IRB Number:

07-006033

Trial Status:

Open for Enrollment

Phase: III

Why is this study being done?

Study Rationale:
Parents/ Guardians are being asked to allow their child to take part in this study because their child is less than three years old and has a tumor called a high risk medulloblastoma or primitive neuroectodermal tumor (PNET). Left untreated, these tumors are always fatal.


It is common to enroll children and adolescents with cancer in a clinical trial that seeks to improve cancer treatment over time. Clinical trials include only people who choose to take part.


What is the current standard of treatment for this disease?
Treatment for high risk medulloblastoma or primitive neuroectodermal tumor (PNET) in children less than 36 months old usually involves surgery to remove as much of the tumor as possible followed by chemotherapy (anti-cancer drug therapy) and sometimes radiation.

There is no standard treatment for infants and young children with very high-risk medulloblastoma/PNET. Several research studies have treated children less than three years with medulloblastoma/PNET with intense chemotherapy and stem cell rescue. After surgery, patients were given intense chemotherapy (induction) after which the patients own blood stem cells were collected (harvested) and then more intense chemotherapy was given (consolidation). After the intense chemotherapy, the patient?s own blood stem cells were given back to the patient to help recovery (rescue). Blood stem cells are the cells from which new blood cells develop such as red blood cells, white blood cells, and platelets. Blood stem cells can be found in the peripheral blood (bloodstream) or the soft tissue of the bone, called the bone marrow. This approach has been used in an attempt to improve patient survival and to delay, reduce and possibly eliminate radiation therapy.

In some children whose medulloblastoma/PNET came back or got worse, this intense treatment with stem cell rescue improved survival. The treatment has also been used with newly diagnosed patients with high risk medulloblastoma and PNET. Children with minimal tumor left after surgery and/or after chemotherapy appeared to do better. In a clinical trial called ?Head Start 2?, a chemotherapy drug, methotrexate was added to a four drug combination (induction) used in several earlier trials. This was then followed by the intense chemotherapy with stem cell rescue (consolidation). In children with tumors that had metastasized (spread), high rates of complete disappearance of tumor were noted.

Similarly, another clinical study evaluated three cycles of the same four-drug combination (Induction), followed by three cycles with stem cell rescue (consolidation). Side effects for each of the three consolidation cycles with stem cell rescue? often appeared less than the side effects seen with the first three cycles of chemotherapy.

Why is this study being done?
The purpose of this study is to compare two experimental treatment regimens to see if one is better for patients with high risk medulloblastoma or primitive neuroectodermal tumor (PNET). Each regimen consists of induction, consolidation, and blood stem cell rescue.

The difference in the regimens is that in one regimen an additional drug, methotrexate, will be added to the induction therapy. The researchers would like to know if adding methotrexate will prove more effective than not adding methotrexate during induction therapy. The researchers do not know if adding methotrexate will prove more effective and it may cause additional side effects.

Researchers are also going to compare tests and surveys to see how the treatments on this study are affecting the quality of life and development of subjects.

Researchers are also going to do research tests on some of the tumor tissue taken out during surgery. These tests are being done to better understand things about the tumor cells such as the kinds of proteins in them and if they have any genetic differences. The research staff will also collect some blood for these research tests. About one teaspoon of blood will be taken before the child starts treatment. An attempt will be made to obtain this sample at the same time the child is having other routine blood tests.

Who is Eligible to Participate in the Study?

-Age less than three years old
-Diagnosed with a tumor called a high risk medulloblastoma or primitive neuroectodermal tumor (PNET)

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

What is Involved With this Study?

Before the child begins the study:
The child will already have had surgery to remove some or all of the tumor. Then, they will need to have the following exams, tests or procedures to find out if they are eligible for the study. These exams, tests and procedures are part of regular cancer care and may
be done even if the parent/ guardian do not allow their child to join the study. If their child has had some of them recently, they may or may not need to be done again. This will be up to the child's study doctor.

- MRI scans of the brain and spine to see if there is any tumor left
- Lumbar puncture procedure (spinal tap) to look at the cerebrospinal fluid
- Physical and Neurological examinations
- Blood tests
- Urine tests
- Hearing tests
- Test to see how the kidneys are functioning
- Tests to measure how well the heart functions
- Tests to measure how well the lungs function
- Tests of hormone function

Some of the tissue already taken and copies of the films used to make the diagnosis of the child's disease will be sent to central review centers as part of COG (Children's
Oncology Group) quality control.

In addition to the central review, some tissue will be sent to a COG approved laboratory and tested to find out if a certain genetic mutation, an INI1 alteration, is present in the tumor cells. (A mutation is a change in the normal structure of the gene.) If the mutation is found in the tumor tissue then blood will also be tested to find out if normal cells contain the mutation too.

The presence of an INI1 mutation indicates that the tumor is a type of atypical teratoid/rhabdoid tumor (AT/RT) rather than a medulloblastoma or PNET. Although
they are all tumors of the central nervous system researchers think that treatment against AT/RT is more effective when it includes surgery, chemotherapy and radiation therapy. Radiation therapy is not part of therapy on this study.

During the study
If the exams, tests and procedures show that the child can be in the study, and the parent/ guardian choose to allow their child to take part, then their child will need the following tests and procedures during the study. Most are part of regular cancer care.

- MRI scans of the brain and spine to see if there is any tumor left
- Lumbar puncture (spinal tap) procedure to look at the cerebrospinal fluid
- Physical and Neurological examinations
- Blood tests
- Urine tests
- Hearing tests
- Test to see how the kidneys are functioning
- Tests to measure how well the heart functions
- Tests to measure how well the lungs function

Because the child is on this study the research staff would like to do some tests and surveys to see how the treatment on this study is affecting the child's life and the way the child is developing. These tests and surveys are called neuropsychological tests. Researchers will give the tests at the end of induction, and at one and three years after the therapy is done. The tests will take about 1 ½ to 2 ½ hours.

Random Assignment
The child will receive one of two different treatment plans. The treatment plan they receive 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.

If the child is randomized to Regimen A, the child will get three cycles of induction therapy with common chemotherapy drugs, vincristine, etoposide, cyclophosphamide and
cisplatin. During this time, blood stem cells will be collected.

If the tumor goes away with the induction therapy, the child will then have three cycles of consolidation chemotherapy with thiotepa and carboplatin. With each cycle of consolidation when the drugs are done, a portion of the child's blood stem cells will be given back to them (stem cell rescue).

If the tumor has gotten smaller but is not completely gone or does not change in size after induction chemotherapy, the child may have another surgery to try to remove the rest of the tumor. After recovering from surgery, the child will then have three cycles of consolidation chemotherapy with thiotepa and carboplatin. With each cycle of
consolidation when the drugs are done, a portion of the child's blood stem cells will be given back to them (stem cell rescue).

If the child is randomized to Regimen B the child will have three cycles of induction chemotherapy with the same drugs used in Regimen A (vincristine, etoposide,
cyclophosphamide and cisplatin) plus the additional drug methotrexate. The rest of the therapy is the same as on Regimen A and includes three cycles of consolidation therapy with thiotepa and carboplatin, and stem cell rescue.

Other drugs will be given to all patients to help with the side effects of the study drugs.
These drugs include:
- Filgrastim (also called G-CSF) to help the child's blood counts recover after chemotherapy
- Mesna to help prevent bleeding in the bladder when the child gets Cyclophosphamide

If the child is randomized to Regimen B the child will also get Leucovorin to help them recover from the effects of the Methotrexate

A central line will be used to give the chemotherapy drugs on this study. A central line is a type of tubing inserted into a large vein in the chest by a surgeon during a short
operation.

If at any time during the study the child's tumor gets larger in size, the child will be taken off study therapy and the child's doctor will discuss other treatment options with the parent/ guardian.

Induction chemotherapy and consolidation chemotherapy will each consist of three 21-day cycles.

Blood stem cells will be collected using a procedure called apheresis. Blood stem cells will be collected through the central line. During apheresis, one side of the catheter will collect circulating blood into a machine that filters out the blood stem cells. The filtered blood will be returned to the child's body through the other side of the catheter. Each apheresis procedure takes about four to six hours. The procedure may need to be done several times during induction to collect enough blood stem cells for the infusion. During consolidation, the child's stored blood stem cells will be returned (re-infused) into the
child's body through a catheter, like a transfusion. This will happen about 48 hours after the last Thiotepa dose of each cycle has been given.

Patients will require hospitalization for administration of chemotherapy and may possibly require readmission to the hospital between cycles of therapy for treatment of
fever associated with low blood counts or lowered immunity, for treatment of some possible infections, for nutritional support or possibly for pain control.

Although radiation therapy is not a part of this clinical trial, the child's healthcare providers may or may not recommend that the child receive radiation therapy after
completion of this trial. Parents/ Guardians should discuss this possibility with the child's study doctors and healthcare providers. They will discuss the possible benefits and side effects of radiation therapy as they differ depending upon the age of the child, where tumor is located, the area of the brain irradiated and the dose of radiation used.

How long will the Study run?

Patients in this clinical trial are expected to receive treatment on this study for about six months. After treatment, patients will have follow-up examinations and
medical tests. The research staff will continue to collect some medical information about how the child is doing for ten years after the last patient starts the study.

Sponsor(s): Children's Oncology Group

Study Activation/Registration Date: 02/19/2008

IRB Review and Approval Date: 01/31/2008

Study Type: Treatment

Projected Accrual: The plan is to have up to 100 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: 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: 05/13/2008