IRB Number:

1757-03

Trial Status:

Open for Enrollment

Phase: III

Why is this study being done?

This study is being done to:
- Improve the outcome of patients with Ewing sarcoma.
- Compare the survival of patients in a study of:
- standard drug treatment and whole lung irradiation versus
- high dose, stronger drug treatment followed by replacement of peripheral blood stem cells (transplant). Stem cells are the cells that create new blood cells, such as red blood cells, white blood cells, and platelets. They can be found in the peripheral blood (bloodstream) or the soft tissue of the bone, called the bone marrow.

Patients are being asked to take part in this study because they have a type of cancer called Ewing sarcoma that has spread to the lung or pleura (lining of the lung and chest cavity).
Ewing sarcoma is a cancerous tumor that forms in the bone or soft connective tissues.
These tumors spread quickly to other areas of the body including the lungs. Ewing
sarcoma is always fatal without treatment.

The standard treatment for patients with Ewing sarcoma with disease that has spread to the lungs or pleura is standard dose chemotherapy and whole lung radiation therapy. It is possible that stronger chemotherapy, using high doses of standard chemotherapy drugs may improve the outcome (survival) for these patients. However, the side effects of using both whole lung radiation therapy and high dose chemotherapy would be too much to combine these treatments.

Who is Eligible to Participate in the Study?

-Age 49 years old or younger
-Diagnosed with Ewing sarcoma that has spread to the lung or pleura (lining of the lung and chest cavity)
-No prior chemotherapy

*More specific, detailed eligibility and/ or exclusion criteria are associated with this trial.

What is Involved With this Study?

All patients will start treatment with six courses of chemotherapy with the following medications: vincristine, ifosfamide, doxorubicin and etoposide (VIDE). Details of how
these medications are given are described below.

After these courses of VIDE, the next types of treatment depend on whether patients need early radiation therapy or not. Some patients will need early radiation therapy because of the location of their tumor. Some patients will get radiation therapy near the brain or spinal cord. This early radiation therapy will be directed at the original tumor and not to the lungs. If patients do need early radiation therapy or radiation therapy near the brain or spinal cord, then after VIDE they will receive chemotherapy which consists of seven courses of treatment with the following medications: vincristine, actinomycin-D and ifosfamide (VAI). The VAI medications will follow surgery (if surgery is possible). Completion of treatment with VAI is followed by whole lung radiation therapy.

Most patients will not need early radiation therapy or radiation therapy near the brain or spinal cord. These patients will be put in one of two groups by chance (as in the flip of a coin) following surgery (if surgery is possible), either:
1) the treatment described above just like the early radiation patients (that is, VAI followed by whole lung radiation therapy), or
2) one course of VAI followed by an investigational treatment consisting of stronger, high-dose chemotherapy followed by stem cell transplant.

Details of the different treatments are described below.

Methods for Giving Drugs
Most of the drugs used in this study will be given using a needle put into a vein (intravenous or I.V.). Patients who get the transplant regimen will be given some drugs by mouth. Patients will also get a drug called a growth factor to help the blood counts get better after treatment. This drug is usually given by needle under the skin. A medication called MESNA will also be given because it protects the bladder during treatment with the drug named ifosfamide.

The drugs in this study will be given in this way:
Group 1) Courses 1-6 (All patients) VIDE
Vincristine - given I.V. push on day 1
Ifosfamide - given I.V. over one to three hours, on days 1, 2 and 3, with MESNA
Doxorubicin - given I.V. over four hours, on days 1, 2 and 3
Etoposide - given I.V. over one hour, days 1, 2 and 3

The time in between courses will be 21 days, or more if it takes the patient longer to get better
from the side effects of the treatment, whichever happens last.

After the third or fourth course of treatment of VIDE is done, the patient's stem cells (unspecialized cells in the blood which give rise to specific types of blood cells) will be collected using a procedure called apheresis. Stem cells can often be collected through a central line. If this is not possible, a catheter will be placed into another large vein in the patient's chest or groin. During apheresis, one side of the catheter will collect circulating blood into a machine that filters out the stem cells. The filtered blood will be returned to the patient's body through the other side of the catheter. Each apheresis procedure takes about 4 to 6 hours. The procedure may need to be done several times to collect enough stem cells for the transplant. If patients do end up getting the high-dose chemotherapy treatment later on (as described above), then after that is done, their stored stem cells will be returned (that is, transplanted) into their body through a catheter, like a blood transfusion.

After course 6, the patient may have surgery to take out the first tumor. This choice will be made by their study doctor and will depend on where the tumor is located. The study doctor will talk over the surgical procedure and all its risks with the patient at the time the choice is made to do surgery.

If patients need early radiation therapy as described above, and thus are not eligible to get the
stronger high-dose treatment with stem cell transplant, the stem cells collected after courses 3 and/or 4 will be stored and used at a later time if they need to have more treatment.

Group 2) Course 7 (All patients) VAI
Vincristine - given I.V. push on day 1
Actinomycin-D - given I.V. push on day 1 and 2
Ifosfamide - given I.V. over 1-3 hours, on days 1 and 2

3a. Patients needing early radiation therapy and patients randomized to get standard
chemotherapy and radiation therapy to the lung. Courses 8-14:
Vincristine - given I.V. push on day 1
Actinomycin-D - given I.V. push on day 1 and 2
Ifosfamide - given I.V. over 1-3 hours, on days 1 and 2

3b. Patients randomized to get investigational therapy with high dose chemotherapy and peripheral blood stem cell transplant:
Busulfan, melphalan and clonazepam are given in the days before the stem cell infusion.
Melphalan - given I.V. over 30 minutes, on day 6
Busulfan - given by mouth, in four doses each day on days 2, 3, 4, and 5
Clonazepam - given by mouth, on days 1, 2, 3, 4, 5, 6 and 7
Stem cells will be given I.V. on day 8

Standard Medical Tests
Before treatment on this study begins, and while getting treatment, patients will get a series of standard medical tests:
- Physical exam
- Blood tests
- Urine tests
- Bone marrow tests
- X-ray and other imaging tests
- Heart tests (echocardiogram or MUGA and EKG)

Tests on the Bone Marrow
Patients will have at least two bone marrow aspirates (removal of some bone marrow by a fine needle) and biopsies to check the amount of cancer present in the bone marrow. In many cases, children will get medicine by vein to numb the pain and blur the memory. Patients may also receive medicine (anesthesia) to allow the patient to sleep during this test.

Radiation Therapy
Some patients on this study will have radiation therapy. The treatment will be explained to the patient, and their questions will be answered by the radiation oncologist. If during the study a patient requires radiation therapy to the spine, they will not receive busulfa/melphalan or the stem cell transplant, but will receive the other chemotherapy and radiation therapy treatments described above.

Surgery
Some patients on this study will undergo surgery.

How long will the Study run?

Patients will be treated on this study for about 11 months if they get the standard drug treatment and about six to eight months if they get the high-dose transplant treatment. However, patients will keep on having physical exams and blood tests for a few years after treatment so that researchers can continue to see any effects of treatment. In addition, the research staff would like to keep on collecting some information about how the patient is doing for as long as the patient will let the research staff.

Sponsor(s): Children's Oncology Group (COG)

Study Activation/Registration Date: 11/17/2003

IRB Review and Approval Date: 10/16/2003

Study Type: Treatment

Projected Accrual: The plan is to have up to 326 patients participate from multiple medical centers; with 23 at Mayo Clinic.

Costs of Study:There may be standard patient care costs related to participating in a cancer research study.

Principal Investigator: Carola A.S. Arndt, MD

Who can I Contact for Additional Information on this Trial?

Complete Request Form for Cancer Clinical Trial Information at Mayo Clinic or
For more information about this study or other clinical trial options, please contact our Mayo Clinic Cancer Center Clinical Trials Referral Office.

• Patients living within the United States, call 507-538-7623, or e-mail cancerclinicaltrials@mayo.edu


• Patients living outside the United States may call our International Office at 507-284-8884, or e-mail intl.mcr@mayo.edu.

What is/are the Locations of this Clinical Trial?

• Rochester, MN

Last updated: 05/07/2008