IRB Number:

07-006109

Trial Status:

Open for Enrollment

Phase: III

Why is this study being done?

Parents/ Guardians are being asked to allow their child take part in this study because their child has Down syndrome (DS) and has recently been diagnosed with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

AML is a cancer of the bone marrow, the spongy tissue inside large bones where blood cells are made. In AML, the bone marrow makes large numbers of immature white blood
cells called blasts. These blast cells crowd out the normal cells of the bone marrow. They may flood the bloodstream and invade vital organs such as the brain, testes, ovaries, or skin. These cancerous AML cells can sometimes form a solid tumor called a chloroma. Many patients have MDS before they get AML. MDS is a disease in which the body
makes fewer blood cells than usual. Bone marrow in MDS patients does not produce enough healthy blood cells. MDS can develop into leukemia.


What Is The Current Standard Of Treatment For This Disease?
The standard treatment for AML and MDS is to use a combination of cancer-fighting drugs called chemotherapy. Chemotherapy destroys the leukemia cells in the blood and bone marrow. The standard treatment regimen consists of two phases of therapy, called Induction and Intensification. In the Induction phase we try to remove all visible signs of leukemia and allow normal blood cells to be restored. This is called remission. Induction treatment is usually repeated for three cycles of therapy (each cycle 28 days). The next phase of treatment is called Intensification. Intensification chemotherapy is used to kill the few remaining leukemia cells that may have survived Induction. Intensification is usually three cycles of therapy, and includes high dose cytarabine (one of the chemotherapy drugs) in the last cycle. Patients with AML or MDS may also be treated with up to seven doses of cytarabine that is injected into the spinal fluid.

Why Is This Study Being Done?
Research has shown that children with DS are more likely to develop leukemia than children who do not have DS. However, they are also known to respond better to chemotherapy than children with AML who do not have DS.

The overall goal of this study is to see if we can increase the cure rate and decrease the side effects of therapy. Side effects are unintended and unwanted results of treatment. In this study, we will test the effects good and/or bad of changing the order of one of the chemotherapy treatments, high dose cytarabine (Ara-C). Subjects in this study will receive high dose cytarabine earlier in the treatment schedule than in past studies. Since DS patients do well on chemotherapy, study doctors want to see if it is possible to lower the side effects of chemotherapy without lowering the effectiveness of the treatment. Study doctors would like to know the effects good and/or bad of reducing the following chemotherapy treatments:

1) The number of treatments given in the spinal fluid (called ?intrathecal?)
2) The number of doses of daunorubicin, one of the chemotherapy drugs

A secondary goal of the study is to learn more about the biology of AML and MDS in DS patients. These tests are optional and will be done only if the parent/ guardian agree. Briefly, the biology studies will:
? Test for genetic changes in the leukemia cells, and genetic factors which might affect a patient?s likelihood of getting leukemia and outcome with treatment
? Look for very small amounts of cancer cells in the blood and bone marrow, called minimal residual disease (MRD). Researchers want to find out if measuring MRD can be used in the future to decide how great the risk of the cancer coming back is for a person and predict how a patient will do with treatment
? See what happens to high dose cytarabine (one of the chemotherapy drugs) in the body and how much of the drug remains active over an 8-hour period. These are called pharmacokinetic (PK) tests.
? Collect blood and bone marrow specimens and store them in a cell bank for future research into Down syndrome

In summary, the goals of this study are to:
1. See if changing the order of high dose cytarabine in the treatment plan has an affect on the cure rate for DS patients
2. See if lowering the number of treatments into the spinal fluid and the number of doses of daunorubicin will be as effective as standard treatment with fewer side effects
3. Understand the biology of AML and MDS better with the optional biology tests

Who is Eligible to Participate in the Study?

-Age of patient is under 4 years old
-Diagnosed with Down syndrome (DS) and has recently been diagnosed with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

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

What is Involved With this Study?

Treatment Plan
All of the chemotherapy drugs given in this study have been used before to treat children with AML and MDS. The drugs being used are not new but the way they are being given
on this study is new. All patients participating in this study will get the new treatment. The treatment on this clinical trial takes about six months.

Chemotherapy will be given in the following stages:
- Induction 1: chemotherapy given for four days followed by about three weeks of rest.
- Induction 2: chemotherapy is given for nine days followed by about three weeks of rest.
- Induction 3: chemotherapy is given for four days followed by about three weeks of rest.
- Induction 4: chemotherapy is given for four days followed by about three weeks of rest.
- Intensification 1: chemotherapy is given over seven days followed by three weeks of rest.
- Intensification 2: chemotherapy is given over seven days followed by three weeks of rest.

The treatment given in Induction 2 is usually given as the fifth treatment, but in this study it is the second treatment.

Daunorubicin, one of the standard chemotherapy drugs, is being omitted from Intensification 1 and 2 in this study. The 7 standard therapy intrathecal (or IT) cytarabine injections will be omitted from Induction 2 and 4 and Intensification 1 and 2. Patients will instead only be given IT cytarabine injections as part of Induction 1 and 3 for a total of 2 injections.

Drug Therapy: Before child begins the study
Before entering this study, the child had his or her bone marrow and spinal fluid tested for cancer cells. At the time that the spinal fluid was tested, the child may have
received a drug called cytarabine inserted with a needle directly into the spinal fluid (intrathecal or IT). The spinal fluid is taken out and this drug is put in often during the same procedure. If the child had this done, and if there are no further signs of cancer cells in the spinal fluid, then the child will not need IT cytarabine during Induction I of this study. If this drug was not given at the time the spinal fluid was taken out, then the
child will receive IT cytarabine on this study during the first day of treatment.

Drug Therapy: During the study
If cancer cells are found in the spinal fluid after IT cytarabine is given, the patient will be considered as having Central Nervous System (CNS) disease. A patient will also be considered as having CNS disease if they have a chloroma, or solid tumor sometimes found in patients that have AML. CNS disease is very rarely seen in Down syndrome
patients, and it is treated by giving additional IT cytarabine treatment.

Subjects less than 4 years of age will receive six courses of therapy: Induction 1, Induction 2, Induction 3, Induction 4, Intensification 1, and Intensification 2. The
purpose of Induction therapy is to destroy as many cancer cells as possible in the blood and bone marrow. The purpose of Intensification is to kill any remaining cancer cells
that may not be active but could begin to re-grow and cause the cancer to return (called relapse). All courses of therapy last for 28 days (four weeks). The child will be hospitalized for all courses of therapy.

Medical Tests and Evaluations: Before child begins the study
The child will have a bone marrow aspiration and a lumbar puncture (spinal tap) prior to study entry in order to make the proper diagnosis. These procedures are part of regular
cancer care and may be done even if the child does not enroll on this study. The child is eligible for this study depending on the results of these tests.

Medical Tests and Evaluations: During the study
If the results of the diagnostic bone marrow aspiration and lumbar puncture show that the child can be in the study, and the parent/ guardian choose to have their child take part, then the child will need the following tests and procedures. These medical tests are part of regular cancer care and would be given even if the child did not participate in this study. These tests include:

- Physical exams (including height, weight, body surface area, blood pressure, pulse, temperature, and respiration).
- Blood tests
- Tests of kidney function
- Chest X-rays
- Tests of heart function (Echo/EKG or MUGA).
- Tests of liver function.
- Tests of lung function.
- Immunophenotyping (tests on the cancer cells to determine the types of molecules that make up the cancer cells. These molecules are found on the outside of the cells).
- Histocytochemistry (tests on the chemicals and other materials inside the cells by means of staining reactions or other methods).
- Cytogenetic Tests (a portion of bone marrow will be used to study the genetic material within the cells [i.e. chromosomes]. The tests that study chromosomes and chromosomal changes are called cytogenetic tests.

Bone marrow aspirations:
Patients will have about one-half teaspoon of their bone marrow taken with a needle (aspirate). The test may be painful and has some small risk of infection or bleeding. The pain normally lessens within seconds to hours. In many cases, children will get medications by vein to numb the pain and blur the memory. Sometimes they may be given general anesthesia. These tests are necessary to see how well the therapy is working for the child.

How long will the Study run?

The child will be asked to take study drugs for approximately six months if enrolled on
this study. After the child is finished taking study drugs, the study doctor will ask the patient to visit the office for follow-up exams every month for the first 12 months, every three months for the next 12 months, every six months until five years following completion of therapy, and then once a year after that. Echocardiograms will be given once a year for the first five years. After five years, they will be given according to the doctor's orders.
Echocardiograms use sound waves to take pictures of the heart. These tests would most likely be given even if the child was not on this study. The research staff will continue to collect some medical information about how the child is doing for 10 years after the last patient starts the study.

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

Study Activation/Registration Date: 02/21/2008

IRB Review and Approval Date: 01/31/2008

Study Type: Treatment

Projected Accrual: The plan is to enroll up to 205 patients to 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: 05/12/2008