Disseminated Neuroblastoma, Recurrent Neuroblastoma
Conditions
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.
Interventions
DRUGABT-751
Given orally
PROCEDUREquality-of-life assessment
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Disease 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. | 45 |
| Measurable Disease by CT or MRI Scan (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. | 47 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 23 | 34 |
| Overall Study | Ineligible | 1 | 0 |
| Overall Study | Lack of Efficacy | 9 | 7 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Measurable Disease by CT or MRI Scan (ABT-751) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 42 Participants | 45 Participants | 87 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Continuous | 8.46 years | 7.55 years | 8.00 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 41 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 9 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 6 Participants | 13 Participants |
| Race (NIH/OMB) White | 30 Participants | 30 Participants | 60 Participants |
| Region of Enrollment Canada | 0 participants | 10 participants | 10 participants |
| Region of Enrollment Jamaica | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 45 participants | 36 participants | 81 participants |
| Sex: Female, Male Female | 14 Participants | 21 Participants | 35 Participants |
| Sex: Female, Male Male | 31 Participants | 26 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 44 | 24 / 47 |
| serious Total, serious adverse events | 3 / 44 | 4 / 47 |
Outcome results
Primary
1-year Progression-free Survival
PFS probabilities calculated using the Kaplan-Meier method, along 95% confidence intervals, separately for each stratum.
Time frame: 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
Population: The protocol-specified definition of evaluability was applied. This was not an intention-to-treat analysis because patients who did not receive study drug were excluded (inevaluable).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | 1-year Progression-free Survival | 19 percent probability |
| Measurable Disease by CT or MRI Scan (ABT-751) | 1-year Progression-free Survival | 7 percent probability |
Primary
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.
Time frame: From time to enrollment to death due to any cause, assessed up to 5.1 years
Population: The protocol-specified definition of evaluability was applied. This was not an intention-to-treat analysis because patients who did not receive study drug were excluded (inevaluable).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Median Time to Progression as Assessed by Response Evaluation Criteria in Solid Tumors | 45 days |
| Measurable Disease by CT or MRI Scan (ABT-751) | Median Time to Progression as Assessed by Response Evaluation Criteria in Solid Tumors | 42 days |
Secondary
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.
Time frame: Duration of protocol therapy, up to 3 years
Population: Patients who met study eligibility criteria and received at least one dose of oral ABT-751 were evaluable for the response analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Objective Response Rate | 12 Percentage of patients |
| Measurable Disease by CT or MRI Scan (ABT-751) | Objective Response Rate | 2 Percentage of patients |
Secondary
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.
Time frame: From enrollment until 30 days after the end of protocol therapy
Population: All eligible patients who received at least 1 dose of ABT-751 were evaluable for toxicity and included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Percentage of Participants With Grade 3 or Higher Toxicity | 75.0 Percentage of patients |
| Measurable Disease by CT or MRI Scan (ABT-751) | Percentage of Participants With Grade 3 or Higher Toxicity | 72.3 Percentage of patients |
Secondary
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.
Time frame: After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose.
Population: All eligible patients from Group 1 (Disease Evaluable by I-MIBG Scintigraphy (ABT-751)) and Group 2 (Measurable Disease by CT or MRI Scan (ABT-751)) who received the first dose of ABT-751 and participated in the pharmacokinetic studies were included in the analysis and are presented as a single Group, as the interest was in both groups combined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Pharmacokinetics of ABT-751: AUC | 77.5 mg·hours/ml |
Secondary
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.
Time frame: After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose.
Population: All eligible patients from Group 1 (Disease Evaluable by I-MIBG Scintigraphy (ABT-751)) and Group 2 (Measurable Disease by CT or MRI Scan (ABT-751)) who received the first dose of ABT-751 and participated in the pharmacokinetic studies were included in the analysis and are presented as a single Group, as the interest was in both groups combined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Pharmacokinetics of ABT-751: Cmax | 15.3 mg/ml |
Secondary
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.
Time frame: After the first dose of ABT-751, at 0.5, 1, 2, 3, 5, 8, 10-12, and 24 hours post-dose.
Population: All eligible patients from Group 1 (Disease Evaluable by I-MIBG Scintigraphy (ABT-751)) and Group 2 (Measurable Disease by CT or MRI Scan (ABT-751)) who received the first dose of ABT-751 and participated in the pharmacokinetic studies were included in the analysis and are presented as a single Group, as the interest was in both groups combined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Pharmacokinetics of ABT-751: Tmax | 1 hours |
Secondary
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.
Time frame: At baseline
Population: Eligible patients with a QOL evaluation at baseline were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Disease Evaluable by I-MIBG Scintigraphy (ABT-751) | Quality of Life Measured by PedsQL™ Generic Core Scale Version 4.0 | 80 Scores on a scale |
| Measurable Disease by CT or MRI Scan (ABT-751) | Quality of Life Measured by PedsQL™ Generic Core Scale Version 4.0 | 68 Scores on a scale |