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

• Sponsor: Sarcoma Alliance for Research through Collaboration (Other)
• Overall Status: Completed
• CT.gov ID: NCT00304083
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 48
• Locations: 17
• Arms: 2
• Duration (Months): 102
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis Type 1; Sarcoma	Biological: filgrastim; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: ifosfamide; Procedure: conventional surgery; Radiation: radiation therapy	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade Malignant Peripheral Nerve Sheath Tumors
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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.	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
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.	Drug: doxorubicin hydrochloride; Given IV; Drug: etoposide; Given IV; Drug: ifosfamide; Given IV; Procedure: conventional surgery; Patients undergo surgery

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Response Rate (Complete Response and Partial Response) [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.

Secondary Outcome Measures

1. Response of Plexiform Neurofibroma to Neoadjuvant Chemotherapy Using Volumetric MRI Analysis [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

2. Utility of Fludeoxyglucose F18 Positron Emission Tomography (18FDG-PET) and Automated MRI Volumetric Tumor Analysis to Assess Response to Treatment [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.

3. Response Evaluation Using WHO, RECIST, 18 FDG-PET and Volumetric MRI With Percent Necrosis in Tumor Specimens [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.

4. Perform Pathologic Analysis of Tumor Samples to Analyze the Number of Participants With Markers as Predictors of Response [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.

5. Construct Tissue Microarray to Identify Novel Targets for Treatment for the Number of Participants With Available Tissue [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.

6. Identify the Number of Participants With a Serum Biomarker to Predict the Presence of MPNST Versus Benign Plexiform Neurofibroma [After 4 cycles]

   Assess if a serum biomarker can be identified that predicts for the presence of a MPNST versus benign plexiform neurofibroma.

7. Provide Epidemiology and Clinical Presentation of the Number of Participants With NF1-associated MPNSTs. [After 4 cycles]

   Increase the knowledge of the epidemiology and clinical presentation of NF1-associated MPNSTs.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Sarcoma Oncology Center	Santa Monica	California	United States	90403
3	Children's Memorial Hospital - Chicago	Chicago	Illinois	United States	60614
4	Indiana University	Indianapolis	Indiana	United States	46202-5289
5	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
6	Johns Hopkins	Baltimore	Maryland	United States	21231-2410
7	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Bethesda	Maryland	United States	20892-1182
8	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0942
9	University of Minnesota	Minneapolis	Minnesota	United States	55455
10	Carolinas Hematology-Oncology Associates	Charlotte	North Carolina	United States	28203
11	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
12	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
13	Pennsylvania Oncology Hematology Associates	Philadelphia	Pennsylvania	United States	19106
14	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
15	M. D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
16	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah	United States	84112
17	Seattle Cancer Care Alliance at Washington University	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Sarcoma Alliance for Research through Collaboration
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brigitte C. Widemann, MD, National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sarcoma Alliance for Research through Collaboration
• ClinicalTrials.gov Identifier: NCT00304083
• Other Study ID Numbers: SARC006; SARC-006; NCI-06-C-0043; NCI-P6452; UMN-2007CG077; NCT00266890
• First Posted: Mar 17, 2006
• Last Update Posted: Sep 18, 2018
• Last Verified: May 1, 2018

• Keywords provided by Sarcoma Alliance for Research through Collaboration: adult neurofibrosarcoma; childhood neurofibrosarcoma; metastatic childhood soft tissue sarcoma; nonmetastatic childhood soft tissue sarcoma; stage IV adult soft tissue sarcoma; neurofibromatosis type 1
• Additional relevant MeSH terms: Sarcoma; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Nerve Sheath Neoplasms; Neurofibrosarcoma; Doxorubicin; Liposomal doxorubicin; Etoposide; Ifosfamide

Study Results

Participant Flow

Arm/Group Title	NF1 MPNST	Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Period Title: Overall Study
STARTED	34	14
Completed 4 Cycles	22	7
Patients Treated With Surgery	7	3
Patients Treated With Surgery and RT	5	1
Patients Treated With RT Only	4	2
Patients Had Neither RT or Surgery	6	1
COMPLETED	12	6
NOT COMPLETED	22	8

Baseline Characteristics

Arm/Group Title	NF1 MPNST	Sporadic MPNST	Total
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	Total of all reporting groups
Overall Participants	34	14	48
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	33	40	36.5
Sex/Gender, Customized (Count of Participants)
Female	12 35.3%	5 35.7%	17 35.4%
Male	22 64.7%	9 64.3%	31 64.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Response Rate (Complete Response and Partial Response)
Description	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.
Time Frame	After 4 Cycles (1 cycle=21 days)

Outcome Measure Data

Analysis Population Description

37/48 patients total were evaluable for response.

Arm/Group Title	NF1 MPNST	Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	28	9
Partial response	5 14.7%	4 28.6%
Complete response	0 0%	0 0%
Stable Disease	20 58.8%	4 28.6%
Progressive Disease	3 8.8%	1 7.1%

2. Secondary Outcome

Title	Response of Plexiform Neurofibroma to Neoadjuvant Chemotherapy Using Volumetric MRI Analysis
Description	Evaluate the response of plexiformneurofibroma (if present) to neoadjuvant chemotherapy using WHO criteria and volumetric MRI analysis as a tool for response assessment
Time Frame	After 4 Cycles (1 cycle=21 days)

Outcome Measure Data

Analysis Population Description

MRI imaging of the MPNST and plexiform neurofibroma component was not sufficient to allow for volumetric analysis over time. Reasons include differences in imaging technique over time and incomplete coverage of the entire tumor.

Arm/Group Title	NF1 MPNST	Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	0	0

3. Secondary Outcome

Title	Utility of Fludeoxyglucose F18 Positron Emission Tomography (18FDG-PET) and Automated MRI Volumetric Tumor Analysis to Assess Response to Treatment
Description	Evaluate the utility of fludeoxyglucose F18 positron emission tomography (18FDG-PET) and automated MRI volumetric tumor analysis as tools to assess response to treatment.
Time Frame	After 4 cycles

Outcome Measure Data

Analysis Population Description

This assessment involved 18FDG-PET and MRI imaging of the MPNST and plexiform neurofibroma component. Due to technical issues with MRI imaging, data was not reliably collected from any study participant to allow for meaningful analysis.

Arm/Group Title	NF1 MPNST	Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	0	0

4. Secondary Outcome

Title	Response Evaluation Using WHO, RECIST, 18 FDG-PET and Volumetric MRI With Percent Necrosis in Tumor Specimens
Description	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.
Time Frame	After 4 cycles

Outcome Measure Data

Analysis Population Description

33 patients were evaluable for response after cycle 4, response evaluation using WHO and RECIST was performed. Response evaluation was not assessed with 18 FDG-PET and volumetric MRI.

Arm/Group Title	NF1 and Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	33
Responses in agreement	29 85.3%
Responses were not in agreement	4 11.8%

5. Secondary Outcome

Title	Perform Pathologic Analysis of Tumor Samples to Analyze the Number of Participants With Markers as Predictors of Response
Description	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.
Time Frame	After 4 cycles

Outcome Measure Data

Analysis Population Description

The rows are among three different categories: Histologic Variant, Cellularity and Necrosis.

Arm/Group Title	NF1 MPNST	Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	26	11
Histologic Variant- Conventional	15 44.1%	7 50%
Histologic Variant- Perineural	1 2.9%	0 0%
Histologic Variant- Epithelioid	0 0%	2 14.3%
Histologic Variant- Divergent	1 2.9%	0 0%
Histologic Variant- Mixed histology	9 26.5%	2 14.3%
Low Cellularity	0 0%	0 0%
Moderate Cellularity	5 14.7%	4 28.6%
High Cellularity	21 61.8%	7 50%
Necrosis- absent	5 14.7%	1 7.1%
Necrosis 1-10%	8 23.5%	2 14.3%
Necrosis 10-50%	10 29.4%	5 35.7%
Necrosis >50%	3 8.8%	3 21.4%

6. Secondary Outcome

Title	Construct Tissue Microarray to Identify Novel Targets for Treatment for the Number of Participants With Available Tissue
Description	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.
Time Frame	After 4 cycles

Outcome Measure Data

Analysis Population Description

The number of participants vary in the rows from overall number analyzed, due to the tissue that was available for testing.

Arm/Group Title	NF1 MPNST	Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	20	10
EGFR (7p12) amplification	3 8.8%	1 7.1%
TOPO2A (17q21-q22) amplification	5 14.7%	2 14.3%
Her2/Neu (17q11-q12) amplification	2 5.9%	0 0%
Cyclin D1 (11q13) amplification	1 2.9%	2 14.3%
c-MYC (8q24) amplification	5 14.7%	0 0%
N-MYC (2p24) amplification	3 8.8%	1 7.1%
NF1 (17q11) deletion	7 20.6%	0 0%
p16 (9p21) deletion	10 29.4%	3 21.4%
RB (13q14) deletion	1 2.9%	2 14.3%
p53 (17q13) deletion	6 17.6%	2 14.3%

7. Secondary Outcome

Title	Identify the Number of Participants With a Serum Biomarker to Predict the Presence of MPNST Versus Benign Plexiform Neurofibroma
Description	Assess if a serum biomarker can be identified that predicts for the presence of a MPNST versus benign plexiform neurofibroma.
Time Frame	After 4 cycles

Outcome Measure Data

Analysis Population Description

Data looked at response evaluable patients with MPNST and focused on the TOPO2A gene being amplified.

Arm/Group Title	NF1 and Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	20
NF1 patients with gene amplified	3 8.8%
Sporadic patients with gene amplified	2 5.9%

8. Secondary Outcome

Title	Provide Epidemiology and Clinical Presentation of the Number of Participants With NF1-associated MPNSTs.
Description	Increase the knowledge of the epidemiology and clinical presentation of NF1-associated MPNSTs.
Time Frame	After 4 cycles

Outcome Measure Data

Analysis Population Description

Clinical evaluation of patients with NF1 was performed at trial enrollment.

Arm/Group Title	NF1 MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
Measure Participants	34
≥10 subcutaneous neurofibromas	10 29.4%
6 or more CAL	17 50%
Intertriginous freckling	19 55.9%
Neurofibromas	26 76.5%
Plexiform neurofibroma	12 35.3%
Paraspinal neurofibromas	12 35.3%
≥10 cutaneous neurofibromas	13 38.2%
Optic glioma	1 2.9%
Glioma	1 2.9%
Scoliosis	5 14.7%
Intellectual delay	8 23.5%
Hypertension	8 23.5%

Adverse Events

Arm/Group Title	NF1 and Sporadic MPNST
Arm/Group Description	2 cycles of ifosfamide + doxorubicin ('IA') followed by 2 cycles of ifosfamide + etoposide ('IE') prior to local control measures (surgery and/or radiation therapy). Local control with surgery and/or radiation will commence after recovery from toxicities. Patients, who undergo surgery only, will receive 2 more cycles of 'IA' followed by 2 cycles of 'IE' beginning after recovery from surgery. Patients, who receive radiation therapy in addition to surgery, will receive 2 cycles of 'IE' during radiation treatment, as doxorubicin cannot be concurrently administered with radiation therapy, and 2 cycles of 'IA' after completion of radiation treatment. 1 cycle = 21 days Doxo = Doxorubicin 37.5 mg/m2/dose IV over 15 minutes on days 1, 2 Ifos = Ifosfamide 1,800 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5 Etop = Etoposide 100 mg/m2/dose IV over 60 minutes on days 1, 2, 3, 4, 5
All Cause Mortality
	NF1 and Sporadic MPNST
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	NF1 and Sporadic MPNST
	Affected / at Risk (%)	# Events
Total	13/48 (27.1%)
Blood and lymphatic system disorders
Febrile neutropenia	6/48 (12.5%)
Anemia	4/48 (8.3%)
Secondary acute myeloid leukemia	1/48 (2.1%)
Nervous system disorders
Somnolence	4/48 (8.3%)
Psychiatric disorders
Altered mental status	1/48 (2.1%)
Aphasia	1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	NF1 and Sporadic MPNST
	Affected / at Risk (%)	# Events
Total	3/48 (6.3%)
Nervous system disorders
Neurotoxicity	3/48 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.