Trial record 1 of 1 for:    ARST0531
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Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00354835
First received: July 19, 2006
Last updated: February 26, 2014
Last verified: February 2014

July 19, 2006
February 26, 2014
December 2006
January 2015   (final data collection date for primary outcome measure)
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.
Not Provided
Complete list of historical versions of study NCT00354835 on ClinicalTrials.gov Archive Site
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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: Up to 10 years ] [ Designated as safety issue: No ]
    The FFS distribution will be compared between groups of subjects defined by the presence of particular genetic classifiers using a log-rank test. A Cox proportional hazards regression model will be used to compare the FFS distributions between groups of subjects defined by the presence of particular genetic classifiers while adjusting for potential confounding factors and established prognostic factors.
  • Bladder function by disease-free patient/parent self report using a 14 point questionnaire [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
    If the observed rate of bladder dysfunction at a time-point is 15%, then a 95% confidence interval for the true rate would be about +/- 10%. "Year 6" questionnaires will also be requested from patients completing "year 3" questionnaires, provided they remain disease-free to year 6. The cross-sectional data will provide estimates of the rates of bladder dysfunction, whereas the year 6 follow-up questionnaires will allow an assessment of both the late development of bladder dysfunction and whether there is a return of improved bladder function over time.
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Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma
Randomized Study of Vincristine, Dactinomycin and Cyclophosphamide (VAC) Versus VAC Alternating With Vincristine and Irinotecan (VI) for Patients With Intermediate-Risk Rhabdomyosarcoma (RMS)

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.

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 classifiers.

VIII. To assess the frequency of bladder dysfunction in patients with bladder, prostate, and pelvic sites of RMS 3-6 years after study enrollment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms within 42 days of initial surgery or biopsy.

ARM I (VAC): Patients receive VAC chemotherapy comprising vincristine sulfate IV over 1 minute on day 1 of weeks 1-13, 16, 19-25, 28, 31-37, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40; and cyclophosphamide IV over 1 hour on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40.

ARM II (VAC/VI): Patients receive VAC chemotherapy alternating with VI chemotherapy comprising vincristine sulfate IV over 1 minute on day 1 of weeks 1-13,16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1,13, 22, 28, 34, and 40; cyclophosphamide IV over 1 hour on day 1 of weeks 1,10, 13, 22, 28, 34, and 40; and irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 7, 16, 19, 25, 31, and 37.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients* in both arms also undergo radiotherapy 5 days a week for 4-6 weeks beginning in week 4 (except patients with alveolar RMS rendered group I by amputation OR patients needing week 1 emergency radiotherapy for symptomatic spinal cord compression).

NOTE: *Individualized local control plan that deviates from protocol-mandated radiotherapy allowed for patients =< 24 months of age.

After completion of study treatment, patients are followed up every 2-4 months for 4 years and then annually for 5-10 years.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Malignant Mesenchymoma
  • Adult Rhabdomyosarcoma
  • Alveolar Childhood Rhabdomyosarcoma
  • Childhood Malignant Mesenchymoma
  • Embryonal Childhood Rhabdomyosarcoma
  • Embryonal-botryoid Childhood Rhabdomyosarcoma
  • Nonmetastatic Childhood Soft Tissue Sarcoma
  • Previously Untreated Childhood Rhabdomyosarcoma
  • Stage I Adult Soft Tissue Sarcoma
  • Stage II Adult Soft Tissue Sarcoma
  • Stage III Adult Soft Tissue Sarcoma
  • Drug: irinotecan hydrochloride
    Given IV
    Other Names:
    • Campto
    • Camptosar
    • CPT-11
    • irinotecan
    • U-101440E
  • Biological: dactinomycin
    Given IV
    Other Names:
    • ACT-D
    • actinomycin C1
    • AD
    • Cosmegen
    • DACT
  • Drug: cyclophosphamide
    Given IV
    Other Names:
    • CPM
    • CTX
    • Cytoxan
    • Endoxan
    • Endoxana
  • Drug: vincristine sulfate
    Given IV
    Other Names:
    • leurocristine sulfate
    • VCR
    • Vincasar PFS
  • Radiation: radiation therapy
    Undergo radiotherapy
    Other Names:
    • irradiation
    • radiotherapy
    • therapy, radiation
  • Other: laboratory biomarker analysis
    Correlative studies
  • Other: questionnaire administration
    Ancillary studies
  • Active Comparator: Arm I (chemotherapy, radiotherapy)
    Patients receive VAC chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-13, 16, 19-25, 28, 31-37, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 13, 16, 19, 22, 25, 28, 31, 34, 37,and 40; and cyclophosphamide IV over 1 hour on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40. Patients may also undergo radiotherapy 5 days a week for 4-6 weeks beginning in week 4.
    Interventions:
    • Biological: dactinomycin
    • Drug: cyclophosphamide
    • Drug: vincristine sulfate
    • Radiation: radiation therapy
    • Other: laboratory biomarker analysis
    • Other: questionnaire administration
  • Experimental: Arm II (chemotherapy, radiotherapy)
    Patients receive VAC chemotherapy alternating with VI chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 13, 22, 28, 34, and 40; cyclophosphamide IV over 1 hour on day 1 of weeks 1,10, 13, 22, 28, 34, and 40; and irinotecan hydrochloride IV over 1 hour on days 1-5 of weeks 4, 7, 16, 19, 25, 31, and 37. Patients may also undergo radiotherapy 5 days a week for 4-6 weeks beginning in week 4.
    Interventions:
    • Drug: irinotecan hydrochloride
    • Biological: dactinomycin
    • Drug: cyclophosphamide
    • Drug: vincristine sulfate
    • Radiation: radiation therapy
    • Other: laboratory biomarker analysis
    • Other: questionnaire administration
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
486
Not Provided
January 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients with newly diagnosed embryonal RMS, botryoid or spindle cell variants of embryonal RMS, ectomesenchymoma, or alveolar RMS are eligible for this study
  • Enrollment on COG-D9902 to confirm local histologic diagnosis with central pathology review is required for all patients
  • Patients may be enrolled on ARST0531 and start protocol treatment prior to receipt of central pathology review results
  • Patient must have Intermediate-risk RMS defined as:

    • Embryonal, botryoid, or spindle cell RMS, or ectomesenchymoma: stage 2 or 3 and group III OR
    • Alveolar RMS: stage 1-3 and group I-III
  • Staging ipsilateral retroperitoneal lymph node dissection (SIRLND) is required for all patients >= 10 years of age with paratesticular tumors and for patients < 10 years with clinically or radiographically involved lymph nodes (except when extensive lymph node involvement, defined as two or more lymph nodes > 2 cm in dimension, is identified by imaging studies)
  • Regional lymph node sampling or sentinel lymph node procedure is required for histologic evaluation in patients with extremity tumors
  • Clinically or radiographically enlarged nodes should be sampled for histologic evaluation
  • Detection of metastasis by optional FDG PET (not required for study enrollment); FDG PET may detect abnormalities suggestive of metastasis not identified by bone scan, computed tomography (CT), or bone marrow aspiration/biopsy; the prognostic significance of FDG PET-detected abnormalities is not clear; FDG PET-detected abnormalities MUST be confirmed to be metastases by an additional imaging modality (such as magnetic resonance imaging [MRI] or CT) OR pathologic confirmation; unless FDG PET abnormalities are confirmed by another imaging modality or biopsy, FDG PET abnormalities will NOT be considered evidence of metastasis
  • Patients must have a performance status of 0, 1, or 2; the Lansky performance score should be used for patients < 16 years and the Karnofsky performance score for patients >= 16 years
  • Patients who have received prior chemotherapy (excluding steroids) or radiation therapy, except for patients transferring from ARST0331 (low-risk study), are not eligible
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • 1 month to < 6 months: 0.4 mg/dL
    • 6 months to < 1 year: 0.5 mg/dL
    • 1 to < 2 years: 0.6 mg/dL
    • 2 to < 6 years: 0.8 mgt/dL
    • 6 to < 10 years: 1 mg/dL
    • 10 to < 13 years: 1.2 mg/dL
    • 13 to < 16 years: 1.5 mg/dL (males) or 1.4 mg/dL (females)
    • >= 16 years: 1.7 mg/dL (males) or 1.4 mg/dL (females)
  • Patients with urinary tract obstruction by tumor must meet the renal function criteria AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract
  • Total bilirubin =< 1.5 x upper limit of normal for age
  • Peripheral absolute neutrophil count (ANC) >= 750/uL
  • Platelet count >= 75,000/uL (transfusion independent)
  • No evidence of uncontrolled infection
  • Patients must be able to undergo radiation therapy, if necessary, as specified in the protocol
  • Female patients of childbearing potential must have a negative pregnancy test
  • Female patients who are breast feeding must agree to stop breast feeding
  • Sexually active patients of childbearing potential must be willing to use effective contraception during therapy and for at least 1 month after treatment is completed
  • 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
Both
up to 49 Years
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Canada,   New Zealand,   Puerto Rico,   Switzerland
 
NCT00354835
ARST0531, NCI-2009-00427, COG-ARST0531, CDR0000487560, ARST0531, ARST0531, U10CA098543
Yes
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Douglas Hawkins Children's Oncology Group
Children's Oncology Group
February 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP