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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Neuroblastoma; Disseminated Neuroblastoma
• Intervention / Treatment: Procedure: quality-of-life assessment; Drug: ABT-751

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.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Measurable disease by CT or MRI scan (ABT-751 chemotherapy); 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.	Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment; Drug: ABT-751; Given orally; Other Names: E7010
Experimental: Evaluable by I-MIBG scintigraphy (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.	Procedure: quality-of-life assessment; Ancillary studies; Other Names: quality of life assessment; Drug: ABT-751; Given orally; Other Names: E7010

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.

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Elizabeth Fox, MD, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): March 30, 2015

Study Registration Dates

• First Submitted: February 15, 2007
• First Submitted That Met QC Criteria: February 15, 2007
• First Posted (Estimate): February 19, 2007

Study Record Updates

• Last Update Posted (Actual): July 17, 2019
• Last Update Submitted That Met QC Criteria: July 2, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma
• Other Study ID Numbers: ANBL0621; U10CA098543 (U.S. NIH Grant/Contract); NCI-2009-00402 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); NCI-07-C-0074; CDR0000529858 (Other Identifier: Clinical Trials.gov); NCI-P6554; COG-ANBL0621 (Other Identifier: Children's Oncology Group)