Official Title: “Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma”

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 with or without isotretinoin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known which treatment regimen is more effective in treating young patients with neuroblastoma.

PURPOSE: This phase III trial is comparing different regimens of combination chemotherapy and surgery with or without isotretinoin to see how well they work in treating young patients with neuroblastoma.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: September 2012

OBJECTIVES:

Primary - 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. - Maintain an overall 3-year OS rate of ≥ 90% for patients within each group. - 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. - 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. - 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. - Reduce surgical morbidity for patients with stage 4S neuroblastoma by allowing for biopsy only, rather than complete surgical resection, of the primary tumor. - Systematically study the outcome of patients with stage 4S neuroblastoma who are unable to undergo biopsy for biology-based risk assignment.

Secondary - Determine the results of a standard retrieval approach for patients with residual disease after 8 courses of initial therapy. - Determine the results of a standard retrieval approach for patients with progressive, nonmetastatic disease. - Identify additional biological surrogate markers for disease relapse and/or metastatic progression. - Describe the neurologic outcome of patients with paraspinal neuroblastoma primary tumors.

OUTLINE: This is a multicenter study. Patients are assigned to 1 of 3 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 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 courses 1-2 of initial chemotherapy. Patients with a partial response (PR) proceed to observation. Patients without a PR continue to receive 2-6 additional courses of chemotherapy (beginning with course 3) until PR is achieved. Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy. - Group 2: Patients receive courses 1-4 of initial chemotherapy. Patients with a PR proceed to observation. Patients without a PR continue to receive 2-4 additional courses of chemotherapy (beginning with course 3) until PR is achieved. Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy. - Group 3: Patients receive courses 1-8 of initial chemotherapy. Patients under 12 months of age with stage 4 disease who achieve a very good (VG) PR 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. - Observation: Patients do not receive any more treatment but are followed to make sure the tumor does not get worse or come back. - 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. - 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 study. - 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 study. - Surgery: With the exception of patients with INSS 4S disease, patients will 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 patients, after course 4 for group 2 patients, and after course 4 or 8 for group 3 patients).

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

Intervention(s) in this Clinical Trial

• Drug: carboplatin
  • Given IV
• Drug: cyclophosphamide
  • Given IV
• Drug: doxorubicin hydrochloride
  • Given IV
• Drug: etoposide
  • Given IV
• Drug: isotretinoin
  • Oral, twice daily
• Drug: topotecan hydrochloride
  • Given IV
• Procedure: conventional surgery
  • With the exception of patients with INSS 4S disease, patients will undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Group 1
  • Patients receive courses 1-2 of initial chemotherapy. Patients with a partial response (PR) proceed to observation. Patients without a PR continue to receive 2-6 additional courses of chemotherapy (beginning with course 3) until PR is achieved. Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy comprising cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment with retrieval chemotherapy repeats every 21 days for up to 6 courses. Some patients may then receive isotretinoin therapy. Some patients may also undergo surgery.
• Experimental: Group 2
  • Patients receive courses 1-4 of initial chemotherapy. Patients with a PR proceed to observation. Patients without a PR continue to receive 2-4 additional courses of chemotherapy (beginning with course 3) until PR is achieved. Patients who do not achieve a PR after additional chemotherapy proceed to retrieval chemotherapy. Patients receive Retrieval chemotherapy as in group 1. Some patients may then receive isotretinoin therapy. Some patients may also undergo surgery.
• Experimental: Group 3
  • Patients receive courses 1-8 of initial chemotherapy. Patients under 12 months of age with stage 4 disease who achieve a very good (VG) PR 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. Patients receive Retrieval chemotherapy as in group 1. Some patients may then receive isotretinoin therapy. Some patients may also undergo surgery.

Primary Measures

• Overall survival
  • Safety Issue?: No
• Event-free survival
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed neuroblastoma or ganglioneuroblastoma
• Newly diagnosed disease
• Intermediate-risk disease
• Meets 1 of the following criteria:
• Group 1
• International Neuroblastoma Staging System (INSS) stage 2A/2B < 50% resected or biopsy only, age 0 to 12 years, MYCN-not amplified (NA), any histology, any 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, age ≥ 365 days to 12 years, MYCN-NA, FH, normal 1p and 11q
• INSS stage 4S, age < 365 days, MYCN-NA, FH, DI > 1, normal 1p and 11q, but clinically symptomatic
• Group 2
• INSS stage 2A/2B < 50% resected or biopsy only, age 0 to ≤ 12 years, MYCN-NA, any histology and ploidy, 1p loss of heterozygosity (LOH) and/or unb11q LOH (or data missing for either)
• INSS stage 3, < 365 days old, MYCN-NA, FH, DI > 1, 1p LOH and/or unb11q LOH (or data missing for either)
• inss Stage 3, < 365 days old, MYCN-na, either DI = 1 and/or unfavorable histology (UH), normal 1p and 11q
• INSS stage 3, ≥ 365 days to 12 years old, MYCN-NA, FH, 1p LOH and/or unb11q
• LOH (or data missing for either)
• INSS stage 4, < 365 days old, MYCN-NA, FH, DI > 1, normal 1p and 11q
• INSS stage 4S, < 365 days old, MYCN-NA, either UH and any ploidy, or FH and DI = 1, normal 1p and 11q
• INSS stage 4S, < 365 days old, MYCN-NA, FH, DI > 1, 1p LOH and/or unb11q LOH (or data missing for either) and clinically symptomatic
• INSS stage 4S, < 365 days old, unknown MYCN, histology, and/or ploidy
• Group 3
• INSS stage 3, < 365 days old, MYCN-NA, either DI = 1 and/or UH, 1p LOH and/or unb11q LOH (or data missing for either)
• INSS stage 3, 365 to < 547 days old, MYCN-NA, UH, any ploidy, any 1p and 11q
• INSS stage 4, < 365 days old, 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, 365 to < 547 days old, MYCN-NA, FH, DI > 1, any 1p and 11q
• INSS stage 4S, < 365 days old, MYCN-NA, either UH and any ploidy or FH and DI = 1 and 1p LOH and/or unb11q LOH (or data missing for either)
• Must be enrolled on protocol COG-ANBL00B1

PATIENT CHARACTERISTICS:

• See Disease Characteristics

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy with the exception of the following:
• Patients with intradural tumor extension and emergent paresis can be given chemotherapy according to COG-ANBL0531 prior to biopsy provided the biopsy is subsequently performed within 96 hours
• Patients without symptoms may be enrolled and treated immediately with chemotherapy at the discretion of the investigator if it is considered to be in the best interest of the patient (e.g., a patient with intradural tumor extension who is at risk of developing neurologic deficits)
• Prior dexamethasone allowed at the discretion of the investigator

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 12 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Children's Oncology Group

Overall Clinical Trial Officials and Contacts

Clare Twist, MD Study Chair Lucile Packard Children's Hospital at Stanford University Medical Center  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00499616

Study ID Number: CDR0000554708

ClinicalTrials.gov Identifier: NCT00499616

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database