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Combination Chemotherapy in Treating Patients With Stage III or Stage IV Malignant Peripheral Nerve Sheath Tumors

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: NCT00304083
Recruitment Status : Completed
First Posted : March 17, 2006
Results First Posted : May 25, 2018
Last Update Posted : September 18, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sarcoma Alliance for Research through Collaboration

Tracking Information
First Submitted Date  ICMJE March 15, 2006
First Posted Date  ICMJE March 17, 2006
Results First Submitted Date  ICMJE April 16, 2018
Results First Posted Date  ICMJE May 25, 2018
Last Update Posted Date September 18, 2018
Study Start Date  ICMJE December 2005
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
Number of Participants With Response Rate (Complete Response and Partial Response) [ Time Frame: After 4 Cycles (1 cycle=21 days) ]
WHO criteria was used to determine responses due to the nonspherical shape of most MPNST. Complete Response (CR), Disappearance of all target lesions; Partial response (PR), >=50% decrease of target lesions.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00304083 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
  • Response of Plexiform Neurofibroma to Neoadjuvant Chemotherapy Using Volumetric MRI Analysis [ Time Frame: After 4 Cycles (1 cycle=21 days) ]
    Evaluate the response of plexiformneurofibroma (if present) to neoadjuvant chemotherapy using WHO criteria and volumetric MRI analysis as a tool for response assessment
  • Utility of Fludeoxyglucose F18 Positron Emission Tomography (18FDG-PET) and Automated MRI Volumetric Tumor Analysis to Assess Response to Treatment [ Time Frame: After 4 cycles ]
    Evaluate the utility of fludeoxyglucose F18 positron emission tomography (18FDG-PET) and automated MRI volumetric tumor analysis as tools to assess response to treatment.
  • Response Evaluation Using WHO, RECIST, 18 FDG-PET and Volumetric MRI With Percent Necrosis in Tumor Specimens [ Time Frame: After 4 cycles ]
    Correlate response evaluation using WHO, RECIST, 18 FDG-PET and volumetric MRI with percent necrosis in tumor specimens from patients who undergo surgery for local control after chemotherapy.
  • Perform Pathologic Analysis of Tumor Samples to Analyze the Number of Participants With Markers as Predictors of Response [ Time Frame: After 4 cycles ]
    Evaluate the molecular biology of sporadic and NF1-associated MPNSTs by performing a detailed pathologic analysis of tumor samples with the goal to analyze if markers can be identified that predict for response to chemotherapy or outcome.
  • Construct Tissue Microarray to Identify Novel Targets for Treatment for the Number of Participants With Available Tissue [ Time Frame: After 4 cycles ]
    Construct a tissue microarray from submitted tumor samples that will be used in the future to identify novel targets for treatment of MPNSTs. The tissue microarray looked at various gene deletions and amplifications.
  • Identify the Number of Participants With a Serum Biomarker to Predict the Presence of MPNST Versus Benign Plexiform Neurofibroma [ Time Frame: After 4 cycles ]
    Assess if a serum biomarker can be identified that predicts for the presence of a MPNST versus benign plexiform neurofibroma.
  • Provide Epidemiology and Clinical Presentation of the Number of Participants With NF1-associated MPNSTs. [ Time Frame: After 4 cycles ]
    Increase the knowledge of the epidemiology and clinical presentation of NF1-associated MPNSTs.
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 Combination Chemotherapy in Treating Patients With Stage III or Stage IV Malignant Peripheral Nerve Sheath Tumors
Official Title  ICMJE Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade Malignant Peripheral Nerve Sheath Tumors
Brief Summary

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, ifosfamide, and etoposide, 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 with or without radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving combination chemotherapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating patients with stage III or stage IV malignant peripheral nerve sheath tumors.

Detailed Description

OBJECTIVES:

Primary

  • Determine the clinical response rate (complete and partial) in patients with sporadic or neurofibromatosis type 1 (NF1)-associated high-grade stage III or IV malignant peripheral nerve sheath tumors (MPNSTs) after treatment with 4 courses of chemotherapy comprising doxorubicin hydrochloride and ifosfamide (IA) followed by etoposide and ifosfamide (IE).

Secondary

  • Evaluate the utility of fludeoxyglucose F18 positron emission tomography (^18FDG-PET) and automated MRI volumetric tumor analysis as tools to assess response to treatment.
  • Correlate response evaluation by 2-dimensional WHO criteria, 1-dimensional RECIST criteria, ^18FDG-PET, and volumetric MRI with percent necrosis in tumor specimens from patients who undergo surgery for local control after chemotherapy.
  • Evaluate the response of plexiform neurofibroma(s) (if present) to chemotherapy using WHO criteria and automated volumetric MRI analysis.
  • Evaluate the molecular biology of sporadic and NF1-associated MPNSTs by performing a detailed pathologic analysis of tumor samples with the goal to analyze if markers can be identified that predict for response to chemotherapy or outcome.
  • Construct a tissue microarray from submitted tumor samples, that will be used in the future to identify novel targets for treatment of MPNSTs.
  • Assess if a serum biomarker can be identified, that predicts for the presence of a MPNST versus benign plexiform neurofibroma.
  • Increase the knowledge of the epidemiology and clinical presentation of NF1-associated MPNSTs.

OUTLINE: This is a multicenter study. Patients are stratified according to type of malignant peripheral nerve sheath tumor (MPNST) (sporadic MPNST vs neurofibromatosis type 1 [NF1]-associated MPNST). Patients receive 1 of 2 treatment regimens depending on the location of the MPNST and tumor response to chemotherapy.

  • Chemotherapy and local control by radiotherapy and surgery: Patients receive doxorubicin hydrochloride and ifosfamide (IA) chemotherapy comprising doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 and ifosfamide IV over 1 hour on days 1-5. Treatment repeats every 21 days for 2 courses in the absence of unacceptable toxicity. Patients then receive etoposide and ifosfamide (IE) chemotherapy comprising etoposide IV over 1 hour and ifosfamide IV over 1 hour on days 1-5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim (G-CSF) subcutaneously (SC) after each chemotherapy course beginning on day 6 or 7 and continuing until blood counts recover or pegfilgrastim SC once on day 6 or 7.

After recovery from chemotherapy, patients undergo radiotherapy and receive 2 more courses of IE during radiotherapy followed by 2 more courses of IA after completion of radiotherapy. Some patients may then undergo surgery.

  • Chemotherapy and local control by surgery: Patients receive 2 courses of IA followed by 2 courses of IE as above. After recovery from chemotherapy, patients undergo surgery. After recovery from surgery, patients receive 2 more courses of IA followed by 2 more courses of IE in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 74 patients will be accrued for this study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Neurofibromatosis Type 1
  • Sarcoma
Intervention  ICMJE
  • Biological: filgrastim
    Given subcutaneously
  • Drug: doxorubicin hydrochloride
    Given IV
  • Drug: etoposide
    Given IV
  • Drug: ifosfamide
    Given IV
  • Procedure: conventional surgery
    Patients undergo surgery
  • Radiation: radiation therapy
    Patients undergo radiotherapy
Study Arms  ICMJE
  • Experimental: Chemotherapy and local control by radiotherapy and surgery
    Patients receive doxorubicin hydrochloride and ifosfamide (IA) chemotherapy. Treatment repeats every 21 days for 2 courses in the absence of unacceptable toxicity. Patients then receive etoposide and ifosfamide (IE) chemotherapy. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim (G-CSF) subcutaneously (SC) after each chemotherapy course. After recovery from chemotherapy, patients undergo radiotherapy and receive 2 more courses of IE during radiotherapy followed by 2 more courses of IA after completion of radiotherapy. Some patients may then undergo surgery.
    Interventions:
    • Biological: filgrastim
    • Drug: doxorubicin hydrochloride
    • Drug: etoposide
    • Drug: ifosfamide
    • Procedure: conventional surgery
    • Radiation: radiation therapy
  • Experimental: Chemotherapy and local control by surgery
    Patients receive 2 courses of IA followed by 2 courses of IE as above. After recovery from chemotherapy, patients undergo surgery. After recovery from surgery, patients receive 2 more courses of IA followed by 2 more courses of IE in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: doxorubicin hydrochloride
    • Drug: etoposide
    • Drug: ifosfamide
    • Procedure: conventional surgery
Publications * Not Provided

*   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: September 14, 2018)
48
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE June 2014
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • Newly diagnosed sporadic or neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs)

    • Stage III or stage IV (metastatic) disease
  • Measurable disease, defined as at least 1 tumor that is measurable in 2 dimensions on CT scan or MRI

PATIENT CHARACTERISTICS:

  • Ejection fraction normal by echocardiogram or MUGA
  • Serum creatinine normal for age OR creatinine clearance > 60 mL/min
  • SGPT < 5 times upper limit of normal (ULN)
  • Bilirubin < 2.5 times ULN
  • Absolute neutrophil count ≥ 1,500/mm^3*
  • Hemoglobin ≥ 9.0 g/dL*
  • Platelet count ≥ 100,000/mm^3*
  • ECOG performance status 0-2
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 6 months after completion of study treatment NOTE: * Unsupported

PRIOR CONCURRENT THERAPY:

  • No prior chemotherapy for MPNST
  • Prior surgical resection of MPNST allowed provided residual or recurrent measurable disease is present
  • Recovered from toxic effects of all prior therapy
  • At least 3 weeks since prior chemotherapy or biologic therapy for treatment of a plexiform neurofibroma, optical pathway tumor, or other NF1-associated tumor (in patients with NF1)
  • At least 6 weeks since prior radiotherapy for treatment of a plexiform neurofibroma, optical pathway tumor, or other NF1-associated tumor (in patients with NF1)
  • At least 4 weeks since prior radiotherapy to the area involved by MPNST
  • No other concurrent growth factors (e.g., sargramostim [GM-CSF] or interleukin-11)

    • Concurrent epoetin alfa allowed
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Canada
 
Administrative Information
NCT Number  ICMJE NCT00304083
Other Study ID Numbers  ICMJE SARC006
SARC-006
NCI-06-C-0043
NCI-P6452
UMN-2007CG077
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sarcoma Alliance for Research through Collaboration
Study Sponsor  ICMJE Sarcoma Alliance for Research through Collaboration
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Brigitte C. Widemann, MD National Cancer Institute (NCI)
PRS Account Sarcoma Alliance for Research through Collaboration
Verification Date May 2018

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