Clinical trial NCT00304083: Combination Chemotherapy in Treating Patients With Stage III or Stage IV Malignant Peripheral Nerve Sheath Tumors
Official title: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade Malignant Peripheral Nerve Sheath Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neurofibromatosis Type 1
Sarcoma
Keywords: adult neurofibrosarcoma
childhood neurofibrosarcoma
metastatic childhood soft tissue sarcoma
nonmetastatic childhood soft tissue sarcoma
stage IV adult soft tissue sarcoma
neurofibromatosis type 1
Lead sponsor: Sarcoma Alliance for Research through Collaboration
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-03-17
Enrollment: 48
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Response Rate (Complete Response and Partial Response)
timeFrame: After 4 Cycles (1 cycle=21 days)
Secondary outcomes:
measure: Response of Plexiform Neurofibroma to Neoadjuvant Chemotherapy Using Volumetric MRI Analysis
timeFrame: After 4 Cycles (1 cycle=21 days)
measure: Utility of Fludeoxyglucose F18 Positron Emission Tomography (18FDG-PET) and Automated MRI Volumetric Tumor Analysis to Assess Response to Treatment
timeFrame: After 4 cycles
measure: Response Evaluation Using WHO, RECIST, 18 FDG-PET and Volumetric MRI With Percent Necrosis in Tumor Specimens
timeFrame: After 4 cycles
measure: Perform Pathologic Analysis of Tumor Samples to Analyze the Number of Participants With Markers as Predictors of Response
timeFrame: After 4 cycles
measure: Construct Tissue Microarray to Identify Novel Targets for Treatment for the Number of Participants With Available Tissue
timeFrame: After 4 cycles
measure: Identify the Number of Participants With a Serum Biomarker to Predict the Presence of MPNST Versus Benign Plexiform Neurofibroma
timeFrame: After 4 cycles
measure: Provide Epidemiology and Clinical Presentation of the Number of Participants With NF1-associated MPNSTs.
timeFrame: After 4 cycles
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Comprehensive Cancer Center
state: Alabama
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Charlotte
country: United States
facility: Carolinas Hematology-Oncology Associates
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Oncology Hematology Associates
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: M. D. Anderson Cancer Center at University of Texas
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance at Washington University
state: Washington
Study officials:
affiliation: National Cancer Institute (NCI)
name: Brigitte C. Widemann, MD
role: PRINCIPAL_INVESTIGATOR
References: