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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00499616




Registration number
NCT00499616
Ethics application status
Date submitted
10/07/2007
Date registered
11/07/2007
Date last updated
21/06/2019

Titles & IDs
Public title
Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma
Scientific title
Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma
Secondary ID [1] 0 0
COG-ANBL0531
Secondary ID [2] 0 0
ANBL0531
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuroblastoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - carboplatin
Treatment: Drugs - cyclophosphamide
Treatment: Drugs - doxorubicin hydrochloride
Treatment: Drugs - etoposide
Treatment: Drugs - topotecan hydrochloride
Treatment: Drugs - Isotretinoin
Treatment: Surgery - Surgery
Treatment: Drugs - Filgrastim

Experimental: Group 2 (chemotherapy, surgery) - 2 courses of initial chemotherapy (6 wks) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Partial response (PR) to chemo go to observation. No PR: 2-6 additional courses of chemo (beginning course 3 - cyclophosphamide, etoposide, filgrastim, carboplatin, doxorubicin hydrochloride). No PR after additional chemotherapy proceed to retrieval chemo: cyclophosphamide and topotecan hydrochloride on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may also undergo surgery.

Experimental: Group 3 (chemotherapy, surgery) - 4 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, filgrastim. Patients with a PR after chemo proceed to observation. No PR receive 2-4 additional courses of chemotherapy (beginning with course 5) - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. No PR after additional chemo proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.

Experimental: Group 4 (chemotherapy, surgery, antineoplastic therapy) - 8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. Patients < 12 months of age with stg 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) to chemo proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide and topotecan hydrochloride. Some patients may also undergo surgery.

Experimental: Non-intermediate risk enrolled on intermediate risk trial - The no treatment group assignment patients may have received some treatment on ANBL0531 but they were not evaluable on this study due to being non-intermediate risk and hence did not receive a treatment assignment on ANBL0531.


Treatment: Drugs: carboplatin
Given IV

Treatment: Drugs: cyclophosphamide
Given IV

Treatment: Drugs: doxorubicin hydrochloride
Given IV

Treatment: Drugs: etoposide
Given orally

Treatment: Drugs: topotecan hydrochloride
Given IV

Treatment: Drugs: Isotretinoin
Given orally

Treatment: Surgery: Surgery
With the exception of patients with INSS 4S disease, patients undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.

Treatment: Drugs: Filgrastim
Administered subcutaneously or by IV beginning 24-48 hrs after the last dose of chemotherapy & continuing daily until the ANC is greater than or equal to 1500 following the myelosuppressive nadir . Supportive care given to stimulate neutrophil recovery following chemotherapy and to shorten the duration of chemotherapy-induced neutropenia. On ANBL0531 the use of filgrastim was required for patients less than 60 days of age and was optional for other patients.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival (OS) Rates - OS time is calculated from date of enrollment until death, or until last contact if the patient is alive.
Timepoint [1] 0 0
3 years
Primary outcome [2] 0 0
Definitive Determination of the Prognostic Ability of 1p and 11q - Addressed by a descriptive comparison of the EFS and OS rates for patients with 1p loss vs without 1p loss, and for those with unbalanced 11q vs normal 11q.
Timepoint [2] 0 0
At baseline
Primary outcome [3] 0 0
Comparison Between Reduce Intensity of Therapy for Patients With Stage 4 Neuroblastoma and Favorable Biological Features and Patients < 1 Year of Age With Stage 4 Neuroblastoma Treated on COG-A3961 - Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age.
Timepoint [3] 0 0
Up to 3 years
Primary outcome [4] 0 0
Comparison Between Reduce Intensity of Therapy for Patients With Unfavorable Histology Neuroblastoma and Patients Unfavorable Histology Neuroblastoma Treated on COG-A3961 - Addressed by the interim stopping rule and the comparison, by INSS stage, to the historical EFS rate of the analogous cohort of patients < 1 yrs of age
Timepoint [4] 0 0
Up to 3 years
Primary outcome [5] 0 0
Reduced Surgical Morbidity for Patients With Stage 4S Neuroblastoma - Descriptive analyses of the proportion of stage 4S infants that experience a surgical or post-operative event.
Timepoint [5] 0 0
Up to 3 years
Primary outcome [6] 0 0
Outcome of Patients With Stage 4S Neuroblastoma Who Are Unable to Undergo Biopsy for Biology-based Risk Assignment - Kaplan-Meier curves and lifetables of Event Free Survival (EFS) and Overall Survival (OS) rates will be generated to describe the outcome of the stage 4S infants unable to undergo biopsy.
Timepoint [6] 0 0
From baseline to up to 10 years
Primary outcome [7] 0 0
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Event Free Survival (EFS) - To test the predictive ability of the extent of surgical resection for EFS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.
Timepoint [7] 0 0
Up to 10 years
Primary outcome [8] 0 0
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Overall Survival (OS) Rates - To test the predictive ability of the extent of surgical resection for OS, log-rank tests will be performed comparing complete surgical resection vs. without complete surgical resection.
Timepoint [8] 0 0
Up to 10 years
Primary outcome [9] 0 0
Correlation Between Extent of Surgical Resection With the Maintenance of Local Control, Surgical Complication Rate - To test for the association of the extent of surgical resection (CR vs <CR) with surgical complications rate (complications of any kind vs no complications at all), a chi-square test will be performed.
Timepoint [9] 0 0
Up to 10 years
Secondary outcome [1] 0 0
Second-event-free Survival (E2FS) - E2FS (from time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.
Timepoint [1] 0 0
From the time of the first progressive, non-metastatic event until the subsequent occurrence of relapse, progressive disease, secondary malignancy, or death; up to 3 years
Secondary outcome [2] 0 0
Second-Overall Survival - OS (from the time of first event) will be calculated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.
Timepoint [2] 0 0
From the time of the first progressive, non-metastatic event; up to 3 years
Secondary outcome [3] 0 0
Biological Surrogate Markers - Multivariable analyses will be performed to identify variables of prognostic interest.
Timepoint [3] 0 0
At baseline and surgery
Secondary outcome [4] 0 0
Neurologic Symptoms - Percentage of patients with neurologic symptoms will be calculated. Includes patients with paraspinal or intraspinal tumors, including epidural tumors with or without spinal cord compression. Neurologic symptoms include back or extremities neurologic symptoms, motor deficit, abnormal sensation, abnormal bladder/bowel sphincteric function, chronic pain in back or extremities, scoliosis, kyphosis, or clinically relevant/functional abnormality in size or contour of leg or foot.
Timepoint [4] 0 0
At baseline
Secondary outcome [5] 0 0
Association Between Surgical Biopsy Technique With Adequacy of Tissue Acquisition for Biologic Studies, and With Complications Associated With the Biopsy Procedure - A chi-square test will be performed.
Timepoint [5] 0 0
During and after surgery
Secondary outcome [6] 0 0
Image Defined Risk Factor (IDRF) - Percentage of patients with presence of one or more IDRFs will be calculated. IDRFs describe anatomic features which may make surgical resection more difficult.
Timepoint [6] 0 0
At baseline

Eligibility
Key inclusion criteria
DISEASE CHARACTERISTICS:

- Histologically confirmed neuroblastoma, ganglioneuroblastoma, or
ganglioneuroma/maturing subtype

- Newly diagnosed disease

- Intermediate-risk disease

- Needle biopsies or involved bone marrow are not sufficient for INPC histologic
classification

- Meets 1 of the following criteria:

- Group 2

- International Neuroblastoma Staging System (INSS) stage 2A/2B; < 50%
resected or biopsy only; = 12 years of age; MYCN-not amplified (NA); any
histology and ploidy; normal 1p and 11q

- INSS stage 3; age < 365 days; MYCN-NA; favorable histology (FH);
hyperdiploid (DI) > 1; normal 1p and 11q

- INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; normal 1p and 11q

- INSS stage 4S; age < 365 days; MYCN-NA; FH; DI >1; normal 1p and 11q;
clinically symptomatic

- Group 3

- INSS stage 2A/2B; < 50% resected or biopsy only; = 12 years of age; MYCN-NA;
any histology and ploidy; 1p loss of heterozygosity (LOH) and/or unb11q LOH
(or data missing for either)

- INSS stage 3; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH
(or data missing for either)

- INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or unfavorable histology
(UH); normal 1p and 11q

- INSS stage 3; 365 days to 12 years of age; MYCN-NA; FH; 1p LOH and/or unb11q
LOH (or data missing for either)

- INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; normal 1p and 11q

- INSS stage 4S; age < 365 days; MYCN-NA; either UH and any ploidy or FH and
DI = 1; normal 1p and 11q

- INSS stage 4S; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH
(or data missing for either); clinically symptomatic

- Group 4

- INSS stage 3; age < 365 days; MYCN-NA; DI = 1 and/or UH; 1p LOH and/or
unb11q LOH (or data missing for either)

- INSS stage 3; age 365 to < 547 days; MYCN-NA; UH; any ploidy; any 1p and 11q

- INSS stage 4, age < 365 days; MYCN-NA; DI = 1 and/or UH; any 1p and 11q

- INSS stage 4; age < 365 days; MYCN-NA; FH; DI > 1; 1p LOH and/or unb11q LOH
(or data missing for either)

- INSS stage 4; age 365 to < 547 days; MYCN-NA; FH; DI > 1; any 1p and 11q

- INSS stage 4S; age < 365 days; MYCN-NA; UH and any ploidy or FH and DI = 1;
1p LOH and/or unb11q LOH (or data missing for either)

- INSS stage 4S; age < 365 days; unknown or incomplete biologic features

8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin
hydrochloride, etoposide, filgrastim.

Patients < 12 months of age with stg 3, 4, or 4S disease who achieve a very good PR (VGPR)
to chemo (with the exception of resolution of skin or liver metastases in stage 4S
patients) proceed to observation. Patients 12-18 months of age with stg 3 or 4 who achieve
VGPR proceed to isotretinoin therapy. No VGPR proceed to retrieval chemo - cyclophosphamide
and topotecan hydrochloride. Some patients may also undergo surgery.

- Must already be enrolled on protocol COG-ANBL00B1

- Simultaneous enrollment on COG-ANBL00B1 and this study allowed for clinical
situations in which emergent treatment may be indicated including, but not
limited to, the following criteria:

- Epidural or intraspinal tumors with existing or impending neurologic
impairment

- Periorbital or calvarial-based lesions with existing or impending cranial
nerve impairment

- Anatomic or mechanical compromise of critical organ function by tumor (e.g.,
abdominal compartment syndrome, urinary obstruction)

- Asymptomatic but, in the opinion of the treating physician, it is in the
patient's best interest to begin chemotherapy immediately due to impending
risk of neurologic impairment or organ dysfunction

- If patient receives study chemotherapy prior to undergoing diagnostic biopsy, the
biopsy must be performed within 96 hours of beginning study therapy

- The only exception to this requirement is for patients with stage 4S disease who
are considered too ill to undergo a diagnostic procedure will be waived the
requirement for diagnostic tissue submission but will still need to be enrolled
on COG-ANBL00B1

- For patients with stage 4S disease who are very ill and in whom an open
biopsy to obtain tissue for diagnosis and biologic studies is considered
medically contraindicated, every effort should be made to obtain some tumor
tissue by either fine-needle aspiration of a metastatic site of disease
and/or sampling of involved bone marrow, so that this tumor sample can be
submitted for MYCN determination

- Patients who require emergent therapy, either prior to the diagnostic biopsy or before
biology features are available, can be enrolled simultaneously on COG-ANBL00B1 and
COG-ANBL0531 to receive emergent protocol therapy

- In emergent circumstances, COG-ANBL0531 protocol therapy may be initiated prior
to enrollment on study as long as the patient has neuroblastoma by clinical
diagnosis, all other COG-ANBL0531 eligibility criteria are met, and the
COG-ANBL0531 Initial Therapy consent has been signed prior to starting protocol
therapy; in this circumstance ANBL0531 enrollment must occur within 4 working
days of starting protocol therapy

- Clinical situations in which emergent enrollment and treatment may be indicated
include, but are not limited to, the following circumstances:

- Epidural or intraspinal tumors with existing or impending neurologic
impairment

- Periorbital or calvarial-based lesions with existing or impending cranial
nerve impairment

- Anatomic or mechanical compromise of critical organ function by tumor (e.g.,
abdominal compartment syndrome, urinary obstruction)

- Evolving hepatomegaly in infants less than 2 months of age

PATIENT CHARACTERISTICS:

- See Disease Characteristics

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No other prior chemotherapy or radiotherapy with the exception of dexamethasone

- No participation in another COG study with tumor therapeutic intent
Minimum age
No limit
Maximum age
12 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA
Recruitment hospital [1] 0 0
Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 0 0
Royal Children's Hospital - Brisbane
Recruitment hospital [3] 0 0
Women's and Children's Hospital - North Adelaide
Recruitment hospital [4] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment postcode(s) [2] 0 0
4029 - Brisbane
Recruitment postcode(s) [3] 0 0
5006 - North Adelaide
Recruitment postcode(s) [4] 0 0
6001 - Perth
Recruitment outside Australia
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United States of America
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Alabama
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Arizona
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Connecticut
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Delaware
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District of Columbia
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North Carolina
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Oregon
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Wisconsin
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Alberta
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British Columbia
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Manitoba
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Newfoundland and Labrador
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Nova Scotia
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Saskatchewan
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Netherlands
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Nijmegen
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New Zealand
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Auckland
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New Zealand
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Christchurch
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Puerto Rico
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Santurce

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
RATIONALE: Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, and
doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either
by killing the cells or by stopping them from dividing. Isotretinoin may help neuroblastoma
cells become more like normal cells, and grow and spread more slowly. Giving combination
chemotherapy before surgery may make the tumor smaller and make it more likely that the tumor
can be surgically removed. It is not yet known what is the minimal amount of chemotherapy
needed to achieve sufficient tumor shrinkage to control intermediate risk neuroblastoma and
prevent tumor recurrence or metastases.

PURPOSE: This phase III trial is designed to reduce therapy for patients with favorable
biology intermediate risk neuroblastoma by decreasing the number of chemotherapy cycles
administered and by allowing for up to 50% residual tumor volume for patients with localized
disease.
Trial website
https://clinicaltrials.gov/show/NCT00499616
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clare Twist, MD
Address 0 0
Lucile Packard Children's Hospital at Stanford University Medical Center
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications