IRB Number:

07-006053

Trial Status:

Open for Enrollment

Phase: I

Why is this study being done?

Patients have been treated in the past for a cancer of the blood cells called acute lymphoblastic leukemia (ALL). Patients are being asked to take part in this study because the leukemia has come back (relapsed) and is of intermediate risk. The term "risk" refers to the chance of the cancer coming back again after treatment for this relapse. The patient's leukemia is defined as "intermediate risk" because one of the following apply:
-The leukemia returned in their bone marrow (with or without leukemia in
other parts of their body) 3 years or more after they were first diagnosed
with ALL.
-The leukemia returned in the patient's central nervous system (spinal fluid) and/or the testes (but not in the bone marrow) less than 18 months after they were first diagnosed with ALL.

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. Many different chemotherapy treatment programs have been used for children with intermediate risk relapse of ALL, and there is no real standard treatment at this time. Patients have a choice between other treatments for ALL and this clinical trial.

What Is The Current Standard Of Treatment For This Disease?
There is no generally accepted standard treatment for intermediate risk relapse of ALL at this time. Combination chemotherapy has been the main treatment for children with intermediate risk relapsed ALL. Several studies have used various combinations and had similar outcomes in the number of children treated successfully.

The first month of treatment usually involves chemotherapy very similar to that given to treat ALL for the first time. Children with intermediate risk relapse have an excellent chance of going into a second remission (disappearance of all signs and symptoms of ALL).
However, the risk that the leukemia will come back after getting into remission is definitely higher than it was when the patient was first diagnosed with ALL. Because of this, the treatment that is given for relapse is more intensive (stronger) than that given to treat ALL for the first time. Like the first treatment for ALL, treatment for intermediate risk relapse has several phases. All phases of treatment are very important. The total length of chemotherapy treatment used for intermediate risk relapse varies from about 1.5 to 2.5 years in most cases.

Some doctors also recommend bone marrow (stem cell) transplants for some children and adolescents with intermediate risk relapse. This study will recommend bone marrow transplant for children with intermediate risk relapse that go into a second remission and have a matched family donor. About 20 to 30 percent of patients will have a close match. This use of bone marrow transplant is considered to be a valid treatment. Also, radiation therapy is sometimes used in relapsed ALL, especially if the relapse involves organs such as the brain or testes.

Why Is This Study Being Done?
Since there is no standard treatment regimen for children with intermediate risk relapse of ALL, the major goal of this study is to establish an effective therapy. The study treatment plan is based on an earlier plan (?POG 9412?) which showed a good effect in children who had a relapse of ALL in the brain. In this study, the treatment will be strengthened by giving higher doses of chemotherapy drugs more often. This study is to determine how effective this treatment is for all types of intermediate risk relapse.

Patients received vincristine during their first treatment for ALL, and it is part of treatments commonly used for relapsed ALL. The standard dose of vincristine is 1.5 milligrams/square meter (mg/m2)with a maximum dose of 2 mg. Higher doses of vincristine have been used to treat children with other forms of cancer and a recent Dutch trial has also used a higher dose to treat children with ALL. The researchers want to see if a higher dose of vincristine (2 mg/m2 with a maximum dose of 2.5 mg) can get rid of the cancer for as long as possible in more patients with relapsed ALL.


Researchers want to compare the effects, good and/or bad, of chemotherapy with a high dose of vincristine against chemotherapy with a standard dose of vincristine. The research staff want to find out which dose is better. In this study, patients will get either the high dose of vincristine or the standard dose of vincristine. Patients will not get both.

The goals of this study are:
1) To find out the effectiveness and side effects of the high dose combination chemotherapy treatment for all patients on this study.
2) To find out the effectiveness and side effects of higher dose vincristine compared to standard dose vincristine.

In addition to the treatment goals, researchers would like to use specimens collected on this study to answer some research questions that might benefit future patients. Patients can choose to be in this clinical trial without taking part in this research portion.

One of the biology research goals involves a test to measure minimal residual disease (MRD). This test measures numbers of leukemia cells that are too small to be counted using traditional methods. Researchers will use it to find out if leukemia is still present in the bone marrow. The research staff also want to study the genetic make-up of the cancer cells to try to learn about why people get cancer and if the genes in the cancer cells can predict how someone will respond to treatment.

Biology Research Goals (Optional Participation):
1) To find out if MRD levels can be used to tell how well a patient with relapsed ALL is responding to treatment. Researchers also want to find out if high MRD levels can be used to identify people at higher risk of another relapse.
2) To study genetic changes, and patterns within the genes of the leukemia cells. The research staff hope to learn more about disease resistance and find out if they can predict how well someone will respond to chemotherapy.
3) To find out if a) differences that occur naturally in genes (polymorphisms) might be part of the reason why some people develop leukemia and b) if those differences influence why some patients have certain side effects with treatment.

Who is Eligible to Participate in the Study?

-Age 1 year old to less than age 30 years old
-Treated in the past for a cancer of the blood cells called acute lymphoblastic leukemia (ALL)
-Patient's leukemia has come back (relapsed) and is of intermediate risk

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

What is Involved With this Study?

All of the chemotherapy drugs given in this study have been used before to treat children with relapsed leukemia. The drugs being used are not new but the way they are being
given on this study is new. In this study, the experimental treatment will involve giving some drugs at higher doses or more often than they have been given in previous studies.

The differences include:
- Methotrexate given into a vein (IV infusion) will be given in high doses
- High dose cytarabine (Ara-C) will be given more often
- Additional doses of vincristine will be given during the phases of treatment called "Intensification"

The differences listed above will apply to all subjects treated on this study. In addition, some subjects will receive a higher dose of vincristine throughout therapy, as explained below under "Random Assignment".

Random Assignment
Patients will go on one of two different arms of the treatment plan. The arm they are assigned to 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 arm of the study.

The only difference between treatments on the two arms is that patients will receive a different dose of vincristine during some stages of therapy. Some patients will be randomized to receive the standard dose of vincristine during treatment (Arm A); others will get a more intensive (higher) dose of vincristine (Arm B).

The dose given to patients on each arm is shown below. The rest of the therapy will be the same in both groups of patients.

Arm A: The standard dose of vincristine is 1.5 mg/m2 (The maximum dose given will be 2 mg).

Arm B: The intensive (experimental) dose of vincristine is 2 mg/m2 (The maximum dose given will be 2.5 mg). This dose has been given to children with ALL for many years, but not using this schedule or with this combination of other chemotherapy drugs.

The rest of the therapy will be the same for both groups of patients.

Treatment Plan
The treatment plan involves cancer fighting medicine called chemotherapy and may include radiation therapy. Treatment on this clinical trial will take about 27 months (a
little over two years). It is divided into seven stages: Induction 1; Induction 2; Induction 3; Intensification 1; Re-induction; Intensification 2 and Maintenance.

After the Induction 3 phase of treatment, patients that have a matched family member that is a suitable donor for bone marrow transplant will be recommended to have a bone
marrow transplant rather than receive the rest of the chemotherapy treatment. Bone marrow transplant may be offered as part of a different research study. The doctor will discuss that decision with the patient in more detail because it is not part of this research study.

All patients that do not get a bone marrow transplant will receive all seven stages of therapy.


Tests and Procedures Common to All Subjects with Relapsed ALL Treated on this Study.

Standard tests and procedures during therapy
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
- X-rays and scans to monitor the patient's response to treatment or side effects.
- Tests to monitor heart and lung functioning
- Bone Marrow Aspirations to see if the leukemia is responding to treatment.
- Spinal Taps to check for leukemia cells in the spinal fluid and to give chemotherapy into the spinal fluid.
- Test to measure patient's heart function (Echocardiogram)
- Testicular exams (in males)
- Testicular biopsies

Standard follow up tests and procedures done after stopping therapy
The following tests and procedures are part of the regular follow up for patients treated for relapsed ALL and may be done even if the patient does not join the study.

1st year after therapy:
- Physical exam, labs to monitor blood counts and blood chemistries every 1-2 months,
- Kidney function test every two months until levels are normal.
- Bone marrow aspirations, spinal taps and a test to measure the patient's heart function
(Echocardiogram) as often as their doctor considers it necessary.

2nd year after therapy:
- Physical exam and labs to monitor blood counts and blood chemistries every three months
- Echocardiogram as often as the doctor considers it necessary.

Years 3-5 after therapy:
- Physical exam and labs to monitor blood counts and blood chemistries every 6-12 months
- Echocardiogram as often as the doctor considers it necessary.

How long will the Study run?

Patients in this clinical trial are expected to receive treatment on this study for about 2-2½ years. After treatment, patients will have follow-up examinations and
medical tests for five years.

The research staff would like to continue to find out about the patient's health for about five years after the study closes to new patients. Keeping in touch with the patient and checking on how their health is every year for a while after the study closes helps the researchers understand the long-term effects of the study.

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

Study Activation/Registration Date: 02/14/2008

IRB Review and Approval Date: 01/31/2008

Study Type: Treatment

Projected Accrual: The plan is to have up to 418 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: 05/12/2008