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

• ClinicalTrials.gov Identifier: NCT02176967
• Recruitment Status: Recruiting
• First Posted: June 27, 2014
• Last Update Posted: October 21, 2022
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: June 26, 2014
• First Posted Date: June 27, 2014
• Last Update Posted Date: October 21, 2022
• Actual Study Start Date: July 28, 2014
• Estimated Primary Completion Date: September 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 2, 2019)

Overall survival (OS) (Strata 1-4) [ Time Frame: 3 years ]

OS time is calculated from date of enrollment until death, or until last contact if the patient is alive.

Original Primary Outcome Measures (submitted: June 26, 2014)

• 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 ]
  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 ]
  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.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: June 26, 2014)

• Time to intervention or tumor progression [ Time Frame: Up to 5 years ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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.
• Bone abnormalities on bilateral tibial radiographs [ Time Frame: Up to 5 years ]
  Will be assessed by a descriptive analysis of bone abnormalities identified on plain films of bilateral tibias obtained before and after isotretinoin therapy for Group D patients.
• PK and pharmacogenomic parameters of isotretinoin [ Time Frame: Day 14 of course 1 ]
  Will be assessed by determining if there is a relationship between the peak serum concentration level and EFS, which will be tested with a Cox proportional hazards model. To determine if there is a relationship between the peak serum concentration level and toxicity rates, Kendall's Tau statistic will be calculated. Variability in peak serum concentration between body surface area and weight based dosing regimen will be assessed by descriptive analysis.

Current Other Pre-specified Outcome Measures (submitted: August 2, 2019)

• Time to intervention or tumor progression [ Time Frame: Up to 3 years ]
  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 3 years ]
  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 3 years ]
  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 ]
  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 ]
  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 ]
  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 (overall survival [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 3 years ]
  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 ]
  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 Image Defined Risk Factors (IDRF) in L2 tumors [ Time Frame: Up to 3 years ]
  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.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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.

EXPLORATORY 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 up to 10 years post-enrollment.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Ganglioneuroblastoma
• Localized Resectable Neuroblastoma
• Localized Unresectable Neuroblastoma
• Neuroblastoma

Intervention

• Drug: Carboplatin
  Given IV
  Other Names:

  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
• Other: Clinical Observation
  Undergo clinical observation
  Other Name: observation
• Drug: Cyclophosphamide
  Given IV
  Other Names:

  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
• Drug: Doxorubicin Hydrochloride
  Given IV
  Other Names:

  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin HCl
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
• Drug: Etoposide
  Given IV
  Other Names:

  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16
  • VP 16-213
  • VP-16
  • VP-16-213
  • VP16
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Pharmacological Study
  Optional correlative studies

Study Arms

• Experimental: Group A (clinical observation)
  Patients undergo clinical observation for 96 weeks in the absence of disease progression.
  Interventions:

  • Other: Clinical Observation
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
• 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.
  Interventions:

  • Drug: Carboplatin
  • Other: Clinical Observation
  • Drug: Cyclophosphamide
  • Drug: Doxorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
• 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.
  Interventions:

  • Drug: Carboplatin
  • Other: Clinical Observation
  • Drug: Cyclophosphamide
  • Drug: Doxorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 23, 2015): 621
• Original Estimated Enrollment (submitted: June 26, 2014): 803
• Estimated Study Completion Date: September 30, 2026
• Estimated Primary Completion Date: September 30, 2026 (Final data collection date for primary outcome measure)

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 or APEC14B1 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.]); horner syndrome is not considered neurologic compromise
  • 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 or APEC14B1
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 18 Months (Child)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Australia, Canada, New Zealand, Puerto Rico, Saudi Arabia, United States

Administrative Information

• NCT Number: NCT02176967
• Other Study ID Numbers: ANBL1232; NCI-2014-00677 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); s15-00462; ANBL1232 ( Other Identifier: Children's Oncology Group ); ANBL1232 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract ); U10CA098543 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Holly J Meany; Children's Oncology Group

• PRS Account: Children's Oncology Group
• Verification Date: August 2022