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High-Dose Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Metastatic Rhabdomyosarcoma or Ectomesenchymoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00354744
Recruitment Status : Completed
First Posted : July 20, 2006
Results First Posted : January 10, 2014
Last Update Posted : January 29, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE July 19, 2006
First Posted Date  ICMJE July 20, 2006
Results First Submitted Date  ICMJE September 3, 2013
Results First Posted Date  ICMJE January 10, 2014
Last Update Posted Date January 29, 2020
Study Start Date  ICMJE July 2006
Actual Primary Completion Date January 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 15, 2020)
  • Number of Patients With Complete or Partial Response Assessed by RECIST Criteria [ Time Frame: Protocol week 6 evaluation ]
    Volumetric measurements of the primary tumor using an elliptical model (0.5 x the product of the 3 largest perpendicular diameters) to assess response to neoadjuvant therapy. The RECIST (Response Evaluation Criteria in Solid Tumors) from the NCI will be used for assessment of the size of measurable metastases, including nodal metastases. Primary Tumor Measurement: Technical guidelines for cross-sectional imaging computed tomography (CT) slice thickness should be 5mm or less and the diameter of the "measurable" mass should be at least twice the reconstructed slice thickness. Smaller masses are considered detectable, but will be counted as "non-measurable." Complete Response (CR): Complete disappearance of the tumor confirmed at >4 weeks. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment. Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest volume obtained since the beginning.
  • Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy [ Time Frame: From enrollment to up to 2 years ]
    Adverse events are reported for patients receiving concurrent irinotecan hydrochloride and radiotherapy.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2019)
Percentage of Patients Event Free at 4 Years Following Study Entry [ Time Frame: 4 years ]
Event-free survival: Time to recurrence, second malignancy, or death as a first event, estimated from a Kaplan Meier curve
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE High-Dose Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Metastatic Rhabdomyosarcoma or Ectomesenchymoma
Official Title  ICMJE Intensive Multi-Agent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide (IE) and Vincristine/Doxorubicin/Cyclophosphamide (VDC) for Patients With High-Risk Rhabdomyosarcoma
Brief Summary

RATIONALE: Drugs used in chemotherapy, such as vincristine, irinotecan, ifosfamide, etoposide, doxorubicin, cyclophosphamide, and dactinomycin, 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 high-dose combination chemotherapy together with radiation therapy may kill more tumor cells.

PURPOSE: This phase III trial is studying how well giving high-dose combination chemotherapy together with radiation therapy works in treating patients with newly diagnosed metastatic rhabdomyosarcoma or ectomesenchymoma.

Detailed Description

OBJECTIVES:

Primary

  • Improve the early disease control interval for patients with newly diagnosed, high-risk, metastatic rhabdomyosarcoma or ectomesenchymoma using intensive, interval-compression therapy (comprising vincristine, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin) that permits maximal early exposure to known effective agents.
  • Determine the feasibility and assess immediate- and short-term side effects of concurrent irinotecan hydrochloride and radiotherapy in these patients.

Secondary

  • Expand the available data for response to irinotecan hydrochloride and vincristine in previously untreated patients with high-risk rhabdomyosarcoma.
  • Evaluate, prospectively, and validate gene expression values with the intent to define the best diagnostic predictors and more powerful prognostic classifiers.

OUTLINE: This is a prospective, nonrandomized, multicenter study. Patients are stratified according to prognostic factors predictive of outcome (e.g. histology, bone/bone marrow involvement, and number of metastatic sites).

Patients receive high-dose chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51; irinotecan hydrochloride IV over 1 hour on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; and ifosfamide IV over 1 hour and etoposide IV over 30-60 minutes on days 1-5 of weeks 9, 13, 17, 26, and 30. Patients also receive doxorubicin hydrochloride IV continuously over 24 hours on days 1 and 2 of weeks 7*, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; and dactinomycin IV over 1-5 minutes on day 1 of weeks 35, 38, 41, and 44 in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim (G-CSF) subcutaneously in weeks 7-9, 11-13, 15-17, 22, 26, 28-30, 32, 33, 35, 38, and 41-44 beginning 24-36 hours after the last chemotherapy dose and continuing until blood counts recover.

NOTE: *Patients undergoing early radiotherapy for intracranial extension do not receive doxorubicin in week 7.

Beginning at week 20 (or week 1 for patients with parameningeal tumors with intracranial extension [or spinal cord compression] requiring emergency radiotherapy), patients also undergo radiotherapy once a day, 5 days a week, for approximately 5½ weeks. Some patients may also undergo second-look surgery.

After completion of study treatment, patients are followed periodically for ≥ 10 years.

PROJECTED ACCRUAL: A total of 75 patients will be accrued for this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sarcoma
Intervention  ICMJE
  • Biological: dactinomycin

    Age based dosage: ≥ 1 year 0.045 mg/kg IV x 1(maximum dose 2.5 mg), < 1 year 0.025 mg/kg.

    Day 1 of Weeks 35, 38, 41 and 44.

    Given IV

    Other Names:
    • Actinomycin-D
    • Cosmegen
    • NSC #3053
  • Drug: cyclophosphamide

    Age based dosage: ≥ 3 years 1200 mg/m2, <3 years 40 mg/kg.

    Day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41 and 44.

    Given IV

    Other Names:
    • Cytoxan
    • NSC #26271
  • Drug: doxorubicin hydrochloride

    Age based dosage: ≥ 1 year: 37.5mg/m²/day, < 1 year: treat with 50% doses calculated on a m2 basis. Total dose 75 mg/m².

    Days 1 and 2 of weeks 7, 11, 15, 28 and 32.

    Given IV

    Other Names:
    • Adriamycin
    • NSC #123127
  • Drug: etoposide

    Age based dosage: ≥ 1 year: 100 mg/m²/day, < 1 year: treat with 50% doses calculated on a m2 basis.

    Days 1-5 of weeks 9, 13, 17, 26 and 30.

    Given IV

    Other Names:
    • VePesid
    • Etopophos
    • VP-16
    • NSC #141540
  • Drug: ifosfamide

    Age based dosage: ≥ 1 year: 1800 mg/m²/day, < 1 year: treat with 50% doses calculated on a m2 basis.

    Days 1-5 of weeks 9, 13, 17, 26 and 30.

    Given IV

    Other Names:
    • Isophosphamide
    • Iphosphamide
    • Z4942
    • Ifex
    • NSC #109724
  • Drug: irinotecan hydrochloride

    Dosage 50 mg/m2-max dose 100 mg/day.

    Days 1-5 of weeks 1, 4, 20, 23, 47 and 50.

    Given IV

    Other Names:
    • CPT-11
    • Camptothecin-11
    • 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin
    • Camptosar
    • NSC #616348
  • Drug: vincristine sulfate

    Age based dosage: ≥ 3 years 1.5 mg/m2 (max dose 2 mg), ≥ 1 year and < 3 years 0.05 mg/kg (max dose 2 mg), < 1 year 0.025 mg/kg.

    Days 1-5 of weeks 1, 2, 3, 4, 5, 7, 8, 11, 12, 15, 16, 20, 21, 22, 23, 24, 28, 29, 32, 33, 35, 38, 41, 42, 43, 44, 47, 48, 50, and 51.

    Given IV

    Other Names:
    • Oncovin
    • VCR
    • LCR
    • NSC #67574
  • Procedure: conventional surgery
    Resection of the primary tumor with a surrounding "envelope" of normal tissue
  • Radiation: radiation therapy
    Radiotherapy beginning at Week 20 to the primary tumor and to the metastatic sites excepting those with parameningeal tumors with intracranial extension (direct extension into the brain) and those requiring emergency radiotherapy
  • Biological: filgrastim

    5 micrograms/kg/day (max 300 micrograms) beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/μL whichever comes last.

    Given subcutaneously.

    Other Names:
    • Granulocyte Colony-Stimulating Factor
    • r-metHuG-CSF
    • G-CSF
    • Neupogen
    • NSC #614629
Study Arms  ICMJE Experimental: High Risk Rhabdomyosarcoma
Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients.
Interventions:
  • Biological: dactinomycin
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide
  • Drug: ifosfamide
  • Drug: irinotecan hydrochloride
  • Drug: vincristine sulfate
  • Procedure: conventional surgery
  • Radiation: radiation therapy
  • Biological: filgrastim
Publications * Weigel B, Lyden E, Anderson JR, et al.: Early results from Children's Oncology Group (COG) ARST0431: intensive multidrug therapy for patients with metastatic rhabdomyosarcoma (RMS). [Abstract] J Clin Oncol 28 (Suppl 15): A-9503, 2010.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 27, 2013)
109
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE June 30, 2019
Actual Primary Completion Date January 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • Histologically confirmed high-risk rhabdomyosarcoma or ectomesenchymoma

    • Prior enrollment on COG-D9902 to confirm local histological diagnosis required

      • Tissue must be submitted for pathologic review within 2 days of patient registration on COG-D9902
    • Newly diagnosed disease
    • Metastatic disease (stage IV, clinical group IV)
  • Has undergone initial surgical procedure (including biopsy) that provided the definitive diagnosis within the past 42 days
  • Parameningeal and paraspinal tumors allowed

    • Patients with parameningeal (without intracranial extension [ICE]) and paraspinal tumors should begin study chemotherapy at week 1 and radiotherapy at week 20
  • Patients with evidence of ICE, as defined by contrast MRI showing that primary tumor touches, displaces, invades, distorts, or otherwise causes a signal abnormality of the dura in contiguity to the primary site in brain or spinal cord, are eligible

    • ICE is presumed to exist if the cerebrospinal fluid cytopathology is positive for tumor at diagnosis
  • Patients requiring emergency radiotherapy are eligible

    • Patients requiring emergency radiotherapy (for intracranial extension or spinal cord impingement) should begin study chemotherapy at week 1 (irinotecan hydrochloride and vincristine) concurrently with radiation therapy

PATIENT CHARACTERISTICS:

  • ECOG or Zubrod performance status (PS) 0-2 (Lansky PS 50-100% for patients < 10 years of age and Karnofsky PS 50-100% for patients ≥ 10 years of age)
  • Absolute neutrophil count ≥ 750/mm³*
  • Platelet count ≥ 75,000/mm³*
  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40 mL/min for infants < 1 year of age)
  • Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract
  • SGPT < 2.5 times normal
  • Bilirubin < 1.5 mg/dL
  • Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by MUGA
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during study and for ≥ 1 month after study completion
  • No evidence of uncontrolled infection
  • Able to undergo radiotherapy NOTE: *Abnormal blood counts allowed if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma

PRIOR CONCURRENT THERAPY:

  • No prior chemotherapy except steroids
  • No prior radiotherapy
  • No concurrent aprepitant during ifosfamide or doxorubicin hydrochloride chemotherapy
  • No concurrent dexrazoxane
  • No concurrent sargramostim (GM-CSF) or pegfilgrastim
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 49 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   Puerto Rico,   Switzerland,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00354744
Other Study ID Numbers  ICMJE ARST0431
CDR0000489215 ( Other Identifier: Clinical Trials.gov )
COG-ARST0431 ( Other Identifier: Children's Oncology Group )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Brenda Weigel, MD Masonic Cancer Center, University of Minnesota
Study Chair: Carola A Arndt, MD Mayo Clinic
PRS Account Children's Oncology Group
Verification Date February 2019

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