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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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 Summary:

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 (i
Sponsor: Children's Oncology Group

Current Primary Outcome:

• 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.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• 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.

Original Secondary Outcome:

• 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.

Dates:
Date Received: June 26, 2014
Date Started: July 2014
Date Completion:
Last Updated: September 23, 2016
Last Verified: September 2016