Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma

Basic Trial Information

Objectives

Primary

1. Reduce therapy for patients with intermediate-risk neuroblastoma while maintaining a 3-year overall survival (OS) rate of ≥ 95% by using a response-based duration of therapy algorithm.
2. Maintain an overall 3-year OS rate of ≥ 90% for patients within each group.
3. Utilize loss of heterozygosity, prospectively, at 1p36 and 11q23 to refine risk-stratification and treatment assignment, allowing patients whose tumors lack these chromosomal abnormalities to receive a reduction in therapy, and compare the outcome with patients treated on COG-A3961.
4. Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 4 neuroblastoma and favorable biological features and maintain a 3-year event-free survival (EFS) rate consistent with that for patients < 1 year of age with stage 4 neuroblastoma treated on COG-A3961.
5. Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 3 MYCN-nonamplified but unfavorable histology neuroblastoma and maintain a 3-year EFS rate consistent with that for patients < 1 year of age with stage 3, MYCN-nonamplified, unfavorable histology neuroblastoma treated on COG-A3961.
6. Reduce surgical morbidity for patients with stage 4S neuroblastoma by allowing for biopsy only, rather than complete surgical resection, of the primary tumor.
7. Systematically study the outcome of patients with stage 4S neuroblastoma who are unable to undergo biopsy for biology-based risk assignment.
8. Determine if the extent of surgical resection correlates with the maintenance of local control, EFS and/or OS rates, and surgical complication rate.

Secondary

1. Determine the results of a standard retrieval approach for patients with residual disease after 8 courses of initial therapy.
2. Determine the results of a standard retrieval approach for patients with progressive, nonmetastatic disease.
3. Identify additional biological surrogate markers for disease relapse and/or metastatic progression.
4. Describe the neurologic outcome of patients with paraspinal neuroblastoma primary tumors.
5. Correlate surgical biopsy technique with adequacy of tissue acquisition for biologic studies and with complications associated with the biopsy procedure.
6. Prospectively validate the prognostic ability of the International Neuroblastoma Risk Group image-defined risk factor system, and compare the institutional assessment of image-defined risk factors with that of central review.

Entry 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 1
    • 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); hyperdyploid (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 2
    • 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 3
    • 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
  • Group 4
    • INSS stage 3, age < 365 days, MYCN-NA, either 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 3
    • INSS stage 4, age < 365 days, MYCN-NA either 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, either UH and any ploidy or FH and DI = 1 and 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 4S, age < 365 days, unknown MYCN, histology, and/or ploidy

• 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

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

Patient Characteristics:

• See Disease Characteristics

Expected Enrollment

Outcomes

Overall survival
Event-free survival

Outline

This is a multicenter study. Patients are assigned to 1 of 4 treatment groups by risk-stratification based on age, stage (INSS stage 2, 3, 4, or 4S), MYCN status (amplified vs not amplified), histopathologic classification, and tumor DNA index.

• Initial chemotherapy: Courses of initial chemotherapy are administered every 21 days according to group assignment as outlined below:
  • Course 1: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 2: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.
  • Course 3: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 4: Patients receive carboplatin IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 5: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 6: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.
  • Course 7: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 8: Patients receive cyclophosphamide IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1.
    • Group 1: Patients receive 2 courses of initial chemotherapy. Patients with a partial response (PR) (50-90% reduction in volume) to chemotherapy proceed to observation. Patients without a PR receive 2-6 additional courses of chemotherapy (beginning with course 3). Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy.

    • Group 2: Patients receive 4 courses of initial chemotherapy. Patients with a PR after chemotherapy proceed to observation. Patients without a PR receive 2-4 additional courses of chemotherapy (beginning with course 5). Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy.

    • Group 3: Patients receive 8 courses of initial chemotherapy. Patients under 12 months of age with stage 3, 4, or 4S (not including liver metastases) disease who achieve a very good PR (VGPR) (> 90% reduction in the volume of the primary tumor and resolution of metastatic disease) to chemotherapy proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease who achieve a VGPR proceed to isotretinoin therapy. Patients who do not achieve a VGPR proceed to retrieval chemotherapy.

    • Group 4: Patients receive 8 courses of initial chemotherapy. If a VGPR cannot be achieved following 8 courses of first-line chemotherapy +/- surgery, then retrieval chemotherapy with cyclophosphamide/topotecan for 2-6 courses is administered until a VGPR can be achieved with a combination of chemotherapy and surgery.

• Retrieval chemotherapy*: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 6 courses.
  • Groups 1 and 2: Patients with a PR after 2-6 courses of retrieval chemotherapy proceed to observation. Patients without a PR after 2-6 courses of retrieval chemotherapy are removed from protocol therapy.

  • Group 3: Patients under 12 months of age with stage 4 disease with a VGPR after retrieval chemotherapy proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease who achieve a VGPR after retrieval chemotherapy proceed to isotretinoin therapy. Patients who do not achieve a VGPR after retrieval chemotherapy are removed from protocol therapy.

  • Group 4: Group 4 patients who fail to achieve a VGPR or who develop progressive, non-metastatic disease within 3 years of study enrollment proceed to isotretinoin therapy. Isotretinoin is also administered to the following Group 4 patients:
    • Age 365 to < 547 days at diagnosis, INSS stage 3, MYCN-NA, unfavorable histology, any ploidy
    • Age 365 to < 547 days at diagnosis, INSS stage 4, MYCN-NA, favorable histology, DI > 1

   [Note: *Patients who have previously received cyclophosphamide and topotecan to achieve first PR/VGPR are not eligible for this Retrieval Therapy.]

• 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. Reassessment for definitive surgery (for patients who undergo biopsy only or partial resection at diagnosis) is made at the completion of scheduled chemotherapy (after course 2 for group 1, after course 4 for group 2, and after course 8 for groups 3 and 4).

• Isotretinoin therapy: Beginning 3-4 weeks after completion of chemotherapy or 2 weeks post-operatively (for patients who undergo surgical resection), patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for up to 10 years.

Data from patients with low-risk disease who are observed following surgical resection only and are not enrolled on ANBL0531, are collected for study objectives.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Clare Twist, MD, Protocol chair		Ph: 650-723-5535
Mary Lou Schmidt, MD, Protocol co-chair		Ph: 312-996-6143 Email: mls3@uic.edu

Related Information

PDQ® clinical trial COG-A3961
PDQ® clinical trial COG-ANBL00B1

Registry Information
Official Title		Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma
Trial Start Date		2007-10-08
Trial Completion Date		2012-09-06 (estimated)
Registered in ClinicalTrials.gov		NCT00499616
Date Submitted to PDQ		2007-06-04
Information Last Verified		2011-07-01
NCI Grant/Contract Number		CA98543

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