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A Phase II Study of AZD2171 in Adult Patients With Neurofibromatosis Type 1 and Extensive Plexiform and Paraspinal Neurofibromas

Phase 2
18 Years
Open (Enrolling)
Neurofibromatosis Type 1, Plexiform Neurofibroma, Spinal Cord Neurofibroma

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Trial Information

A Phase II Study of AZD2171 in Adult Patients With Neurofibromatosis Type 1 and Extensive Plexiform and Paraspinal Neurofibromas


I. Assess the efficacy of AZD2171, in terms of volume change in target tumors by
3-dimensional magnetic resonance imaging (3D MRI).

II. Describe and define the toxicities of AZD2171 in these patients.


I. Assess the value of 3D MRI data analysis in evaluating plexiform or paraspinal
neurofibromas compared to conventional 2-dimensional MRI data analysis.

II. Assess the value of delayed contrast-enhanced MRI (DCE-MRI) in determining changes in
vascularity of neurofibromas before and during treatment. III. Assess the quality of life
of patients treated with AZD2171. IV. Evaluate the effect of AZD2171 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 AZD2171 on human tumor grafts
in experimental animals.

V. Evaluate relevant pharmacodynamic markers (circulating endothelial cells [CECs] and
vascular endothelial growth factor-2 [VEGF2] levels) and pharmacogenetics analyses
(variation in kdr/flk-1 and other genes) in response to AZD2171.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor location
(peripheral vs paraspinal plexiform neurofibroma). Patients receive oral AZD2171 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

Inclusion Criteria:

- Diagnosis* of neurofibromatosis type 1 (NF1) and extensive plexiform and/or
paraspinal neurofibromasproducing pain (not controlled by use of over-the-counter
medications), progressive neurologic deficit, or significant neurologic
consequenceswith 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

- 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 orthinning
of long-bone cortex)

- First-degree relative with NF1

- Patients with documented mutation in neurofibromin gene with onlysymptomatic
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 beaccurately
measured as 8.0 cm^3 with 3-dimensional (3D) MRI

- Skin lesions are consideredmeasurable (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 goodsurgical candidates due to high risk of damage to vital
structures or spinal cordinjury are eligible

- No evidence of progressive optic glioma, malignant glioma, malignant peripheralnerve
sheath tumor, or other cancer requiring treatment with chemotherapy orradiotherapy

- ECOG performance status 0-3

- WBC ≥ 3,000/mm^3

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 8.0 g/dL

- Bilirubin normal (patients with Gilbert's syndrome allowed despite elevated

- 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
orbiologic composition to AZD2171

- 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

- See Disease Characteristics

- More than 30 days since prior investigational agents

- More than 4 weeks since prior radiotherapy, chemotherapy, hormonal therapy directed
at thetumor, immunotherapy, biologic therapy (e.g., interferon), or majorsurgery

- 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

- No concurrent use of drugs or biologics with proarrhythmic potential

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of confirmed tumor response (complete response [CR] or partial response [PR])

Outcome Description:

Decision Rule: The largest success proportion where the proposed treatment regimen would be considered ineffective in this population is 5% (i.e. null hypothesis). Conversely, the smallest success proportion that would warrant subsequent studies with the proposed regimen in this patient population is 15%. The null hypothesis is that the true success proportion in a given patient population is at most 5%. A maximum of 60 evaluable patients can be used to test the null hypothesis with this two-stage Simon design with modifications consistent with a Fleming design.

Outcome Time Frame:

Baseline to end of treatment

Safety Issue:


Principal Investigator

Dusica Babovic-Vuksanovic

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

May 2006

Completion Date:

Related Keywords:

  • Neurofibromatosis Type 1
  • Plexiform Neurofibroma
  • Spinal Cord Neurofibroma
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform



Howard University Hospital Washington, District of Columbia  20060
Mayo Clinic Rochester, Minnesota  55905
Washington University School of Medicine Saint Louis, Missouri  63110
Massachusetts General Hospital Cancer Center Boston, Massachusetts  02114
Dana-Farber Cancer Institute Boston, Massachusetts  02115
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Case Western Reserve University Cleveland, Ohio  44106
Wayne State University Detroit, Michigan  48202
University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470