Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2016 by Children's Oncology Group
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT02176967
First received: June 26, 2014
Last updated: March 18, 2016
Last verified: March 2016
  Purpose
This phase III trial studies how well response and biology-based risk factor-guided therapy works in treating younger patients with non-high risk neuroblastoma. Sometimes a tumor may not need treatment until it progresses. In this case, observation may be sufficient. Measuring biomarkers in tumor cells may help plan when effective treatment is necessary and what the best treatment is. Response and biology-based risk factor-guided therapy may be effective in treating patients with non-high risk neuroblastoma and may help to avoid some of the risks and side effects related to standard treatment.

Condition Intervention Phase
Ganglioneuroblastoma
Localized Resectable Neuroblastoma
Localized Unresectable Neuroblastoma
Recurrent Neuroblastoma
Regional Neuroblastoma
Stage 4 Neuroblastoma
Other: Clinical Observation
Drug: Carboplatin
Drug: Etoposide
Drug: Cyclophosphamide
Drug: Doxorubicin Hydrochloride
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
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: Utilizing Response- and Biology-Based Risk Factors to Guide Therapy in Patients With Non-high-risk Neuroblastoma

Resource links provided by NLM:


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

Primary Outcome Measures:
  • OS (Strata 1-4) [ Time Frame: From the date of enrollment until death or until last contact if the patient is alive, assessed up to 3 years ] [ Designated as safety issue: No ]
    Will be addressed by a one-sample, one-sided log-rank test comparison of the overall survival of patients in each individual stratum to the benchmark 3-year OS rate of 99%. If the log-rank test does not detect a statistically significant reduction from 99% and if the EFS interim monitoring rule is not triggered, then it may be assumed that a 3-year OS rate consistent with 99% has been maintained within each stratum.

  • EFS (Stratum 5) [ Time Frame: From the date of enrollment until the first relapse, progressive disease, secondary malignancy, or death or until last contact if none of these occur, assessed up to 3 years ] [ Designated as safety issue: No ]
    If the 3-year EFS rate observed for patients in Stratum 5 is statistically significantly greater than the constant benchmark 3-year EFS rate of 70% observed for comparable Group D patients in the historical study A3961 using a one-sample, one-sided log-rank test and the EFS interim monitoring rule is not triggered, then it may be assumed that the target 3-year EFS has been achieved and the augmented regimen in this study is superior to that on the previous study.


Secondary Outcome Measures:
  • Time to intervention or tumor progression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by a descriptive analysis for the cohort of patients with localized tumors who progress after an initial period of observation.

  • Type of intervention required [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by a descriptive analysis for the cohort of patients with localized tumors who progress after an initial period of observation.

  • Site of progression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by a descriptive analysis for the cohort of patients with localized tumors who progress after an initial period of observation.

  • Pharmacokinetic (PK) profile of carboplatin and etoposide in patients with stage Ms disease, including peak concentration, area under the curve, clearance, volume of distribution, half-life, and mean residence time [ Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours on days 1 and 2 of either course 1 or 7 ] [ Designated as safety issue: No ]
    The coefficient of variation will be calculated to quantify the degree of inter-patient and intra-patient variability of etoposide and carboplatin PK. The relationship between patient characteristics will be assessed graphically in an exploratory fashion and with regression models and if appropriate, Spearman's rank correlation coefficient will be used. Correlations between PK parameters and the symptom score and hepatic and renal dysfunction will be explored. Logistic regression models adjusting for patient level covariates will be explored.

  • Genomic profile of tumors [ Time Frame: Up to time of biopsy or surgical resection ] [ Designated as safety issue: No ]
    Will be assessed by determining the presence or absence of each segmental aberration (segmental loss at 1p, 3p, 4p, or 11q or segmental gain at 1p, 2p, or 17q), both at initial biopsy and at the time of subsequent biopsy or surgical resection, and correlating with patient characteristics using a chi-squared test and with outcome using a log-rank test. In cases with specimens from diagnosis and at the time of subsequent biopsy/resection, the profiles will be compared focusing on changes in the copy number pattern.

  • Histology of tumor specimens [ Time Frame: Up to time of biopsy or surgical resection ] [ Designated as safety issue: No ]
    Will be assessed by a descriptive analysis of the histology of tumor specimens obtained at the time of subsequent biopsy or surgical resection.

  • Salvage rate (OS) of patients with tumor relapse or disease progression [ Time Frame: From the date of enrollment until death or until last contact if the patient is alive, assessed up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by calculating the overall survival for the cohort of patients with tumor relapse or disease progression.

  • Procedural complication rate [ Time Frame: Up to 60 days after surgery ] [ Designated as safety issue: No ]
    Will be assessed by determining the complication rate for each type of procedure (initial biopsy and resection [intraoperative and postoperative]) and correlating the occurrence of surgical complications with the degree of surgical resection using a Wilcoxon rank-sum test (to account for the ordering of the surgical resection categories).

  • Rate of reduction in IDRF in L2 tumors [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be assessed by computing the proportion of patients with L2 tumors for which each particular IDRF and any IDRF is present at diagnosis and then absent after observation or chemotherapy. In addition, McNemar's test for paired observations will be applied to determine whether there is a difference in the proportion of each IDRF and any IDRF present before and after observation or chemotherapy.


Estimated Enrollment: 621
Study Start Date: July 2014
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A (clinical observation)
Patients undergo clinical observation for 96 weeks in the absence of disease progression.
Other: Clinical Observation
Undergo clinical observation
Other Name: observation
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Optional correlative studies
Other Name: pharmacological studies
Experimental: Group B (clinical observation, first-line chemotherapy)
Patients undergo clinical observation for 3 years in the absence of disease progression. Upon disease progression, patients undergo surgery or receive first-line chemotherapy comprising carboplatin IV over 1 hour on day 1 (courses 1, 2, 4, 6, and 7), etoposide IV over 1 hour on days 1-3 (courses 1, 3, 4, 5, and 7), cyclophosphamide IV over 1 hour on day 1 (courses 2, 3, 5, 6, and 8), and doxorubicin hydrochloride IV over 15 minutes on day 1 (courses 2, 4, 6 and 8). Treatment with chemotherapy repeats every 21 days for 2-8 courses in the absence of disease progression or unacceptable toxicity. Once a PR or better is achieved, patients undergo clinical observation for 3 years.
Other: Clinical Observation
Undergo clinical observation
Other Name: observation
Drug: Carboplatin
Given IV
Drug: Etoposide
Given IV
Other Name: Lastet
Drug: Cyclophosphamide
Given IV
Drug: Doxorubicin Hydrochloride
Given IV
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Optional correlative studies
Other Name: pharmacological studies
Experimental: Group C (clinical observation, first-line chemotherapy)
Patients at high risk for deterioration and a poor outcome immediately receive first-line chemotherapy as in Group B. All other patients undergo clinical observation for 3 years in the absence of disease progression. Upon disease progression, patients receive first-line chemotherapy as in Group B. Once a PR or better is achieved, patients undergo clinical observation for 3 years.
Other: Clinical Observation
Undergo clinical observation
Other Name: observation
Drug: Carboplatin
Given IV
Drug: Etoposide
Given IV
Other Name: Lastet
Drug: Cyclophosphamide
Given IV
Drug: Doxorubicin Hydrochloride
Given IV
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Optional correlative studies
Other Name: pharmacological studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 17 Months   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be:

    • < 12 months (< 365 days) of age at diagnosis with INRG stage L1; or
    • < 18 months (< 547 days) of age at diagnosis with INRG stage L2 or stage Ms neuroblastoma/ganglioneuroblastoma
  • Enrollment on ANBL00B1 is required for all newly diagnosed patients
  • Patients must have newly diagnosed v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) non-amplified neuroblastoma (International Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or MYCN non-amplified ganglioneuroblastoma verified by histology
  • Patients must meet the specified criteria for one of the treatment groups defined below; genomic features include MYCN gene amplification, segmental chromosome aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number gain at 1q, 2p, or 17q) and deoxyribonucleic acid (DNA) index

    • "Favorable" genomic features are defined by one or more whole-chromosome gains or hyperdiploid tumor (DNA index > 1) in the absence of segmental chromosome aberrations as defined above
    • "Unfavorable" genomic features are defined by the presence of any segmental chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number gain at 1q, 2p, or 17q) or diploid tumor (DNA index = 1); this includes copy neutral loss of heterozygosity (LOH)
    • Only patients with MYCN non-amplified tumors are eligible for this study
  • Group A: patients < 12 months (< 365 days) of age with newly diagnosed INRG stage L1 neuroblastoma/ganglioneuroblastoma who meet the following criteria:

    • Greatest tumor diameter < 5 cm of adrenal or non-adrenal origin
    • Patients with non-adrenal primaries are eligible, but must have positive uptake on metaiodobenzylguanidine (MIBG) scan or elevated catecholamine metabolites (urine or serum) to support the diagnosis of neuroblastoma
    • No prior tumor resection or biopsy
  • Group A will be further split into two subsets, which are mutually exclusive, for statistical purposes

    • Group A1:

      • > 6 months and < 12 months of age with an adrenal primary tumor < 5 cm in greatest diameter OR
      • Patients less than 6 months of age with an adrenal primary tumor > 3.1 and < 5 cm in greatest diameter OR
      • < 12 months of age with a non-adrenal primary site < 5 cm in greatest diameter
    • Group A2: =< 6 months of age with an adrenal primary site and tumor =< 3.1 cm in greatest diameter.
  • Group B: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage L2 neuroblastoma/ganglioneuroblastoma who meet the following criteria:

    • No life threatening symptoms or no impending neurologic or other organ function compromise (e.g. 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 [abdominal compartment syndrome, urinary obstruction, etc.])
    • No prior tumor resection, tumor biopsy ONLY
    • Only patients with both favorable histology and favorable genomic features will remain on study as part of Group B; the institution will be notified of histologic and genomic results within 3 weeks of specimen submission on ANBL00B1
  • Group C: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage Ms neuroblastoma/ganglioneuroblastoma
  • No prior radiotherapy or chemotherapy, with the exception of dexamethasone, which is allowed
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

  • Patients with MYCN amplified tumors are not eligible
  • Group B and C patients who do not enroll on ANBL1232 within 4 weeks of definitive diagnostic procedure
  • Group A and C patients, not required to undergo tumor biopsy, who do not enroll on ANBL1232 within 4 weeks of confirmatory imaging study
  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: NCT02176967

  Show 107 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Holly Meany, MD Children's Oncology Group
  More Information

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT02176967     History of Changes
Other Study ID Numbers: ANBL1232  NCI-2014-00677  ANBL1232  ANBL1232  U10CA098543  U10CA180886 
Study First Received: June 26, 2014
Last Updated: March 18, 2016
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Neuroblastoma
Ganglioneuroblastoma
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
Carboplatin
Doxorubicin
Etoposide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 28, 2016