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

Sarcoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00304083
• Other study ID #: SARC006
• Secondary ID: SARC-006NCI-06-C
• Status: Completed
• Phase: Phase 2
• Start date: December 2005
• Est. completion date: June 2014

Study information

• Verified date: May 2018
• Source: Sarcoma Alliance for Research through Collaboration
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00266890

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Nerve Sheath Neoplasms
• Neurilemmoma
• Neurofibroma
• Neurofibromatoses
• Neurofibromatosis 1
• Neurofibromatosis Type 1
• Sarcoma

Intervention

Biological:
• filgrastim
Given subcutaneously

Drug:
• doxorubicin hydrochloride
Given IV
• etoposide
Given IV
• ifosfamide
Given IV

Procedure:
• conventional surgery
Patients undergo surgery

Radiation:
• radiation therapy
Patients undergo radiotherapy

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Johns Hopkins	Baltimore	Maryland
United States	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Bethesda	Maryland
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Carolinas Hematology-Oncology Associates	Charlotte	North Carolina
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	M. D. Anderson Cancer Center at University of Texas	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Pennsylvania Oncology Hematology Associates	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah
United States	Sarcoma Oncology Center	Santa Monica	California
United States	Seattle Cancer Care Alliance at Washington University	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Sarcoma Alliance for Research through Collaboration	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Response Rate (Complete Response and Partial Response)	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.	After 4 Cycles (1 cycle=21 days)
Secondary	Response of Plexiform Neurofibroma to Neoadjuvant Chemotherapy Using Volumetric MRI Analysis	Evaluate the response of plexiformneurofibroma (if present) to neoadjuvant chemotherapy using WHO criteria and volumetric MRI analysis as a tool for response assessment	After 4 Cycles (1 cycle=21 days)
Secondary	Utility of Fludeoxyglucose F18 Positron Emission Tomography (18FDG-PET) and Automated MRI Volumetric Tumor Analysis to Assess Response to Treatment	Evaluate the utility of fludeoxyglucose F18 positron emission tomography (18FDG-PET) and automated MRI volumetric tumor analysis as tools to assess response to treatment.	After 4 cycles
Secondary	Response Evaluation Using WHO, RECIST, 18 FDG-PET and Volumetric MRI With Percent Necrosis in Tumor Specimens	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.	After 4 cycles
Secondary	Perform Pathologic Analysis of Tumor Samples to Analyze the Number of Participants With Markers as Predictors of Response	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.	After 4 cycles
Secondary	Construct Tissue Microarray to Identify Novel Targets for Treatment for the Number of Participants With Available Tissue	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.	After 4 cycles
Secondary	Identify the Number of Participants With a Serum Biomarker to Predict the Presence of MPNST Versus Benign Plexiform Neurofibroma	Assess if a serum biomarker can be identified that predicts for the presence of a MPNST versus benign plexiform neurofibroma.	After 4 cycles
Secondary	Provide Epidemiology and Clinical Presentation of the Number of Participants With NF1-associated MPNSTs.	Increase the knowledge of the epidemiology and clinical presentation of NF1-associated MPNSTs.	After 4 cycles