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

Alternate Title

Cediranib Maleate in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine

Basic Trial Information

Objectives

Primary

1. Assess the efficacy of cediranib maleate, in terms of volume change in target tumors by 3-dimensional (3D) MRI in patients with neurofibromatosis type 1 and extensive plexiform and/or paraspinal neurofibromas.
2. Describe and define the toxicities of cediranib maleate in these patients.

Secondary

1. Assess the value of 3D MRI data analysis in evaluating plexiform or paraspinal neurofibromas compared to conventional 2-dimensional MRI data analysis.
2. Assess the value of delayed contrast-enhanced MR imaging in determining changes in vascularity of neurofibromas before and during treatment.
3. Assess the quality-of-life of patients treated with cediranib maleate, using North Central Cancer Treatment Group Supplemental Quality of Life Questionnaire and 2 Inventories (Pain and Fatigue).
4. Evaluate the effect of cediranib maleate on biological changes of human neurofibroma by comparing pre- and post-treatment specimens from patients involved in this trial or, alternatively, by evaluating the effect of cediranib maleate on human tumor grafts in experimental animals.
5. Evaluate relevant pharmacodynamic markers (circulating endothelial cells and vascular endothelial growth factor-2 [VEGF2] levels) and pharmacogenetics analyses (variation in kdr/flk-1 and other genes) in response to cediranib maleate.

Entry Criteria

Disease Characteristics:

• Diagnosis* of neurofibromatosis type 1 (NF1) and extensive plexiform and/or paraspinal neurofibromas producing pain (not controlled by use of over-the-counter medications), progressive neurologic deficit, or significant neurologic consequences with continuous tumor growth
  • Extensive paraspinal neurofibroma defined as a neurofibroma that involves multiple neural roots at ≥ 3 spinal levels with connection between the levels or extending laterally along the nerves
    • Symptomatic neurofibromas at < 3 spinal levels, but surgical treatment is not possible, allowed

   [Note: * Histologic confirmation of tumor not required in the presence of consistent clinical and radiographic findings]

• Meets ≥ 2 diagnostic criteria for NF1, including the following:
  • Six or more café-au-lait spots (≥ 1.5 cm in postpubertal patients)
  • Freckling in the axilla or groin
  • Optic glioma
  • Two or more Lisch nodules
  • Distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long-bone cortex)
  • First-degree relative with NF1

• Patients with documented mutation in neurofibromin gene with only symptomatic plexiform and/or paraspinal neurofibroma who do not fulfill the above clinical criteria are eligible

• Measurable disease, defined as ≥ 1 lesion whose longest diameter can be accurately measured as 8.0 cm³ with 3-dimensional (3D) MRI
  • Skin lesions are considered measurable (e.g., plexiform neurofibromas), but MRI imaging still required for 3D measurement

• Patients with symptomatic neurofibroma, in whom surgery is not feasible, who refuse surgery or are not good surgical candidates due to high risk of damage to vital structures or spinal cord injury are eligible

• No evidence of progressive optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiotherapy

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 30 days since prior investigational agents
• More than 4 weeks since prior radiotherapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, biologic therapy (e.g., interferon), or major surgery
• No concurrent medication that may markedly affect renal function (e.g., vancomycin, amphotericin, or pentamidine)
• No concurrent CYP interactive medications
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, carbamazepine, or phenobarbital)
• No concurrent use of drugs or biologics with proarrhythmic potential

Patient Characteristics:

• ECOG performance status 0-3
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8.0 g/dL
• Bilirubin normal (patients with Gilbert syndrome allowed despite elevated bilirubin)
• Alkaline phosphatase normal
• AST and ALT ≤ 2.5 times upper limit of normal
• Thyroid-stimulating hormone and free thyroxin normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Ejection fraction ≥ 50% by echocardiogram
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other uncontrolled, serious medical condition that would preclude study participation, including any of the following:
  • Cardiac arrhythmia
  • Diabetes
  • Serious infection
  • Significant cardiac, pulmonary, hepatic, or other organ dysfunction
• No psychiatric illness or social situation that would preclude study compliance
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib maleate
• No New York Heart Association class III or IV disease
  • Class II disease controlled with treatment and increased monitoring allowed
• No systolic blood pressure (BP) > 130 mm Hg and diastolic BP > 90 mm Hg
• No history of familial long QT syndrome
• Mean QTc ≤ 470 msec (with Bazett's correction) by EKG
• QTc prolongation ≤ 500 msec
• No other significant ECG abnormality within the past 14 days

Expected Enrollment

A total of 65 patients will be accrued for this study.

Outcomes

Proportion of confirmed tumor response (complete or partial response)

Toxicity as measured by NCI CTCAE v4.0
Survival time as measured by Kaplan-Meier
Time to disease progression as measured by Kaplan-Meier
Duration of response as measured by Kaplan-Meier
Time to treatment failure due to progression, toxicity, or refusal as measured by Kaplan-Meier
Relationship between 3-D MRI measurements and 2-D MRI measurements as measured by linear regression, Pearson's correlation coefficient, and Bland-Altman approach
Tumor objective response determined by 3D MRI and conventional 2-D MRI as measured by Kappa statistic
Quality of life (QOL) as measured by the Brief Pain Inventory, Brief Fatigue Inventory, and North Central Cancer Treatment Group Supplemental QOL Questionnaire
Biological changes in pre- and post-treatment human and/or mouse xenograft tumor tissue as measured by immunostaining for CD34, CD31, and vascular endothelial growth factor (VEGF)
Correlation of biological changes in pre- and post-treatment tumor tissue with tumor objective response, imaging measures (tumor volume, delayed contrast-enhanced MRI [DCE-MRI]), and QOL
Levels of VEGF and soluble FLT(sFLT) measured as surrogate markers of angiogenesis
Correlation of serum vs tumor VEGF
Effect of cediranib maleate on VEGF serum levels as measured at baseline and every 4 weeks during treatment
Correlation of VEGF serum levels with response, time to progression, and survival
Correlation of circulating endothelial cells with clinical response and with other angiogenic biomarkers
Pharmacogenetics analyses (variation in kdr/flk-1 and other genes) at 6 months after completion of study treatment

Outline

This is a multicenter study. Patients are stratified according to tumor location (peripheral vs paraspinal plexiform neurofibroma).

Patients receive oral cediranib maleate once daily on days 1-28. Treatment repeats every 28 days for 26 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease may continue treatment beyond 26 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, prior to course 2, prior to course 4, and every 6 courses thereafter.

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Dusica Babovic-Vuksanovic, MD, Protocol chair		Ph: 507-284-3215

U.S.A.
Alabama
	Birmingham
	UAB Comprehensive Cancer Center
		Clinical Trials Office - UAB Comprehensive Cancer Center	Ph:  205-934-0309
District of Columbia
	Washington
	Howard University Cancer Center
		Clinical Trials Office - Howard University Cancer Center	Ph:  202-806-9122
Illinois
	Chicago
	University of Chicago Cancer Research Center
		Clinical Trials Office - University of Chicago Cancer Research Center	Ph:  773-834-7424
Massachusetts
	Boston
	Massachusetts General Hospital
		Clinical Trials Office - Massachusetts General Hospital	Ph:  877-726-5130
Michigan
	Detroit
	Barbara Ann Karmanos Cancer Institute
		Clinical Trials Office - Barbara Ann Karmanos Cancer Institute	Ph:  313-576-9363
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Missouri
	Saint Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Gerald Linette, MD, PhD	Ph:  314-747-7222 800-600-3606
Ohio
	Cleveland
	Case Comprehensive Cancer Center
		Clinical Trials Office - Case Comprehensive Cancer Center	Ph:  800-641-2422

Registry Information
Official Title		A Phase II Study of AZD2171 in Adult Patients with Neurofibromatosis Type 1 and Extensive Plexiform and Paraspinal Neurofibromas
Trial Start Date		2006-05-19
Trial Completion Date		2009-07-31 (estimated)
Registered in ClinicalTrials.gov		NCT00326872
Date Submitted to PDQ		2006-03-07
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CM62205, CM17104, CA15083

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