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

Phase 2

Completed

Conditions: Disseminated Neuroblastoma
Recurrent Neuroblastoma

Interventions: Drug: ABT-751
Procedure: quality-of-life assessment

Registration Number: NCT00436852

Lead Sponsor: Children's Oncology Group

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 92

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Measurable disease by CT or MRI scan (ABT-751 chemotherapy)	quality-of-life assessment	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.
Evaluable by I-MIBG scintigraphy (ABT-751)	quality-of-life assessment	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.
Measurable disease by CT or MRI scan (ABT-751 chemotherapy)	ABT-751	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.
Evaluable by I-MIBG scintigraphy (ABT-751)	ABT-751	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.

Primary Outcome Measures

Name	Time	Method
Median Time to Progression as Assessed by Response Evaluation Criteria in Solid Tumors	From time to enrollment to death due to any cause, assessed up to 5.1 years	Median time to progression observed on ABT-751, along with 95% confidence intervals.
1-year Progression-free Survival	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	PFS probabilities calculated using the Kaplan-Meier method, along 95% confidence intervals, separately for each stratum.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate	Duration of protocol therapy, up to 3 years	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.
Quality of Life Measured by PedsQL™ Generic Core Scale Version 4.0	At baseline	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.
Percentage of Participants With Grade 3 or Higher Toxicity	From enrollment until 30 days after the end of protocol therapy	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.
Pharmacokinetics of ABT-751: Tmax	After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose.	Values of the time to maximum observed concentration (Tmax) will be determined for the first dose.Descriptive statistics for these variables will be provided.
Pharmacokinetics of ABT-751: Cmax	After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose.	Values of the maximum observed concentration (Cmax) will be determined for the first dose.Descriptive statistics for these variables will be provided.
Pharmacokinetics of ABT-751: AUC	After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose.	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.

Trial Locations

Locations (12): Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States