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

• Proportion of confirmed tumor response (complete response [CR] or partial response [PR]) [ Time Frame: Baseline to end of treatment ] [ Designated as safety issue: No ]
  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.
  
  
• Efficacy of AZD2171 as assessed by volume change in target tumors by 3D MRI [ Time Frame: At baseline, prior to each subsequent course (q 28+/- 3 days), and at end of treatment, and followed until death or 2 years from registration ] [ Designated as safety issue: No ]

  Target lesions should be selected on the basis of their size (lesions with the largest volume) and their suitability for accurate repetitive measurements (either by imaging techniques or clinically). A sum of the volumes for all target lesions will be calculated and reported as the baseline volume.

  CR: Disappearance of all target lesions. PR: At least a 30% decrease in the volume of target lesions taking as reference the baseline volume.

  
  
• Toxicities of AZD2171 as assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [ Time Frame: At baseline, week 1 and week 2 of course 1, prior to each subsequent course (q 28+/- 3 days), at end of treatment, and followed until death or 2 years from registration ] [ Designated as safety issue: Yes ]
  

• Survival time as measured using Kaplan-Meier method [ Time Frame: From registration to death (due to any cause) ] [ Designated as safety issue: No ]
  
• Time to disease progression as measured using Kaplan-Meier method [ Time Frame: From registration to documentation of disease progression ] [ Designated as safety issue: No ]

  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.

  
  
• Duration of Response as assessed using the method of Kaplan-Meier [ Time Frame: From time of confirmed tumor objective response as CR or PR to the date of progression ] [ Designated as safety issue: No ]
  
• Time to treatment failure as assessed using the method of Kaplan-Meier [ Time Frame: From the date of randomization to the date at which the patient is removed from treatment due to progression, toxicity, or refusal ] [ Designated as safety issue: No ]
  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.
  
  
• Comparison of 3D MRI data analysis and conventional 2D MRI data analysis as assessed using linear regression and a Bland-Altman approach [ Time Frame: At baseline, prior to each subsequent course (q 28+/- 3 days), and at end of treatment ] [ Designated as safety issue: No ]
  Linear regression and Pearson's correlation coefficieint will be used to assess the relationship between 3-D and 2-D MRI measurements. A Bland-Altman approach will be used to assess the amount of agreement between the two measurement methodologies. In addition, tumor objective response will be determined based on 3-D MRI measurements and 2-D measurements. The agreement between the tumor objective responses based on the two different methodologies will be assessed with a Kappa statistic.
  
  
• Changes in vascularity of neurofibromas before and during treatment as assessed using DCE-MRI [ Time Frame: At baseline, prior to each subsequent course (q 28+/- 3 days), and at end of treatment ] [ Designated as safety issue: No ]
  This protocol is limited to DCE-MRI using T1 weighted studies with low molecular weight gadolinium (Gd) chelates. The primary end points of these DCE-MRI studies are the Initial Area Under the Gd Curve measured over 60 second and over 3 minutes. Relative changes in signal intensity at each of 3 post contrast time points will be assessed compared with the non-contrast baseline. The difference between follow-up DCE-MRI measures and baseline will be correlated with changes in tumor volume, tumor objective response status, changes in patient symptoms, and changes in quality of life (QOL).
  
  
• QOL as assessed using the Brief Pain Inventory (short form) and Brief Fatigue Inventory and QOL trajectory over time (North Central Cancer Treatment Group Supplemental Quality of Life Questionnaire) [ Time Frame: At baseline, prior to each subsequent course (q 28+/- 3 days), and at end of treatment ] [ Designated as safety issue: No ]
  One particular descriptive analysis will be to plot the scores of each patient over time, connecting the values corresponding to a specific patient by a line. Analyses are intended to be descriptive and hypothesis-generating in nature. QOL endpoints will include the absolute percentage change from baseline value to each evaluation as well as the maximum and minimum value observed during treatment. Determination of significant changes in QOL over time will be assessed using a signed rank test comparing the change at each assessment point from baseline.
  
  
• Effect of AZD2171 on biological changes of human neurofibroma as assessed by comparing pre- and post-treatment specimens or by evaluating the effect of AZD2171 on human tumor grafts in experimental animals [ Time Frame: At baseline and after each course (q 28+/- 3 days) ] [ Designated as safety issue: No ]
  
• Levels of CECs and pharmacogenetic analyses (variation in kdr/flk-1 and other genes) [ Time Frame: Prior to initiating therapy on day 1, 15, day 28 and every 84 days thereafter and at the time of termination from the study (pharmacogenetic analysis only at baseline) ] [ Designated as safety issue: No ]
  We will correlate CEC's with clinical response and the other angiogenesis biomarkers. We will specifically assess the validity of this test as a monitoring tool and a predictive marker of response.
  
  
• Comparison of pre- and post-treatment human and/or mouse xenograft tumor tissue as measured by immunostaining (for CD34, CD31, VEGF, VEGFR and phosho-VEGFR) and in situ hybridization (ISH) for VEGF gene amplification [ Time Frame: Baseline and after 6 months of treatment ] [ Designated as safety issue: No ]
  Analyses of biological changes in pre-treated and post-treated tumor tissue are intended to be descriptive and hypothesis-generating in nature. Changes in these variables (pre- versus post-treatment) will be determined using a paired test and these measurements will be correlated with tumor objective response, imaging measures (tumor volume, DCE-MRI), and QOL. We will also explore the potential predictive role of baseline tumor VEGFR expression for clinical benefit.
  
  
• Levels of serum VEGF and sFLT as measured by enzyme-linked immunosorbent assay (ELISA) and levels of VEGFRs and phospho-VEGFRs (such as VEGFR-1, -2, and Neuropilin) by western blotting [ Time Frame: Baseline and every 4 weeks during treatment ] [ Designated as safety issue: No ]
  Levels of VEGF and sFLT will be measured as surrogate markers of angiogenesis. We will evaluate the levels of VEGF during treatment to determine the effect of treatment on VEGF and to relate this to response, time to progression and survival. Both serum and tumor VEGF levels will be measured to determine if systemic (serum) VEGF levels are representative of intratumoral VEGF, which will have important clinical implications for clinical trials using anti-angiogenic based therapies.
  
  

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.