Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

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.

Further Study Information

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

Trial Contact Information

Trial Lead Organizations/Sponsors

Sarcoma Alliance for Research through Collaboration

Brigitte C. Widemann

Principal Investigator

Denise Reinke, MS, NP

Ph: 734-930-7600

U.S.A.
Alabama
	Birmingham
	UAB Comprehensive Cancer Center
		Julia Adams	Ph: 205-558-2984
			Email: jadams@peds.uab.edu
		Alyssa Reddy, MD	Principal Investigator
California
	Santa Monica
	Sarcoma Oncology Center
		Viky Chua	Ph: 310-552-9999
			Email: vchua@sarcomaoncology.com
		Sant P. Chawla	Principal Investigator
Illinois
	Chicago
	Children's Memorial Hospital - Chicago
		Kelly Verel	Ph: 773-880-8147
			Email: kverel@childrensmemorial.org
		Stewart Goldman	Principal Investigator
Indiana
	Indianapolis
	Indiana University Melvin and Bren Simon Cancer Center
		Kristen Potter	Ph: 317-278-6616
			Email: krpotter@iupui.edu
		Daniel Rushing, MD	Principal Investigator
Iowa
	Iowa City
	Holden Comprehensive Cancer Center at University of Iowa
		Judy Swift, RN, MSN	Ph: 319-356-8699
			Email: judy-swift@uiowa.edu
		Mohammed Milhem, MD	Principal Investigator
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Margaret Fogle	Ph: 410-955-7349
		David Loeb, MD	Principal Investigator
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Lauren Long	Ph: 301-496-0486
			Email: longl@mail.nih.gov
		Brigitte C. Widemann	Principal Investigator
Michigan
	Ann Arbor
	University of Michigan Comprehensive Cancer Center
		D'Andra Featherstone	Ph: 734-936-2712
			Email: dandrah@med.umich.edu
		Scott Scheutze, MD	Principal Investigator
Minnesota
	Minneapolis
	Masonic Cancer Center at University of Minnesota
		Amanda Galster	Ph: 612-625-4443
			Email: gals004@umn.edu
		Christopher Moertel	Principal Investigator
North Carolina
	Charlotte
	Carolinas Hematology-Oncology Associates
		Allison Gruntz, RN	Ph: 704-446-1921
			Email: Allison.Gruntz@carolinashealthcare.org
		Michael Livingston, MD	Principal Investigator
Ohio
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		Kristina Kruskamp	Ph: 513-636-5336
			Email: Kristina.Kruskamp@cchmc.org
		Lars Wagner, MD	Principal Investigator
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		Ratnakar Patti	Ph: 267-426-5503
			Email: pattir@email.chop.edu
		Jean Belasco, MD	Principal Investigator
	Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia
		Debbie Riordan, RN	Ph: 215-829-6712
			Email: debbieriordan@pahosp.com
		Arthur P. Staddon	Principal Investigator
	Pittsburgh
	Children's Hospital of Pittsburgh of UPMC
		Jennifer Paoletti	Ph: 412-692-5059
			Email: paolettijs@chp.edu
		Regina Jakacki	Principal Investigator
Texas
	Houston
	M. D. Anderson Cancer Center at University of Texas
		Rosie Adnin	Ph: 713-563-0004
			Email: radinin@mdanderson.org
		Joseph Ludwig	Principal Investigator
Washington
	Seattle
	Seattle Cancer Care Alliance at Washington University
		Cristina Galer	Ph: 206-667-5971
			Email: cgaler@fhcrc.org
		Eve Rodler, MD	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00304083
Information obtained from ClinicalTrials.gov on March 04, 2012

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