glioblastoma multiforme
  • Gliosarcoma
  • Anaplastic astrocytoma
  • Anaplastic oligodendroglioma
  • Anaplastic mixed oligoastrocytoma
  • Malignant glioma/astrocytoma not otherwise specified (NOS)

   [Note: *Progressive low-grade gliomas or infiltrative brain stem gliomas diagnosed by radiography, instead of biopsy, are allowed in the phase I portion of the study only]




• Failed prior radiation therapy

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy
• At least 6 weeks since prior radiation therapy, or nitrosoureas
• At least 4 weeks since prior temozolomide, carboplatin, or other cytotoxic therapies
• At least 4 weeks since prior resection of recurrent or progressive tumor
• At least 3 weeks since prior procarbazine
• At least 2 weeks since prior vincristine, non-cytotoxic agents (e.g., interferon or tamoxifen), or investigational agents
• Prior coronary artery bypass or angioplasty allowed provided there is no significant coronary artery disease and no myocardial wall dysfunction by cardiac evaluation within the past 3 months
• No concurrent steroids OR on a stable dose of steroids for ≥ 5 days before study entry
• No concurrent standard anticancer chemotherapy, radiation therapy, immunotherapy, or vasoconstrictors for the treatment of migraines (e.g., ergotamine, zolmitriptan, sumatriptan)
• No other concurrent investigational agents

Patient Characteristics:

• Life expectancy > 8 weeks
• Karnofsky performance status 60-100%
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL (transfusion allowed)
• SGOT and bilirubin ≤ 2 times upper limit of normal
• Creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 60 mL/min
• Potassium, calcium, and magnesium normal (electrolyte supplementation allowed)
• No history of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix) unless in remission and off all therapy for that cancer for ≥ 1 year
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3-6 months after completion of study treatment
• No blood donation during and for ≥ 3 months after completion of study treatment
• No significant active hepatic, renal, or psychiatric diseases
• No active infection requiring IV antibiotics
• No significant cardiac event, including symptomatic congestive heart failure or evidence of cardiac ischemia (i.e., angina), within the past 3 months
• No cardiac disease that, in the opinion of the investigator, increases risk of ventricular arrhythmia
• No prior myocardial infarction unless there is no significant coronary artery disease (i.e., negative stress test) and no myocardial wall dysfunction by cardiac evaluation within the past 3 months
• No clinically significant arrhythmia (e.g., multifocal premature ventricular contraction, bigeminy, trigeminy, ventricular tachycardia, bradycardia) that is symptomatic or requires treatment (e.g., drugs or automatic implantable defibrillator)
• No asymptomatic sustained ventricular tachycardia
• No history of QTc prolongation with other medication
• No congenital long QT syndrome
• QTc < 460 msec by ECG or measurable Bazett's correction
• LVEF ≥ 45% by MUGA or echocardiogram, especially for patients with previous anthracycline therapy (total dose > 450 mg/m²), significant cardiovascular disease, or chest irradiation
• No hypertension not controlled by medical therapy (i.e., systolic blood pressure [BP] > 160 mm Hg or diastolic BP > 100 mm HG)
• No other active or serious cardiac disease
• No currently active gastrointestinal disease with diarrhea that may affect the ability of the patient to absorb study drug or tolerate the diarrhea
• No other severe or uncontrolled systemic disease that would preclude study participation

Expected Enrollment

A total of 94 patients will be accrued for this study.

Outcomes

Maximum tolerated dose (Phase I)
Toxicity and pharmacokinetics
Antitumor activity

Outline

This is a phase I, dose-escalation study followed by a phase II study. Patients are stratified according to current use of enzyme-inducing anti-epileptic drugs (EIAEDs) (yes vs no). Patients who are on EIAEDs are enrolled into the phase I portion of the study. Patients who are not on EIAEDs are enrolled into the phase II portion of the study. Patients enrolled in the phase II portion of the study are further stratified according to tumor type (glioblastoma multiforme vs anaplastic glioma).

• Phase I: Patients receive oral ZD6474 once daily on days 1-28. Treatment repeats every 28 days for approximately 1 year in the absence of disease progression or unacceptable toxicity.

  Cohorts of 3-6 patients receive escalating doses of ZD6474 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.




• Phase II: Patients receive ZD6474 as in phase I at an established dose.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Howard Fine, MD, Protocol chair		Ph: 301-402-6298

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937

Related Information

Featured trial article
Web site for additional information

Registry Information
Official Title		A Phase I/II Trial of ZD6474 for Patients with Recurrent High-Grade and Progressive Low-Grade Gliomas
Trial Start Date		2006-01-13
Trial Completion Date		2009-06-30 (estimated)
Registered in ClinicalTrials.gov		NCT00293566
Date Submitted to PDQ		2006-01-04
Information Last Verified		2008-10-24