IRB Number:

07-004144

Trial Status:

Open for Enrollment

Phase: III

Why is this study being done?

Patients are being asked to take part in this research study because they have been diagnosed with a type of cancer called medulloblastoma, a type of brain tumor. This study is for patients with high risk medulloblastoma. The term, risk, refers to the chance of the cancer coming back after treatment.
One or more of the following factors make the cancer more likely to return after treatment:
- The tumor is not at the very back of the brain
- Some of the tumor was not removed by surgery
- The cancer has spread to more than one site
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. Patients have a choice between a standard treatment for medulloblastoma and this clinical trial.

Who is Eligible to Participate in the Study?

-Age 3 up to 22 years
-Newly diagnosed with a type of cancer called medulloblastoma, and considered at high risk for the tumor returning
-No prior treatment received

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

What is Involved With this Study?

Random Assignment
Patients will receive one of four 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. Patients who have had clinical depression or an allergy to parabens or soybeans will be randomized to Regimen A or Regimen B and will not receive isotretinoin.

Treatment Plan
The treatment plan will begin within 31 days after the patient's surgery (to remove the tumor) and will involve a combination of radiation therapy and chemotherapy. The treatment on this clinical trial takes either nine or 15 months (depending on the treatment arm the patient is randomized to) and is divided into two or three stages (also depending on the treatment arm they are randomized to).

The first stage of therapy is called chemoradiotherapy. All patients will receive a combination of radiation therapy and chemotherapy to kill the cancer cells that are left over after surgery. This stage of therapy will take six weeks. Some patients will have an extra chemotherapy drug, carboplatin, added to this treatment phase. In the second stage of therapy, called Maintenance, all patients will receive a combination of chemotherapy drugs. Maintenance therapy will last six months. The goal of maintenance therapy is to kill any remaining cancer cells that are left over from chemoradiotherapy. Some patients will have an extra chemotherapy drug, isotretinoin, added to their regimen of chemotherapy drugs during this stage.

Only some patients will go onto a third stage of therapy, called Continuation.
Continuation therapy will consist of six more months of therapy with the drug isotretinoin. The stages of therapy and chemotherapy drugs that the patient receives will depend upon which treatment arm they are assigned to. The patient will be "randomized" into one of the study groups described below.

All patients will receive the standard therapy for medulloblastoma, but some patients will receive additional drugs during their course of therapy.

The four treatment arms are as follows:
- Arm A: will receive standard chemoradiotherapy (radiation therapy and the drug vincristine). Patients will then receive standard Maintenance chemotherapy.
- Arm B: will receive chemoradiotherapy plus the experimental drug carboplatin. Patients will then receive standard Maintenance chemotherapy.
- Arm C: will receive standard chemoradiotherapy. Patients will then receive Maintenance therapy with the addition of the drug isotretinoin and Continuation therapy with isotretinoin.
- Arm D: will receive chemoradiotherapy plus the experimental drug carboplatin. Patients will then receive Maintenance therapy with the addition of the drug
isotretinoin and Continuation therapy with isotretinoin.

If the patient is randomized to Arm C or Arm D to receive isotretinoin, they will be required to complete the Patient Drug Diary for isotretinoin.

Treatment Plan Tables
The following drug therapies relate to the experimental comparison of the treatment groups in this study.
The following methods will be used to give the two investigational drugs in this study:
- PO - Drug is given by tablet or liquid swallowed through the mouth (PO). This applies to the isoretinoin.
- IV - Drug is given using a needle or tubing inserted into a vein. It can be given by IV push over several minutes or by infusion over minutes or hours. This applies to the carboplatin.

Chemoradiotherapy
All patients will be given radiation therapy five days a week for six weeks. In addition to the radiation therapy all patients will receive the drug vincristine on one day each week. This is standard chemoradiotherapy.

Treatment for patients on Treatment Arm B and D
Carboplatin will be given to patients in Arm B and D on the same days that radiation therapy is given (five days of each week for six weeks).
Patients in treatment Arm A and Arm C will not receive carboplatin during chemoradiotherapy.

When the six weeks of chemoradiotherapy treatment is over all patients will have a six-week rest period with no treatment.

Maintenance chemotherapy
When the rest period is over, all patients will move on to maintenance therapy. Maintenance therapy is part of standard care and all patients will get a combination of standard chemotherapy drugs for this stage. Maintenance therapy will consist of six cycles of chemotherapy that each last 28 days (for all Treatment Arms).

The following is a description of the drugs and other details of standard maintenance therapy:

Therapy for patient on all treatment plans:

Chemoradiotherapy
In the first stage of treatment all patients receive chemoradiotherapy. The purpose of the
chemoradiotherapy phase of therapy is to kill as many of the cancer cells left over from the patient's surgery as possible so the disease goes into remission.

Radiation Therapy
Radiation therapy will begin about four weeks after surgery.
Radiation therapy to the brain and spine will be given five days each week for six weeks.

Chemotherapy
V = Vincristine will be given directly into a vein (for less than 60 seconds) once a week for six weeks. The dose will be 1.5 milligrams/square meter (mg/m2).

Maintenance Chemotherapy
Maintenance chemotherapy would be the second stage of treatment for standard therapy. Maintenance therapy is used in this study but with the addition of isotretinoin for some treatment arms. Below is a description of Maintenance chemotherapy as it is being used in this study for all subjects.

Maintenance chemotherapy begins six weeks after the completion of chemoradiotherapy. Maintenance chemotherapy will consist of six cycles of chemotherapy that each last 28 days.
Maintenance chemotherapy will include the following drugs:
- Cisplatin, given directly into a vein over six hours on Day 1 of each cycle. The dose will be 75 mg/m2.
- Vincristine, given directly into a vein over a few seconds on Days 1 and 8 of each cycle. The dose will be 1.5 mg/m2.
- Cyclophosphamide, given into a vein over one hour on Days 2 and 3 of each cycle.
The dose will be 1 gram (g)/m2.

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 patient's blood counts recover after chemotherapy given directly into a vein or by inserting a needle into the tissue just under the skin.

Standard tests and procedures
The following tests and procedures are part of regular cancer care and may be done even if the patient does not join the study.
- Frequent labs to monitor blood counts and blood chemistries
- Urine tests to measure how the kidneys are functioning
- Pregnancy test for women able to become pregnant.
- X-rays and scans to monitor the patient's response to treatment.
- Physical exam
- Liver function tests
- Brain function tests
- MRI (magnetic resonance imaging) of brain and spine. MRI uses magnetic waves to look at soft tissue of the body.
- Evaluation of cerebral spinal fluid (CSF) obtained by lumbar puncture.
- Thyroid function tests.
- Growth tests

Treatment for subjects on Treatment Arm C and D
Arm C and D will have an extra chemotherapy drug, isotretinoin, added to the maintenance therapy regimen.
Treatment Arm A and B will not receive isotretinoin as part of maintenance therapy.

Patients in Treatment Arm A and B will have completed study treatment after maintenance therapy and will only have follow-up testing from that point on unless the tumor grows back.

Continuation Therapy
If the patient is in Arm C or D they will have 6 more cycles of therapy with isotretinoin.
Patients in Arm A and B will have no continuation therapy (their treatment is completed after maintenance therapy).

Research study tests and procedures
The following tests will be done as part of this study.
Although the following tests are part of standard care, they may be done more often if
The patient is on this study:
- Hearing tests
- Blood tests
- Quality of life tests

Brain Function and Quality of Life Tests
In addition to the tests above, study doctors will measure the effects of radiation and chemotherapy on the patient's brain function, ability to learn and quality of life (general wellbeing).
The research staff want to know how the patient is feeling physically and emotionally during their cancer treatment. Researchers also want to look at the relationship between the level of brain function and the patient's quality of life. This information will help study doctors better understand how patients feel during treatments and what effects the medicines are having. In the future, this information may help patients and doctors as they decide which medicines to use to treat cancer.

Patients will be asked to complete questionnaires at the following time points:
- After surgery but before starting radiation therapy
- After finishing the radiation therapy
- After finishing standard chemotherapy
- After finishing chemotherapy with isotretinoin, if given
- About two and one half to three years after completing treatment

The Quality of Life (QOL) questionnaires will take less than an hour to fill out each time.
Only patients aged 18 or younger will be asked to complete the QOL questionnaires since they are not appropriate for adult subjects.

Neuropsychological Tests
The research staff will also ask the patient to complete neuropsychological tests (to measure brain function and their ability to learn) within one month of starting treatment and again two and one half to three years years later. The length of the neuropsychological tests will depend on the age of the patient. Younger children will take shorter tests. In general, it will take between 30 minutes and two hours to complete the tests each time.

Follow-Up Tests
Patients will need to have a number of tests and procedures done as part of their follow-up to treatment. The research staff will use these tests to follow the patient's progress, monitor side effects and look for any signs that the disease has returned.
In addition to those tests done to evaluate the cancer, there will be other tests to monitor the effects of the treatment in their body. Some tests, like the brain function tests and hearing tests, will need to be done more frequently than usual because they are in this study.

- An MRI of head will be done every three months from the time of diagnosis until two years after treatment is finished, then every six months for years 3 and 4. An MRI will also be done if the disease gets worse or comes back after therapy.

- An MRI of spine will be done at the same time points described above for the patient's head if their initial spine MRI showed disease.
- A lumbar puncture will be done at the time of diagnosis. If it shows disease at the time of diagnosis, the test will be repeated every three months for the first year, then every six months for years 2 and 3, then once a year for years 4 and 5. A lumbar puncture will also be done if the disease gets worse or comes back after therapy.
- A hearing test will be performed before each cycle that contains cisplatin, then every six months for two years, and then once a year.
- A test to measure thyroid function will be performed every six months for the first year after treatment, and then once a year.
- A test to measure the patient's growth will be performed every six months for the first year after treatment, and then once a year.
- A test to measure brain function will be performed two and one half to three years years after treatment has ended.

How long will the Study run?

What is the current standard of treatment for this disease?
Standard therapy for medulloblastoma may include surgery, radiation therapy to the brain and spinal cord, and chemotherapy. Radiation therapy is the use of high-energy x-rays to kill cancer cells. Chemotherapy means treatment with "cancer-killing" drugs.

Why is this study being done?
The overall goal of this study is to compare the effects, good and/or bad, of the chemotherapy drugs carboplatin and isotretinoin on Patients with high risk medulloblastoma and to find out if one or both are better than standard therapy alone.
In this study patients will get either standard therapy alone, standard therapy plus one of the chemotherapy drugs added to the regimen, or standard therapy plus both of the chemotherapy drugs.

Carboplatin
Both radiation therapy and the drug carboplatin have an anti-cancer effect when given alone. However, studies have shown that when carboplatin is given along with radiation therapy a greater effect is produced than when either is given alone. In this study the research staff will look at whether giving radiation therapy and carboplatin together can improve the rate of survival of patients with high-risk medulloblastoma.

Isotretinoin
The drug isotretinoin has been shown to cause the death of medulloblastoma cancer cells in the laboratory. Isotretinoin has not been tested in children with medulloblastoma but it has been effective in clinical trials for patients with a type of cancer called neuroblastoma. Neuroblastoma is a different kind of tumor that develops in some kinds of nerve cells but not in the brain. The research staff do not know if this drug will be effective in medulloblastoma. This study will look at whether adding isotretinoin to the standard chemotherapy drugs can improve the rate of survival of children with high risk medulloblastoma.

The main aims of this study are to find out if:
- Giving the drug carboplatin along with radiation therapy is more effective than giving radiation therapy alone
- The drug isotretinoin can improve the survival of patients with high risk medulloblastoma

Other aims of this study are to:
- Measure any effects that the different types of treatment have on the patient's quality of life (general well-being)
- Measure the brain function of patients (measuring intelligence, memory, language, nonverbal skills, attention, and academic achievement) and to examine the relationship between the patient's level of brain function and their quality of life.
An additional research aim for which participation is optional is:
- Identify markers in the DNA of tumor tissue that will help researchers know how best to treat patients in the future and to pick the most promising new therapies for future studies

All of the drugs used on this study are U.S. Food and Drug Administration (FDA) approved for various kinds of cancers and commercially available, but using them together with radiation therapy in this way is experimental treatment.

Sponsor(s): Children's Oncology Group

Study Activation/Registration Date: 11/15/2007

IRB Review and Approval Date: 09/18/2007

Study Type: Treatment

Projected Accrual: The plan is to have up to 300 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: Shakila P. Khan, 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: 03/07/2009