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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00499616
First received: July 10, 2007
Last updated: July 18, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Neuroblastoma
Drug: carboplatin
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: etoposide
Drug: topotecan hydrochloride
Drug: Isotretinoin
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Overall survival (OS) rates [ Time Frame: From the date of enrollment until death, or until last contact if the patients is alive, assessed up to 3 years ] [ Designated as safety issue: No ]
    A log-rank test comparison of the overall cohort to the analogous cohort on P9641/A3961 will be used. If these are not statistically significantly different, then it is reasonable to assume that a 3-year OS rate consistent with previous studies (> 95%) has been maintained.


Secondary Outcome Measures:
  • Event-free survival (EFS) rate [ Time Frame: From date of enrollment until the first occurrence of relapse, progressive disease, secondary malignancy, or death or until last contact if none of these events occur, assessed up to 3 years ] [ Designated as safety issue: No ]
    A log-rank test comparison of the overall cohort to the analogous cohort on P9641/A3961 will be used.

  • Second-event-free survival (E2FS) of intermediate risk patients [ Time Frame: From the time of the first progressive, non-metastatic event until the subsequent occurrence of relapse, progressive disease, secondary malignancy, or death ] [ Designated as safety issue: No ]
    Kaplan-Meier curves and life tables of E2FS and OS (from the time of first event) will be generated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.

  • Overall survival time [ Time Frame: From the time of the first progressive, non-metastatic event ] [ Designated as safety issue: No ]
    Kaplan-Meier curves and life tables of E2FS and OS (from the time of first event) will be generated to describe the outcome for patients who have a first progressive, non-metastatic event during Observation and then receive protocol retrieval therapy.

  • Definitive determination of the prognostic ability of 1p and 11q [ Time Frame: At baseline ] [ Designated as safety issue: No ]
    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. Definitive determination of the prognostic ability of 1p and 11q will be based on a pooled analysis of all patients in ANBL00B1

  • 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 [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    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.

  • Comparison between reduce intensity of therapy for patients with unfavorable histology neuroblastoma and patients unfavorable histology neuroblastoma treated on COG-A3961 [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    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

  • Reduced surgical morbidity for patients with stage 4S neuroblastoma [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Kaplan-Meier curves and lifetables of EFS and OS rates will be generated to describe the outcome of the stage 4S infants unable to undergo biopsy. Descriptive analyses will be performed of the symptoms of stage 4S infants.

  • Outcome of patients with stage 4S neuroblastoma who are unable to undergo biopsy for biology-based risk assignment [ Time Frame: From baseline to up to 10 years ] [ Designated as safety issue: No ]
    Kaplan-Meier curves and lifetables of EFS and OS rates will be generated to describe the outcome of the stage 4S infants unable to undergo biopsy. Descriptive analyses will be performed of the symptoms of stage 4S infants.

  • Correlation between extent of surgical resection with the maintenance of local control, EFS and/or OS rates, and surgical complication rate [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    A chi-square test will be performed. To test the predictive ability of the extent of surgical resection for EFS and OS, log rank tests will be performed for various cut-offs: (completer response (CR) vs <CR), (CR, very good partial response (VGPR) vs <VGPR), and (CR/VGPR/PR vs <PR). Descriptive Kaplan-Meier curves will be generated of CR vs VGPR vs PR vs MR vs PD. 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.

  • Biological surrogate markers [ Time Frame: At baseline and surgery ] [ Designated as safety issue: No ]
    Multivariable analyses will be performed to identify variables of prognostic interest.

  • Proportion of patients with neurologic symptoms overall and type of symptom [ Time Frame: On treatment and post-treatment ] [ Designated as safety issue: No ]
    Descriptive analysis will be used.

  • Association between surgical biopsy technique with adequacy of tissue acquisition for biologic studies, and with complications associated with the biopsy procedure [ Time Frame: During and after surgery ] [ Designated as safety issue: No ]
    A chi-square test will be performed.

  • Prognostic ability of the INRG image-defined risk factor (IDRF) system [ Time Frame: At baseline, during and after completion of study treatment ] [ Designated as safety issue: No ]
    A Kaplan - Meier curves of presence vs absence of one or more IDRFs will be generated, and a log rank test performed to compare them, for EFS and OS. The IDRF data will be used to determine the International Neuroblastoma Risk Group Stage (INRGSS) and Kaplan-Meier curves by INRGSS will be generated. To compare the institutional assessment of IDRFs (presence vs absence) with the central review assessment of IDRFs, a chi-square test will be performed. ROC curves will be generated, and the sensitivity and specificity of the institutional assessment will be calculated


Enrollment: 464
Study Start Date: October 2007
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1 (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.
Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • NSC #241240
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC #123127
Drug: etoposide
Given orally
Other Names:
  • VePesid
  • VP-16
  • NSC #141540
Drug: topotecan hydrochloride
Given IV
Other Names:
  • SKF-104864
  • Hycamtin
  • NSC #60969
Experimental: Group 2 (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.
Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • NSC #241240
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC #123127
Drug: etoposide
Given orally
Other Names:
  • VePesid
  • VP-16
  • NSC #141540
Drug: topotecan hydrochloride
Given IV
Other Names:
  • SKF-104864
  • Hycamtin
  • NSC #60969
Experimental: Group 3 (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.
Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • NSC #241240
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC #123127
Drug: etoposide
Given orally
Other Names:
  • VePesid
  • VP-16
  • NSC #141540
Drug: topotecan hydrochloride
Given IV
Other Names:
  • SKF-104864
  • Hycamtin
  • NSC #60969
Drug: Isotretinoin
Given orally
Other Names:
  • 13-cis-retinoic acid
  • RO-43
  • 780
  • Accutane
  • Amnesteem
  • Claravis
  • Sotret
  • NSC#329481
Experimental: Group 4 (chemotherapy, surgery, antineoplastic therapy)
8 courses of initial chemo - carboplatin, cyclophosphamide, doxorubicin hydrochloride, etoposide, filgrastim. If a VGPR cannot be achieved following 8 courses of first-line chemo +/- surgery, or progressive, non-metastatic disease develops within 3 years of study enrollment, then patients receive retrieval chemo - cyclophosphamide and topotecan hydrochloride until VGPR can be achieved. Some patients may also undergo surgery and then proceed to isotretinoin therapy.
Drug: carboplatin
Given IV
Other Names:
  • Paraplatin
  • NSC #241240
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC #26271
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC #123127
Drug: etoposide
Given orally
Other Names:
  • VePesid
  • VP-16
  • NSC #141540
Drug: topotecan hydrochloride
Given IV
Other Names:
  • SKF-104864
  • Hycamtin
  • NSC #60969
Drug: Isotretinoin
Given orally
Other Names:
  • 13-cis-retinoic acid
  • RO-43
  • 780
  • Accutane
  • Amnesteem
  • Claravis
  • Sotret
  • NSC#329481

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 12 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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); 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 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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00499616

  Show 189 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Clare Twist, MD Lucile Packard Children's Hospital at Stanford University Medical Center
Study Chair: Mary Lou Schmidt, MD University of Illinois at Chicago
  More Information

Additional Information:
No publications provided

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00499616     History of Changes
Other Study ID Numbers: ANBL0531, COG-ANBL0531, CDR0000554708, NCI-2009-00400
Study First Received: July 10, 2007
Last Updated: July 18, 2014
Health Authority: United States: Federal Government

Keywords provided by Children's Oncology Group:
regional neuroblastoma
disseminated neuroblastoma
stage 4S neuroblastoma
localized unresectable neuroblastoma
localized resectable neuroblastoma

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Liposomal doxorubicin
Etoposide phosphate
Doxorubicin
Etoposide
Tretinoin
Carboplatin
Topotecan
Isotretinoin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on August 26, 2014