ABT-751 in Treating Children With Neuroblastoma That Has Relapsed or Not Responded to Previous Treatment

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying how well ABT-751 works in treating children with neuroblastoma that has relapsed or not responded to previous treatment. Drugs used in chemotherapy, such as ABT-751, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Compare the time to disease progression in children with refractory or relapsed neuroblastoma treated with ABT-751 vs historical controls. SECONDARY OBJECTIVES: I. Determine the objective response rate in patients with measurable disease treatment with this drug. II. Determine whether ABT-751 improves quality of life of these patients. III. Determine the toxicity of ABT-751. IV. Determine the pharmacokinetic profile of ABT-751 in these patients. OUTLINE: Patients receive oral ABT-751 once daily on days 1-7. Treatment repeats every 21 days for 52 courses in the absence of disease progression or unacceptable toxicity. Blood is collected periodically during course 1 for pharmacokinetic studies. Quality of life is assessed at baseline and prior to each course of treatment. After completion of study treatment, patients are followed up for up to 5.1 years.

Official Title
-----------------
A Phase II Study of ABT-751, an Orally Bioavailable Tubulin Binding Agent, in Children With Relapsed or Refractory Neuroblastoma

Conditions
-----------------
Disseminated Neuroblastoma, Recurrent Neuroblastoma

Intervention / Treatment
-----------------
* Drug: ABT-751
* Procedure: quality-of-life assessment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed neuroblastoma meeting the following criteria: Refractory or relapsed disease No curative treatment option and no additional therapy proven to prolong survival with an acceptable quality of life is available Evidence of disease progression (enlargement of existing measurable tumors or the appearance of new tumors) during prior treatment OR biopsy-proven viable neuroblastoma if stable disease but refractory to prior treatment Previously irradiated soft tissue or bony lesion must meet ≥ 1 of the following criteria: Viable neuroblastoma determined by biopsy ≥ 6 weeks after radiation therapy Growth in the lesion determined by CT scan or MRI Measurable or evaluable disease Measurable disease is defined as ≥ 20 mm in ≥ 1 dimension by MRI, CT scan, or x-ray OR ≥ 10 mm in ≥ 1 dimension by spiral CT scan Evaluable disease is defined as iodine I 123 metaiodobenzylguanidine (^123I MIBG)-positive lesion at ≥ 1 site Must not have measurable disease by CT scan or MRI No elevated urinary catecholamines and/or bone marrow evidence of tumor, without measurable or evaluable disease by imaging modalities (CT scan, MRI, or ^123I MIBG) Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age) Life expectancy ≥ 8 weeks Hemoglobin ≥ 7.5 g/dL (transfusions allowed) Absolute neutrophil count > 250/mm³ Platelet count > 25,000/mm³ (without platelet transfusion support for ≥ 7 days) Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT < 5 times ULN Creatinine normal for age and gender as follows: OR creatinine clearance or radioisotope glomerular filtration rate ≥ 60 mL/min No greater than 0.4 mg/dL (≤ 5 months) No greater than 0.5 mg/dL (6 months-11 months) No greater than 0.6 mg/dL (1 year-23 months) No greater than 0.8 mg/dL (2 years-5 years) No greater than 1.0 mg/dL (6 years-9 years) No greater than 1.2 mg/dL (10 years-12 years) No greater than 1.4 mg/dL (13 years and over [female]) No greater than 1.5 mg/dL (13 years to 15 years [male]) No greater than 1.7 mg/dL (16 years and over [male]) Shortening fraction ≥ 27% by echocardiogram Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-barrier contraception during and for 90 days after completion of study treatment Seizure disorder allowed if controlled and receiving anticonvulsants Neurologic toxicity from prior therapy or tumor involvement ≤ grade 2 No evidence of active graft-vs-host disease No allergy to sulfa-containing medications No known HIV positivity No clinically significant unrelated systemic illness (e.g., serious infection) that would limit study compliance Concurrent filgrastim (G-CSF) allowed if medically indicated Recovered from all prior therapy No prior ABT-751 More than 2 weeks since prior myelosuppressive chemotherapy More than 7 days since prior anticancer biologic agents (e.g., retinoids) More than 4 weeks since prior palliative radiation therapy (small port) or therapeutic ^123I MIBG More than 6 weeks since prior substantial radiation therapy (> 50% pelvis, craniospinal, or total-body radiation) More than 4 months since prior allogeneic stem cell transplantation (SCT) (2 months for autologous SCT) and recovered Infusion of autologous peripheral blood mononuclear cells without high-dose chemotherapy or preparative regimen is not considered SCT More than 30 days since prior investigational drug therapy More than 30 days since prior immunotherapy (monoclonal antibody therapy or vaccine therapy) More than 1 week since prior growth factor treatment No other concurrent anticancer agents, including chemotherapy, immunomodulating agents, or biologic therapy (retinoids) No concurrent radiation therapy, including palliative radiation therapy No concurrent treatment for graft-vs-host disease No concurrent epoetin alfa, sargramostim (GM-CSF), or interleukin-11

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Measurable disease by CT or MRI scan (ABT-751 chemotherapy)<br>Patients receive oral ABT-751 (200 mg/m2) once daily on days 1-7. Treatment repeats every 21 days for 52 courses in the absence of disease progression or unacceptable toxicity. Quality-of-life assessment at baseline and prior to each course of treatment. A pharmacological study (pharmacokinetic profile of ABT-751) will be determined. | Drug: ABT-751<br>* Given orally<br>* Other names: E7010;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|
| Experimental: Evaluable by I-MIBG scintigraphy (ABT-751)<br>Patients receive oral ABT-751 (200 mg/m2) once daily on days 1-7. Treatment repeats every 21 days for 52 courses in the absence of disease progression or unacceptable toxicity. Quality-of-life assessment at baseline and prior to each course of treatment. A pharmacological study (pharmacokinetic profile of ABT-751) will be determined. | Drug: ABT-751<br>* Given orally<br>* Other names: E7010;Procedure: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progression as Assessed by Response Evaluation Criteria in Solid Tumors | Median time to progression observed on ABT-751, along with 95% confidence intervals. | From time to enrollment to death due to any cause, assessed up to 5.1 years | 
| 1-year Progression-free Survival | PFS probabilities calculated using the Kaplan-Meier method, along 95% confidence intervals, separately for each stratum. | From the day of enrollment to the date of disease progression/recurrence , or the date of death (all causes of mortality) if disease progression/recurrence is not reached, assessed up to 1 yr. Pts were to be followed for 5 yrs after completion of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The percentage of patients who are responders will be tabulated, including a 95% confidence interval on the percentage. Responders were defined as patients who achieved a best overall response of complete response (CR) or partial response (PR) at any time on the study including patients who achieved ≥PR and later had progressive disease or relapse. Response in patients with measurable disease will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or by Curie criteria for measuring response by MIBG scans in patients with evaluable disease by 123I-MIBG scan. Per RECIST: CR= Disappearance of all target lesions; PR= at least 30% decrease in the sum of the longest diameter of target lesions. Per Curie criteria: CR= complete resolution of all MIBG positive lesions; PR= resolution of at least one MIBG positive lesion with persistence of other MIBG positive lesions. | Duration of protocol therapy, up to 3 years | 
| Quality of Life Measured by PedsQL™ Generic Core Scale Version 4.0 | The QOL score will be reverse linearly transformed to a 0-100 percentage point scale (0=100, 1=75, 2=50, 3=25, 4=0), with higher scores indicating better health-related quality of life, and the average of all 23 items will be calculated as the composite score. | At baseline | 
| Percentage of Participants With Grade 3 or Higher Toxicity | Percentage of patients with at least one Grade 3 or higher toxicity, as assessed by Common Terminology Criteria for Adverse Events version 3.0, will be tabulated. | From enrollment until 30 days after the end of protocol therapy | 
| Pharmacokinetics of ABT-751: Cmax | Values of the maximum observed concentration (Cmax) will be determined for the first dose.Descriptive statistics for these variables will be provided. | After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose. | 
| Pharmacokinetics of ABT-751: Tmax | Values of the time to maximum observed concentration (Tmax) will be determined for the first dose.Descriptive statistics for these variables will be provided. | After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose. | 
| Pharmacokinetics of ABT-751: AUC | Values of the area under concentration time curve [AUC(0-∞)] will be determined for the first dose. Descriptive statistics for these variables will be provided. | After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose. |