IRB Number:

987-04

Trial Status:

Open for Enrollment

Phase: III

Why is this study being done?

Leukemia is cancer of the blood. It starts in the bone marrow, which is the soft, spongy center of the long bones that makes the three major blood cells: white blood cells to fight infection; red blood cells that carry oxygen; and platelets that help blood clot and stop bleeding. Acute lymphoblastic leukemia (ALL) is a disease in which too many underdeveloped (not normal) infection-fighting white blood cells called "blasts", are found in the blood and bone marrow. These blasts crowd out the normal cells and can be found in the brain, spinal cord, and/or other organs of the body.

ALL is said to be "high risk" because patients have a white blood cell count of over 50,000 and/or they are ten years of age or older. Patients are also classified as "high risk' if any of the following applies:
- They are a male and have leukemia in their testes, regardless of their age and/or white blood cell count
- Patient has gotten treatment with steroid medicines, such as prednisone or decadron, in the month before they were diagnosed with leukemia

This study is being done to see if we can increase the cure rate of high risk ALL without increasing the side effects (unintended and unwanted results) of treatment.

The rate of survival keeps getting better for children and adolescents with high risk ALL. However, leukemia in the central nervous system (CNS) (brain and spinal cord) has become an increasing cause of treatment failure. This study will use an established chemotherapy regimen that has been very effective for treating children and adolescents with high risk ALL and will test if two different changes to this treatment can cure more patients.

Goal #1: To find out if using dexamethasone instead of prednisone during the first month of treatment can improve survival rates without causing more bad side effects. Prednisone and dexamethasone are closely related medicines called "steroids." In previous studies, steroids have been shown to be very effective against ALL, especially when given early in treatment. The standard treatment in high risk ALL is to give prednisone every day for 28 days during the first month of treatment.

When dexamethasone was used for all 28 days of the first month of treatment in many recent U.S. trials for children and adolescents with high risk ALL, there was a higher risk of infection. This included major life-threatening infections.

Because of this, the study will test two things:
- If 14 days of dexamethasone, instead of 28, can be taken without a higher number of bad side effects, and
- If 14 days of dexamethasone will be better than 28 days of prednisone in lowering the number of leukemia cells during the first month of treatment.

Goal#2: To find out if using high doses of methotrexate instead of using lower doses of
methotrexate on a schedule that gradually increases the dose, will keep the cancer from coming back without having more bad side effects.

Methotrexate is a cancer-fighting drug that is very important in the treatment of leukemia.
There are two different ways to give methotrexate during the interim maintenance stage of treatment. We know that both of these ways of giving methotrexate have been very effective in treating ALL, but they have never been directly compared to one another in children and adolescents with high risk ALL.

In"high dose" methotrexate treatment, the same dose of methotrexate is given a total of four times (every two weeks over a nine-week period).

In Capizzi methotrexate, methotrexate is given a total of five times (every 10 days over an eight-week period). Instead of being the same dose (as in high dose methotrexate treatment), Capizzi methotrexate is given at a lower dose the first time, and the amount of the dose slowly increases with each of the later doses. Capizzi methotrexate also includes treatment of another medicine, call PEG-asparaginase, which is given twice during this eight-week stage of treatment.

In addition to the goals related to the changes in treatment, there is an additional research
goal.
Goal#3: To see how quickly patients are helped by the induction phase (reach disease remission) and how well they do after treatment, as measured by the presence or absence of very small numbers of leukemia cells in the bone marrow after the first month of treatment.

Who is Eligible to Participate in the Study?

- Age 1 through 30
- Patients must have newly diagnosed B-precursor ALL.
- Patients shall have had no prior (cytotoxic) chemotherapy with the exception of steroids and intrathecal (given through the spine) cytarabine.

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

What is Involved With this Study?

Random Assignment
Patients will be put in one of four groups by chance (as in the flip of a coin). The patient or the researcher cannot pick the group a patient will be in. A patient has an equal chance of being placed in any of the four treatment groups.

Treatment Plan
There are two parts to the randomization process and they will both happen at the same time when enrolled on this study.

Randomization Part 1: Patient will be randomized to get one of two steroid groups during induction. In one group, patients get dexamethasone for two weeks (14 days). In the other group, patients get prednisone for four weeks (28 days). The remainder of induction treatment will be the same in both groups.

Randomization Part 2: Patient will be randomized to one of two methotrexate treatment groups during Interim Maintenance I. In one group, patients get high dose methotrexate with vitamin replacement called leucovorin. In the other group, patients get Capizzi methotrexate as described previously.

The four treatment groups are called DC, DH, PC, and PH as follows:
DC: two weeks dexamethasone during Induction Capizzi I methotrexate during Interim Maintenance I
DH: two weeks dexamethasone during Induction High dose methotrexate during Interim Maintenance I
PC: four weeks prednisone during Induction Capizzi I methotrexate during Interim Maintenance I
PH: four weeks prednisone during Induction High Dose methotrexate during Interim Maintenance I

Patients who do not get randomized
Some patients on this study will not be randomized because they have characteristics that put them at greater risk of the leukemia coming back (relapsing). Researchers want them to get the more extended treatment available on this study even though it is the one most likely to produce the greatest side effects.

If patients fall into one of the following categories, they will not be randomized but they will be assigned to treatment based upon their specific situation.
- Patients with leukemia in their central nervous system (brain and spinal cord) classified as "CNS3."
- Male patients with signs of leukemia in their testes.
- Patients who have already been treated with steroids (like prednisone,
dexamethasone, prednisolone).
- Patients with leukemia cells that are found to have certain genetic condition affecting a gene called "MLL" have been found to have a higher risk of relapse in some treatment studies. Because of this, if a patient's MLL gene is affected, they will be assigned to stronger treatment or will be removed from the study based upon how well they respond to the first month of treatment.

How long will the Study run?

Patients will be in this study for up to five years.
Females are expected to get treatment on this study for about two and one half years. Males are expected to get treatment on this study for about three and one half years because males get longer maintenance treatment.

After treatment, patients will have follow-up exams and medical tests as part of routine cancer care. The researchers will continue to collect some information about how the patient is doing for 10 years after the last patient starts treatment on study.

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

Study Activation/Registration Date: 06/17/2004

IRB Review and Approval Date: 06/03/2004

Study Type: Treatment

Projected Accrual: The plan is to have up to 2,292 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: 05/07/2008