Protocol Number: 06-C-0043

Title:

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

Number:

06-C-0043

Summary:

This study will examine the response to treatment with chemotherapy followed by surgery to remove malignant peripheral nerve sheath tumors (MPNSTs) in patients with or without neurofibromatosis type 1 (NFI). MPNSTs are cancerous tumors that start in peripheral nerves and can spread rapidly to other areas in the body, particularly the lungs. They are rare in the general population but occur more often in people with NFI, a genetic disorder characterized by skin discoloration called cafe-au-lait spots (flat patches the color of coffee with milk) and non-cancerous tumors called plexiform neurofibromas that grow along the branches of nerves. The only known cure for MPNSTs is complete surgical removal.

Patients of any age with one or more MPNSTs who have not received chemotherapy or radiation therapy for the MPNST and who either have not had prior surgery or who still have tumor after surgery may be eligible for this study. Patients with NF1 may have received prior chemotherapy, excluding ifosfamide, doxorubicin, or etoposide, to treat plexiform neurofibromas. Candidates are screened with blood and urine tests, MUGA (heart nuclear medicine test), echocardiogram (heart ultrasound), x-rays of the chest and primary tumor site, CT of the chest and MRI of the primary tumor site, biopsy (surgical removal of small piece of tumor tissue) or examination of previously obtained biopsy specimen, and positron emission tomography (nuclear medicine test, see below) in patients 5 years old or older.

Participants have a catheter (plastic tube) inserted into a large vein in the chest for administering the chemotherapy and other medicines and for collecting blood samples. Chemotherapy is given in 21 days cycles, with the drugs given on days 1 through 5, followed by a 14-day recovery period. Doxorubicin and ifosfamide are given on days 1 through 5 of cycles 1 and 2, then ifosfamide and etoposide are given on days 1 through 5 of cycles 3 and 4. Patients receive filgrastim or neulasta 24 to 36 hours after the last dose of each cycle to boost white blood cell count. Treatment may continue for up to 8 cycles in patients whose tumor has not grown by the end of the first four cycles. In addition to treatment, patients have the following tests and procedures:

-History, physical examination, blood and urine tests every treatment cycle.

-MUGA or echocardiogram before cycle 3.

-Chest x-rays as medically indicated.

-MRI and CT before cycles 3, 5 and 7.

-Surgery or radiation, or both, for local control of the MPNST at the end of cycle 4. If surgery is performed, a portion of the removed tumor is studied for markers for MPNSTs, gene changes and the effect of chemotherapy on the tumor cells.

-Blood test to look for protein patterns that may predict the presence of MPNST.

-PET before cycle 5. A PET scan is similar to a CT scan, but a small amount of radioactive material is injected into a vein before the scan is done. A special camera detects the material, which accumulates in cancer cells.

-In patients with NF1, a physical examination and family history to help discover risk factors for the development of MPNST in NF1.

After chemotherapy is completed, patients are monitored with examinations, blood tests and scans for long-term side effects of treatments and for any sign of the cancer first monthly, then every 3 months, then every 6 months, and then every year until 5 years from finishing treatment.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Unresectable sporadic or NF1 associated high-grade malignant peripheral nerve sheath tumors (MPNSTs), not previously treated with chemotherapy or radiation therapy. Diagnostic criteria for NF1 are listed in Appendix 3 of the protocol.

Unresectable or metastatic MPNST or potentially resectable MPNST for which neoadjuvant chemotherapy is determined to be the best treatment option by the institutional PI.

Patients must have either a stage III (AJCC TNM staging system, Appendix 1 of the protocol) or stage IV (metastatic) tumor.

Patients must have measurable disease, defined as at least one tumor that is measurable in two dimensions on CT or MRI scan.

Patients who develop a recurrence or progression (WHO criteria) of an MPNST in a previously radiated field may be enrolled if it has been at least 4 weeks since the last dose of radiation therapy. Patients who previously received radiation and develop a local or metastatic recurrence outside of the radiation field are also eligible.

- Children and adults will be eligible with no upper or lower age limit.

- Normal cardiac function (ejection fraction by MUGA or ECHO that is within the institutional normal range).

- Normal serum creatinine for age or creatinine clearance greater than 60 ml/min/1.73 m(2).

Age less than or equal to 5, maximum serum creatinine: 0.8

Age greater than 5 or less than or equal to 10, maximum serum creatinine: 1.0

Age greater than 10 or less than or equal to 15, maximum serum creatinine: 1.2

Age greater than or equal to 15, maximum serum creatinine: Within institutional normal limits

- Adequate liver function (SGPT less than 5 times the upper limit of normal and bilirubin less than 2.5 times the upper limit of normal).

- Normal unsupported hematologic function (absolute neutrophil count greater than or equal to 1500 per microliter, hemoglobin greater than or equal to 9.0 g/dl and platelet count greater than or equal to 100,000 per microliter).

- Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.

- Patients with NF1 may have undergone treatment of a plexiform neurofibroma, optical pathway tumor, or other NF1 associated tumor in the past with biologic agents or chemotherapy excluding ifosfamide, doxorubicin, and etoposide. Patients must have recovered from the toxic effects of all prior therapy before entering this study. Recovery is defined as a toxicity less than grade 2 (CTCAE-version 3), unless otherwise specified in the inclusion and exclusion criteria. These patients must have had the last dose of chemotherapy, or a biologic agent, 3 weeks prior to trial entry, and the last dose of radiation therapy at least six weeks prior to trial entry.

- ECOG performance status of 0, 1, or 2

Score 0 equals status of symptomatic.

Score 1 equals status of symptomatic, fully ambulatory.

Score 2 equals status of symptomatic, in bed less than 50% of the day.

Score 3 equals status of symptomatic, in bed greater than 50% of the day but not bedridden .

Score 4 equals status of bedridden.

Informed Consent: Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients or their legal guardians (if the patient is less than 18 years old). This can be accomplished through an IRB-approved institutional screening protocol or the study-specific protocol. Documentation of the informed consent for screening will be maintained in the patient's research chart. Studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed consent was obtained. An age appropriate assent form for children from 13 through 17 years was developed, and a one page information sheet for children from 7 through 12 years.

EXCLUSION CRITERIA:

- Previous chemotherapy with doxorubicin, ifosfamide or etoposide.

- Previous radiotherapy to the area involved by the MPNST.

- Pregnant or breast feeding females because the chemotherapy administered on this trial could have a detrimental effect on the developing fetus or newborn.

Special Instructions:

Currently Not Provided

Keywords:

Plexiform Neurofibromas

Serum proteomics

Volumetric MRI

Positron Emission Tomography

Tissue Microarray

Recruitment Keyword(s):

Plexiform Neurofibroma

Malignant Peripheral Nerve Sheath Tumors

MPNST

Neurofibromatosis Type 1

NF1

Condition(s):

High Grade Unresectable Malignant Peripheral Nerve Sheath Tumors

MPNST

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Drug: Doxorubicin

Drug: Ifosfamide

Supporting Site:

National Cancer Institute, Department of Defense

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Korf BR. Clinical features and pathobiology of neurofibromatosis 1. J Child Neurol. 2002 Aug;17(8):573-7; discussion 602-4, 646-51. Review.

Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5(6):477-85. Review.

Gutmann DH, Collins FS. The neurofibromatosis type 1 gene and its protein product, neurofibromin. Neuron. 1993 Mar;10(3):335-43. Review.

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