Clinical Trials /

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

NCT02176967

Description:

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.

Related Conditions:
  • Ganglioneuroblastoma
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma
  • Official Title: Utilizing Response- and Biology-Based Risk Factors to Guide Therapy in Patients With Non-high-risk Neuroblastoma

Clinical Trial IDs

  • ORG STUDY ID: ANBL1232
  • SECONDARY ID: NCI-2014-00677
  • SECONDARY ID: ANBL1232
  • SECONDARY ID: ANBL1232
  • SECONDARY ID: U10CA098543
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02176967

Conditions

  • Ganglioneuroblastoma
  • Localized Resectable Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Recurrent Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4 Neuroblastoma

Interventions

DrugSynonymsArms
CarboplatinGroup B (clinical observation, first-line chemotherapy)
EtoposideLastetGroup B (clinical observation, first-line chemotherapy)
CyclophosphamideGroup B (clinical observation, first-line chemotherapy)
Doxorubicin HydrochlorideGroup B (clinical observation, first-line chemotherapy)

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To eliminate therapy as the initial approach for infants < 12 months of age with small
      International Neuroblastoma Risk Group (INRG) stage L1 neuroblastoma while maintaining an
      overall survival (OS) of 99%.

      II. To eliminate therapy as the initial approach for non-high-risk patients < 18 months of
      age with localized neuroblastoma and favorable biology (histologic and genomic features)
      while maintaining an OS of 99%.

      III. To achieve a 3-year OS of > 81% for infants < 18 months of age with INRG stage Ms
      neuroblastoma using objective criteria for early initiation of a response-based treatment
      algorithm.

      SECONDARY OBJECTIVES:

      I. To describe the time to intervention or tumor progression, type of intervention and site
      of progression for patients with localized neuroblastoma who experience progression after an
      initial period of observation.

      II. To characterize the pharmacokinetic profile of the chemotherapeutic agents carboplatin
      and etoposide in patients with stage Ms disease.

      III. To define the genomic profile of tumors from patients with non-high-risk neuroblastoma
      both at initial biopsy and at the time of subsequent biopsy or surgical resection.

      IV. To describe the histology of tumor specimens obtained at the time of subsequent biopsy or
      surgical resection.

      V. To determine the salvage rate (OS) of patients with tumor relapse or disease progression.

      VI. To determine the procedural complication rate (initial biopsy, resection [intraoperative
      and postoperative], subsequent biopsy) and correlate with the degree of surgical resection.

      VII. To determine the rate of reduction in image defined risk factors (IDRF) in L2 tumors
      following observation or chemotherapy.

      OUTLINE: Patients are assigned to 1 of 3 treatment groups.

      GROUP A: Patients undergo clinical observation for 96 weeks in the absence disease
      progression.

      GROUP B: 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 intravenously (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
      partial response (PR) or better is achieved, patients undergo clinical observation for 3
      years.

      GROUP C: 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.

      After completion of study treatment, patients are followed up annually for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Group A (clinical observation)ExperimentalPatients undergo clinical observation for 96 weeks in the absence of disease progression.
    Group B (clinical observation, first-line chemotherapy)ExperimentalPatients 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.
    • Carboplatin
    • Etoposide
    • Cyclophosphamide
    • Doxorubicin Hydrochloride
    Group C (clinical observation, first-line chemotherapy)ExperimentalPatients 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.
    • Carboplatin
    • Etoposide
    • Cyclophosphamide
    • Doxorubicin Hydrochloride

    Eligibility 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
          
    Maximum Eligible Age:17 Months
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure: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
    Safety Issue:
    Description: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.

    Secondary Outcome Measures

    Measure:Time to intervention or tumor progression
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be assessed by a descriptive analysis for the cohort of patients with localized tumors who progress after an initial period of observation.
    Measure:Type of intervention required
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be assessed by a descriptive analysis for the cohort of patients with localized tumors who progress after an initial period of observation.
    Measure:Site of progression
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Will be assessed by a descriptive analysis for the cohort of patients with localized tumors who progress after an initial period of observation.
    Measure: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
    Safety Issue:
    Description: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.
    Measure:Genomic profile of tumors
    Time Frame:Up to time of biopsy or surgical resection
    Safety Issue:
    Description: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.
    Measure:Histology of tumor specimens
    Time Frame:Up to time of biopsy or surgical resection
    Safety Issue:
    Description:Will be assessed by a descriptive analysis of the histology of tumor specimens obtained at the time of subsequent biopsy or surgical resection.
    Measure: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
    Safety Issue:
    Description:Will be assessed by calculating the overall survival for the cohort of patients with tumor relapse or disease progression.
    Measure:Procedural complication rate
    Time Frame:Up to 60 days after surgery
    Safety Issue:
    Description: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).
    Measure:Rate of reduction in IDRF in L2 tumors
    Time Frame:Up to 5 years
    Safety Issue:
    Description: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.

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Children's Oncology Group

    Last Updated

    September 27, 2017