AZD2171 in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine

Study Overview
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Brief Summary
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This phase II trial is studying how well AZD2171 works in treating patients with neurofibromatosis type 1 and plexiform neurofibroma and/or neurofibroma near the spine. AZD2171 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: 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. SECONDARY OBJECTIVES: 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 thereafter.

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

Conditions
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Neurofibromatosis Type 1, Plexiform Neurofibroma, Spinal Cord Neurofibroma

Intervention / Treatment
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* Drug: Cediranib Maleate


Participation Criteria
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Eligibility Criteria
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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 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 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 phenobarbital) No concurrent use of drugs or biologics with proarrhythmic potential

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cediranib maleate)<br>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 thereafter. | Drug: Cediranib Maleate<br> <br> * Other names: Recentin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Tumor Response (Complete Response [CR] or Partial Response [PR]) | Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the volume of target lesions taking as reference the baseline volume. | Baseline to end of treatment, maximum of 26 cycles (28 days/cycle). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Time as Measured Using Kaplan-Meier Method | Survival time is defined as the time from registration to death due to any cause. | From registration to death (due to any cause) max 51 months | 
| Time to Disease Progression as Measured Using Kaplan-Meier Method | Progression (PD): At least a 20% increase in the sum of volumes of target lesions taking as reference the smallest volume recorded since the treatment started or the appearance of one or more new lesions. If a patient dies without documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. | From registration to documentation of disease progression up to 26 cycles (28 days/cycle). | 
| Duration of Response as Assessed Using the Method of Kaplan-Meier | Duration of response is defined for all evaluable patients who have achieved a confirmed tumor objective response as the date at which the patient's objective status is first noted to be either a CR or PR to the date progression is documented. Duration of response will be estimated using the method of Kaplan-Meier. | From time of confirmed tumor objective response as CR or PR to the date of progression max 51 months | 
| Time to Treatment Failure as Assessed Using the Method of Kaplan-Meier | Time to treatment failure is defined to be the time from the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they are removed from treatment. Time to treatment failure will be estimated using the method of Kaplan-Meier. | From the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, or refusal up to 51 months. | 
| Reduction in Self Reported Worst Pain Per Cycle. | Reduction in self reported worst pain per cycle as measured by the Worst Pain scale from the North Central Cancer Treatment Group Brief Pain Inventory (short form). The worst pain scale is from 0-10 (10 is worst pain possible). The per-cycle average reduction in worst pain will be analyzed using generalized linear models to account for repeated measures within patients. | At baseline, prior to each subsequent course (q 28+/- 3 days), and at end of treatment up to 51 months |