Trial Information

Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade Malignant Peripheral Nerve Sheath Tumors

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.