IRB Number:

07-008822

Trial Status:

Open for Enrollment

Phase: III

Why is this study being done?

Patients are being asked to take part in this study because they have high risk neuroblastoma. Neuroblastoma is a type of cancer. Neuroblastoma shows up as a lump or mass in the belly or around the spinal cord in the chest, neck, or pelvis. Neuroblastoma is a cancer of nerve cells. It develops in nerve cells that are outside of the brain. It often spreads to bone, liver, lymph nodes and bone marrow, which is the soft tissue in the center of bones where blood cells are made. Patients in this study have the type of neuroblastoma that is called High Risk because their tumor has spread from where it started or because their type of tumor is harder to treat.

What Is The Current Standard Of Treatment For This Disease?
The treatment for neuroblastoma includes three parts (phases) of therapy called Induction, Consolidation and Maintenance. During Induction therapy anti-cancer drugs (chemotherapy) and surgery are used to kill and remove as much tumor as possible. Blood stem cells are collected during the Induction phase of therapy. After collection the blood stem cells are frozen and stored to be used during the Consolidation phase of treatment. Blood stem cells are the cells that create new blood cells, such as red blood cells, white blood cells, and platelets. Blood stem cells can be collected from the blood by using a machine that can separate out the part of blood that has stem cells and then return the remaining blood back to the patient.

During the Consolidation phase of treatment extremely high doses of chemotherapy are given to better kill any remaining neuroblastoma cells. The extremely high doses of chemotherapy destroy healthy bone marrow. Bone marrow is the soft tissue in the hollow of flat bones of the body that produces new blood cells. The peripheral blood stem cells that were stored during the Induction phase of treatment are given back to the patient after the high dose Consolidation chemotherapy. These stems cells allow the bone marrow to return to normal so that new blood cells can be made. This type of therapy is called a hematopoietic stem cell transplant. Once the patient has healed from the effects of high doses of chemotherapy, radiation therapy is given to the first place the tumor was found and to any additional places where the tumor was found after Induction therapy.

During the third phase of therapy, Maintenance, an oral drug, called cis-retinoic acid (Accutane) is given.

Who is Eligible to Participate in the Study?

-Age 30 years old or younger
-Diagnosed with high risk neuroblastoma

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

What is Involved With this Study?

This study is being done because more than half of the patients with high risk neuroblastoma will not be cured of their disease.

The main purpose of this research study is to find out if using two cycles of high dose Consolidation chemotherapy, instead of one cycle, will decrease the chance that the
neuroblastoma will grow back after therapy. This research study will also find out if adding a new anti-cancer drug to Induction therapy will decrease the number of patients
who have tumor present at the end of the Induction phase of therapy. This research study will also find out if patients whose tumor does not go away with initial therapy will need
a higher dose of radiation therapy.

The treatment will be described in two separate parts.

Part 1 will discuss the use of a drug added to the standard anti-cancer drugs used in the Induction phase of neuroblastoma treatment. It will also explain standard blood stem cell collection and surgery. Patients will not be able to participate in Part 2 of this study if their tumor has grown larger or spread to new areas in their body. Part 2 will discuss the Consolidation and Maintenance phases of therapy. Patients do not have to take part in Part 2 of the study. Patients can discuss this with their doctor and make that decision after they have finished the Induction therapy.

Part 1 of this study will collect information about the patient's neuroblastoma and about the effects of the first phase of treatment, Induction which lasts about 20 weeks (five months). Part 1 of this study will test the addition of the combination of chemotherapy, cyclophosphamide/topotecan, to the standard chemotherapy combinations used in the Induction phase of treatment for high risk neuroblastoma. The use of cyclophosphmaide
and topotecen during induction phase of treatment is experimental. This study is designed to help understand whether this new treatment will increase the ability to kill or remove the patient's tumor cells.

During Part 1 of the study, researchers will:
- Look at how well high risk neuroblastoma responds to this new Induction therapy.
- Study how certain genes (genes direct activities of cells) affect how the patient responds to the cyclophosphamide and topotecan induction chemotherapy.
- Study whether the patietn's immune system (blood cells that help fight infection) can produce cells that will find and kill neuroblastoma.
- Study how topotecan is broken down by the patient's body.
- Study whether new tests can be used to find small amounts of neuroblastoma cells.

Patients will need to have the following exams, tests or procedures to find out if they can be in the study and to check how they are doing during treatment. These exams, tests or procedures are part of regular cancer care and may be done even if the patient does not join the study. If the patient has had some of them recently, they may not need to be repeated. This will be up to the study doctor.

- Physical exam
- Blood tests
- Bone marrow tests
- Pregnancy test for females of childbearing potential prior to treatment
- Various scans (x-ray tests to determine whether the patient's tumor is responding to therapy)
- Tests of kidney function
- Tests of lung and heart function
- Hearing tests
- Urine Tests

Induction Chemotherapy
This treatment uses chemotherapy to make the tumor as small as possible, hopefully allowing it to be removed. All patients will begin treatment with the Induction phase of
chemotherapy, which is divided into six 3-week cycles. There are three different drug combinations used during the six cycles. Cycles 1 and 2 will use the new combination of
cyclophosphamide and topotecan. An additional drug called filgrastim (G-CSF) is given after the chemotherapy. Filgrastim (G-CSF) (granulocyte colony stimulating factor) helps start the production of white blood cells (infection fighting cells) and will help the patient's body recover from treatment. Cycles 3 and 5 use the anti-cancer drugs etoposide and cisplatin, and the drug filgrastim (G-CSF). Cycles 4 and 6 use the anti-cancer drugs vincristine, cyclophosphamide, and doxorubicin and the drugs MESNA and filgrastim (G-CSF). MESNA is given to help protect the bladder from potential damaging effects of cyclophosphamide. The drugs used Cycles 3, 4, 5 and 6 are standard drugs used for the treatment of high risk neuroblastoma study. Cycles of chemotherapy will be given
approximately every 21 days.

Stem Cell Harvest
After the second cycle of Induction is finished, the patient's stem cells will be collected using a procedure called apheresis. During apheresis, the patient's blood is collected into a machine that filters out the stem cells and the filtered blood is returned to the patient's body. This procedure may need to be done several times to collect enough stem cells for the Consolidation phase of therapy. This procedure will be performed at Mayo Clinic. A small sample of the stem cells will be sent to a lab at Children's Hospital of Los Angeles to test for the presence of tumor cells. This is a standard way to test whether
there are neuroblastoma cells in the stem cell collection. The rest of the patient's collected stem cells will be frozen and stored at Mayo Clinic.

The patient's stem cells will only be used for later transplantation if tumor cells can not be found using the standard test performed at Children's Hospital of Los Angeles. If tumor cells are present, another stem cell collection will need to be done following the next cycle of chemotherapy (Cycle 3). The physician may decide that the second collection of stem cells should come from the bone marrow instead of the peripheral blood. This alternative will be discussed in more detail if it is necessary. The second collection of stem cells will also be tested for the presence of tumor cells. If detectable tumor cells are still found, the patient will no longer be eligible for stem cell transplantation and will get another form of therapy as decided by the patient's physician.

During Part 2 of the study, the researchers will:
- Compare the effects, good and/or bad, of using two cycles of high dose Consolidation chemotherapy with one cycle of high dose Consolidation chemotherapy on children with high risk neuroblastoma to find out which is better.
- Study whether a higher dose of radiation, given only to patients with tumor remaining after induction therapy, will decrease the chance that tumor will grow back.
- Study whether the patient's immune system (blood cells that help fight infection) can produce cells that can recognize and kill neuroblastoma.
- Study whether new tests can be used to find small amounts of neuroblastoma cells.
- Study how cis-retinoic acid (Accutane) is broken down by the patient's body and study whether the patient's genes (genes direct activities of cells) effect how the patient
responds to cis-retinoic acid therapy.

Random Assignment
If participating in this part of the study patients will be given one of two different treatment plans. The treatment plan the patient gets is decided by a process called randomization.

Randomization means that the treatment is assigned based on chance. It is a lot like flipping a coin, except that it is done by computer to make sure that there are about the
same number of people on each treatment plan of the study. The patient or their doctor can not choose what treatment the patient will have.

Treatment Plan
The treatment plan involves cancer fighting medicine called chemotherapy plus radiation therapy. The treatment on this part of the clinical trial takes about 9-11 months. It is divided into two stages.

The two different treatment plans are the same except for some differences during the Consolidation phase of therapy. The rest of the treatment that is given is standard therapy
for people with high risk neuroblastoma.

The two treatment arms are as follows:
- A: Single Myeloablative Consolidation Therapy
- B: Tandem Myeloablative Consolidation Therapy

Myeloablative therapy means that the patient will receive very high doses of chemotherapy that will destroy normal bone marrow cells.

Randomization
After finishing induction therapy, patients will be randomized to receive either a single (one cycle) of extremely high dose chemotherapy (Single Myeloablative Consolidation Therapy) or tandem (two cycles) of extremely high dose chemotherapy (Tandem Myeloablative Consolidation Therapy). The rest of the Consolidation therapy and Maintenance therapy will be the same in both groups of patients.

Treatment for participants who are on treatment plan A:
After finishing induction therapy, patients will get one cycle of very high dose chemotherapy and a hematopoietic stem cell transplant. The transplant will begin with
treatment with very high doses of the chemotherapy drugs carboplatin, etoposide and melphalan. Etoposide and carboplatin are given as a continuous infusion for four consecutive days. The drug melphalan is given as a daily dose for three days. After the high dose chemotherapy treatment, the patient's stored stem cells will be given IV (through the central line). These stem cells were collected from the patient during the induction phase of therapy and frozen. This is called a Hematopoietic Stem Cell Transplant. Patients will be given filgrastim (GCSF) starting on the same day they receive their stem cells and continuing until their white blood cells have returned to a safe number, usually about two weeks.

Treatment for participants who are on treatment plan B:
After completion of induction therapy, patients will begin the first of the two cycles of very high dose chemotherapy and hematopoietic stem cell transplant. The first transplant will begin with treatment with very high doses of the chemotherapy drugs thiotepa and
cyclophosphamide given IV over six total days. After the high dose chemotherapy treatment, some of the patient's stored stem cells will be given IV (through the central line). These stem cells were previously collected from the patient during the induction phase and frozen. Patients will be given filgrastim (GCSF) starting on the same day they get their stem cells and they will continue to get filgrastim (GCSF) until their white blood cells have returned to a safe number, usually about two weeks.

Between 6 to 10 weeks from the start of the first treatment a second cycle of very high dose treatment is given. The treatment includes the drugs etoposide and carboplatin, which are given as a continuous infusion for four consecutive days. The drug melphalan is also given
as a daily dose for three days during this treatment. After this second high dose chemotherapy treatment, some of the patient's remaining stored stem cells will be given back to the patient. Patients will be given the same care as the first transplant. Patients will be given filgrastim (GCSF) starting on the same day they get their stem cells and they will continue to get filgrastim (GCSF) until their white blood cells have returned to a safe number, usually about two weeks.

Radiation Therapy
It is standard to give radiation treatment to the area of the main tumor and to areas that still showed signs of active disease at the end of Induction phase of treatment. Radiation therapy will begin after the patient has gotten better from the immediate side effects of the high doses of chemotherapy. If randomized to arm B (two cycles of consolidation chemotherapy) patients will get radiation therapy after they have recovered from the second
transplant. Radiation therapy usually starts about a month after the transplant. The radiation therapy doctors will discuss this with the patient in more detail. The radiation is given in one short session each day, for a period of up to three weeks.

Patients will get a higher dose of radiation treatment if x-ray tests performed at the end of Induction therapy still show tumor (a lump). The higher dose of radiation will only be given to the area where tumor is present. This higher dose of radiation is experimental. The researchers are studying whether this higher dose of radiation will decrease the risk of tumor growing back.

MAINTENANCE PHASE OF THERAPY
Maintenance therapy will begin after the patient has recovered from effects of radiation therapy. Standard therapy during this phase of treatment is to get cis-Retinoic acid (Accutane) therapy. The drug is given by mouth, twice daily for two weeks, followed by
two weeks without the drug. This cycle will be repeated six times for a total of six months of treatment.

Standard Medical Tests
Before treatment on this study begins, and while receiving treatment, patients will have a series of standard medical tests:
- Physical exam
- Blood Tests
- Bone marrow tests
- Tests of vision and hearing
- Urine tests
- Various scans (x-ray tests to see where the tumor is in the patient's body)
- Tests of kidney function
- Tests of lung and heart function
- Hearing tests
- Dental exams

Research study tests and procedures
The following tests will be done because the patient is in part of this study. These tests are not part of standard care.

The researchers would like to collect additional blood to see if certain genes (genes direct the activities of cells) will effect whether the patient experiences bad effects after chemotherapy, to see if the patient's immune system is able to recognize neuroblastoma tumor cells and to test new methods for finding tumor cells. The research staff will get all blood specimens through the patient's central venous catheter. The researchers will try to get these additional blood samples when the patient is already having blood drawn for routine purposes.

The researchers would like to use any leftover portions of thier bone marrow that is not needed to treat the patient to carry out special biology research studies to learn more about neuroblastoma. These studies will test new methods for finding tumor cells.

How long will the Study run?

The study will last about 3 to 4 years.

The first part of the treatment takes about five months. As long as the patient's tumor doesn't get worse, they will be offered the option to continue on Part 2 of this clinical trial once they have completed Induction therapy. Patients will need to get more therapy for neuroblastoma whether or not they take part in Part 2. The researchers will continue to collect some medical information about how the patient is doing for 10 years after the last patient starts the study.

Sponsor(s): Children's Oncology Group

Study Activation/Registration Date: 03/24/2008

IRB Review and Approval Date: 01/31/2008

Study Type: Treatment

Projected Accrual: The plan is to have up to 495 patients participate from multiple medical centers.

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

Principal Investigator: Vilmarie Rodriguez, 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: 06/06/2008