Clinical Trial: Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Randomized Study of Vincristine, Dactinomycin and Cyclophosphamide (VAC) Versus VAC Alternating With Vincristine and Irinotecan (VI) for Patients With Intermediate-Risk Rhabdomyosarcoma (RMS)

Brief Summary: This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work when given together with radiation therapy in treating patients with newly diagnosed rhabdomyosarcoma. Drugs used in chemotherapy, such as vincristine sulfate, dactinomycin, cyclophosphamide, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with radiation therapy may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective when given together with radiation therapy in treating patients with rhabdomyosarcoma.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To compare the early response rates, failure-free survival (FFS), and survival of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with surgery, radiotherapy, and vincristine (vincristine sulfate), dactinomycin and cyclophosphamide (VAC) or VAC alternating with vincristine, irinotecan (irinotecan hydrochloride) (VI).

SECONDARY OBJECTIVES:

I. To compare FFS, local control, and survival of patients with intermediate-risk RMS treated with VAC and early (week 4) radiotherapy vs delayed (week 10) radiotherapy, using data from Intergroup Rhabdomyosarcoma Study (IRS)-IV for historic comparison.

II. To compare the acute and late effects of VAC to VAC alternating with VI, including the toxicity associated with concurrent VI and radiotherapy.

III. To compare the acute and late effects of VAC as delivered on this study to D9803 VAC.

IV. To correlate change in fludeoxyglucose F-18 positron emission tomography (FDG-PET) maximum standard uptake value (SUVmax) from week 1 to week 4 and 15 with FFS.

V. For VI treated patients, to correlate patient UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotype with VI toxicity. VI. To correlate cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6), cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9), and glutathione S-transferase alpha 1 (GSTA1) genotypes with VAC toxicity.

VII. To prospectively evaluate and validate gene expression values with the intent to define the best diagnostic predictors and more powerful prognostic classif
Sponsor: Children's Oncology Group

Current Primary Outcome:

  • Failure-free survival (FFS) [ Time Frame: Time from study enrollment to disease progression, disease relapse, occurrence of a second malignant neoplasm, or death from any cause, assessed up to 7 years ]
    A 1-sided alpha level was chosen as primary interest is in detecting an improvement in FFS under the more intensive therapy. The FFS distributions will be estimated using the Kaplan-Meier method and will be compared between the therapy groups using a log-rank test.
  • Response rate (RR) (complete or partial response) [ Time Frame: At 13 weeks ]
    RR between the treatment groups will be compared using a Chi-square test and an upper 95% confidence interval for the difference (VAC/VI-VAC) in proportions will be estimated using a Normal approximation to the binomial distribution. Patients failing or lost to follow-up before 13 weeks will be coded as non-responders for the comparison of response rates. Hypothesis testing will be performed using a one-sided 0.05 alpha level
  • Overall survival (OAS) [ Time Frame: Up to 10 years ]
    The OAS distributions will be estimated using the Kaplan-Meier method and will be compared between the therapy groups using a log-rank test. The repeated confidence interval method proposed by Bernardo and Ibrahim for cure rate models will be used to monitor for early indications of benefit as well as early indications that the study should be stopped in favor of the null hypothesis of no difference in FFS between VAC alternating with VI and VAC.


Original Primary Outcome:

Current Secondary Outcome:

  • Long-term FFS of patients with intermediate-risk RMS treated with VAC and early (Week 4) radiotherapy compared to delayed (Week 10) radiotherapy, using IRSIV for historic comparison [ Time Frame: Up to 10 years ]
    An analysis plan based on the method of Woolson will be used to monitor for differences in the FFS distribution under the proposed VAC arm relative to the IRS-IV experience for these patients. Outcome data will be formally reviewed, using the Lan-DeMets alpha-spending function implementation of sequential boundaries, after approximately 25%, 50%, 75% and 100% of the expected information has been observed. An alpha spending function of alpha*t will be used, as it is of interest to detect early indications of increased harm relative to historical experience.
  • Local control of patients with intermediate-risk RMS treated with VAC and early (Week 4) radiotherapy compared to delayed (Week 10) radiotherapy, using IRSIV for historic comparison [ Time Frame: From week 4 to week 6 ]
    An analysis plan based on the method of Woolson will be used to monitor for differences in the FFS distribution under the proposed VAC arm relative to the IRS-IV experience for these patients.
  • Overall survival of patients with intermediate-risk RMS treated with VAC and early (Week 4) radiotherapy compared to delayed (Week 10) radiotherapy, using IRSIV for historic comparison [ Time Frame: At 2 years ]
    A similar method of analysis used for the FFS distribution will be used to compare the observed overall survival experience to the historical experience. Cumulative incidence estimators will be used to describe the local failure rate over time.
  • Incidence of toxicity associated with concurrent VI and radiotherapy [ Time Frame: At 12 weeks ]
    The severe toxicity proportion will be estimated for each therapy group during the first 4 courses of chemotherapy and confidence intervals for the difference in proportions will be estimated. Formal interim monitoring for increased risk will be performed after each quarter of the patients who completed the end of the first 4 cycles of chemotherapy (week 12 following concurrent chemotherapy and radiotherapy) using the Lan-DeMets alpha-spending function implementation of sequential boundaries.
  • Acute and late effects of VAC as delivered on this study to D9803 VAC [ Time Frame: Up to 40 weeks ]
    The toxicity rates will be estimated for each phase and course of treatment, and will be compared to the fixed rates under D9803 using one-sided lower confidence intervals for a single proportion without adjustment for multiple comparisons.
  • Change in FDG PET maximum standard uptake value (SUVmax) [ Time Frame: Baseline to week 15 ]
    The FFS distribution will be compared between groups of subjects defined by a change of at least 40% in SUV between weeks 1 and 4 and between weeks 1 and 15 using a long-rank test. A Cox proportional hazards regression model will be used to compare the FFS distributions between groups of subjects defined by the change in SUV (< 40% versus >= 40%) while adjusting for potential confounding factors, including therapy.
  • Incidence of toxicity related to VI treatment in patients with UGT1A1 genotype [ Time Frame: Up to 8 weeks ]
    Proportion of patients experiencing Grade 3-4 diarrhea and the proportion of patients experiencing Grade 3-4 neutropenia between Weeks 4-9 for patients receiving Regimen B (VAC/VI) will be calculated. A Chi-square test will be used.
  • Incidence of toxicity related to VAC treatment in patients with CYP2B6 genotypes [ Time Frame: Up to 3 weeks ]
    The association between mutation status and the occurrence of toxicities during VAC therapy will be investigated using a Chi-square test. The duration of neutropenia and thrombocytopenia will be compared between groups using a 2-sample t-test. Regression modeling will be used to adjust for confounding patient characteristics between genotype groups.
  • Incidence of toxicity related to VAC treatment in patients with CYP2C9 genotypes [ Time Frame: Up to 3 weeks ]
    The association between mutation status and the occurrence of toxicities during VAC therapy will be investigated using a Chi-square test. The duration of neutropenia and thrombocytopenia will be compared between groups using a 2-sample t-test. Regression modeling will be used to adjust for confounding patient characteristics between genotype groups.
  • Incidence of toxicity related to VAC treatment in patients with GSTA1 genotypes [ Time Frame: Up to 3 weeks ]
    The association between mutation status and the occurrence of toxicities during VAC therapy will be investigated using a Chi-square test. The duration of neutropenia and thrombocytopenia will be compared between groups using a 2-sample t-test. Regression modeling will be used to adjust for confounding patient characteristics between genotype groups.
  • Gene expression analysis [ Time Frame: U

    Original Secondary Outcome:

    Information By: Children's Oncology Group

    Dates:
    Date Received: July 19, 2006
    Date Started: December 2006
    Date Completion:
    Last Updated: February 1, 2016
    Last Verified: February 2016