Introduction

This family protocol summary is about the Children’s Oncology Group study AALL1131. It tells who is eligible and gives basic information about the study. More details about the study are in the consent form. You can get this from your oncologist.

AALL1131 is a Phase III clinical trial. A trial is another word for a study. This study (clinical trial) is a therapeutic clinical trial. That means it is done to learn about treatment – its safety and how well it works. The purpose of a Phase III trial is to learn if a new treatment that is known to work in treating a type of cancer is better in some way than the standard treatment. For example, does it have better cure rates, longer control of disease, fewer or less serious side effects, or fewer days in the hospital?

AALL1131 has 1 standard treatment for the high risk group for the first month of therapy. This study also includes 1 treatment for the very high risk group, and an additional treatment option for patients with a specific change seen in the leukemia cells. These treatments are called study arms. Usually, one study arm is the standard or the best proven current treatment. The other study arms have some changes or additions. The new treatment is thought to be at least as good as the standard treatment. It is not known if the new treatment will be better than the standard treatment.

In a Phase III trial, each child may be assigned to a study arm by a method called randomization. This is a process like flipping a coin that assures that each child has a fair and equal chance of being assigned to any of the study arms. This way the study arms can be compared fairly.

In most clinical trials, we will not know which treatment is better until all of the children taking part in the trial have completed treatment and have been getting checked for several years. If one of the treatments is found to be better or safer than the others while the trial is still going on, the trial will be stopped. All children still in the trial will be given the treatment with the best results when possible.

It is important to understand that participating in a clinical trial is entirely voluntary. The decision about whether or not to participate will not affect the care provided by the health care team in any way. You can find additional information about participation in clinical trials at www.childrensoncologygroup.org. Always discuss any questions that you may have with your health care team.

Study Number

AALL1131

Official Title

A Phase III Randomized Trial for Newly Diagnosed High Risk B-precursor Acute Lymphoblastic Leukemia (ALL) Including a Stratum Evaluating Dasatinib in Patients with Ph-like Tyrosine Kinase Inhibitor (TKI) Sensitive Mutations

Trial Opening Date

AALL1131 opened on February 27, 2012. The AALL1131 committee hopes to enroll 5437 patients. It was initially expected to take 5 years to enroll, however due to the addition of a treatment arm on August 29, 2016, the timeframe for enrollment has been extended. There is no set date for study enrollment to end.

General Patient Eligibility

• Age: 1-30 years
• Diagnosis: Newly diagnosed high-risk pre-B acute lymphoblastic leukemia (ALL)

Please consult your doctor to determine whether you or your child may participate in this study.

General Background and Study Goal

Patients diagnosed with ALL are assigned to risk groups based on their age, white blood cell count and genetic factors present at the time of diagnosis. The term ‘risk’ in ‘risk group’ means the ‘risk of the leukemia cells coming back,’ so understanding the risk group helps determine what treatment is best. The current best treatment, also called standard therapy, uses various chemotherapy drugs depending on the risk group. AALL1131 will study treatment options for two risk groups: the high risk group and the very high risk group. The high risk group will receive five phases of chemotherapy and the very high risk group will receive six phases.

Although the overall survival of patients with ALL is good, past studies have shown that some patients will have leukemia cells that reappear during or after completing therapy. This is called ‘relapse’. The need for more intensive treatment may be based upon the response to treatment, measured by minimal residual disease (MRD) in the bone marrow.

MRD is a laboratory measurement that is able to detect very small amounts of leukemia cells in the blood or bone marrow, which helps the treatment team understand how well a patient is likely to do with their future treatment.

Drugs are said to be given ‘intrathecally’ if they are given in the spinal fluid.

Recent studies have shown that some patients will have leukemia cells with specific changes that decrease the chance of the leukemia to respond to the various chemotherapy drugs. This is called ‘treatment failure’. Therefore, if these specific changes are seen in the leukemia cells after the first month of therapy, this study is looking at adding a specific medication that targets these specific leukemia cells, called Dasatinib, to the various chemotherapy drugs.

Children with Down syndrome are very sensitive to chemotherapy drugs and experience more drug side effects than children without Down syndrome. This study is trying to minimize the use of one of these drugs called daunorubicin. If the bone marrow evaluation done after 2 weeks of chemotherapy shows that the leukemia has not responded well to the initial treatment, daunorubicin will be added.

The overall goal of the study is to improve the survival and decrease the relapse of children with pre-B ALL. In children with Down syndrome, the overall goal is to minimize long term side effects while maintaining the very good survival rate.

Summary of the Treatment

After the first month of therapy, patients in the high risk group who have close to no MRD, will no longer continue on the study. These patients will continue on standard therapy. Patients in the very high risk group will be assigned to one treatment arm. Patients with specific changes in the leukemia cells will be assigned to a separate treatment arm after the first month of therapy. Patients with Down syndrome will be assigned one of two different treatment arms based upon the bone marrow response after the first two weeks of treatment.

High Risk group *

• Arm A: standard chemotherapy with one intrathecal drug
• Arm B: standard chemotherapy with three intrathecal drugs
  • * High risk group randomization permanently closed on March,16, 2018 due to learning that there was no benefit to three intrathecal drugs versus one intrathecal drug

Very High Risk group ***

• Control Arm: standard chemotherapy
• Arm 1: standard chemotherapy + cyclophosphamide and etoposide during 2 cycles of chemotherapy (consolidation and delayed intensification)*
• Arm 2: standard chemotherapy + cyclophosphamide, etoposide, and clofarabine during 2 cycles of chemotherapy (consolidation and delayed intensification)**
  • * Arm 1 was closed on February 15, 2017 due to learning that there was no benefit with the use of cyclophosphamide and etoposide resulting in permanent closure of Very High Risk group randomization.
  • ** Arm 2 was closed on September 15, 2014 due to increased complications
  • *** Very High Risk group assignment remains open as of January 2, 2018 for patients who have remaining MRD after the first month of therapy

Dasatinib Arm As of August 29, 2016, all patients with specific changes seen in the leukemia cells will receive the control arm of the very high risk group with the addition of Dasatinib after the first month of therapy.

Patients with Down Syndrome All patients will receive 3 drugs in the first two weeks of Induction and then depending on the 2 week bone marrow response will either continue to receive only 3 drugs, or 3 drugs plus daunorubicin for the remaining 2 weeks. All patients will then continue to receive standard chemotherapy with the exception of a less intensive dose of methotrexate in interim maintenance.

Please refer to the Family Handbook or the Children’s Oncology Group website: www.childrensoncologygroup.org for additional information.

Special Considerations

• Patients must be enrolled on the COG ALL Classification Study (AALL08B1) or the Project Every Child Registry (APEC14B1).
• Patients will receive radiation therapy if leukemia cells were detected at the time of diagnosis in either the central nervous system and/or testes.

Risks and Side Effects

Chemotherapy can cause side effects during and after treatment. All patients will be closely monitored for possible side effects of the medicines. All risks and side effects will be explained by your treatment team during the consent process. They can answer any questions that you may have about giving permission for your child to be in the clinical trial or other aspects of care. Please refer to the consent form for a detailed explanation of the side effects associated with the treatment on this study.

Contact Information

Your child’s oncologist and nurses are the best source for further information

Study Chairs

• Michael James Burke MD
  Children’s Hospital of Wisconsin – Medical College of Wisconsin
• Wanda Lynne Salzer MD
  U.S Army Medical Research and Material Command Combat Casualty Care Research Program

FAMILY PROTOCOL SUMMARY REVIEW/APPROVALS