Introduction

This clinical trial summary is about the Children’s Oncology Group study AALL1732. It explains 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.

AALL1732 is a Phase 3 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?

AALL1732 will include patients with B-cell acute lymphoblastic leukemia (B-ALL), mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy). AALL1732 divides patients into two different groups:

  1. High risk B-ALL patients with favorable characteristics as well as patients in specific identified groups (MPAL and B-LLy), who will receive standard chemotherapy.
  2. High risk B-ALL patients with either neutral (not favorable or unfavorable) or unfavorable characteristics, who will receive the same standard chemotherapy with or without the addition of a new drug called inotuzumab.

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 3 trial, each patient may be assigned to a study arm by a method called randomization. This is a process like flipping a coin to assure that each patient has an 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 patients taking part in the trial have completed treatment and have been getting check-ups for several years. If one of the treatments is found to be better or safer than the other(s) while the trial is still going on, the trial will be stopped. All patients 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

AALL1732

Official Title

A Phase 3 Randomized Trial of Inotuzumab Ozogamicin for Newly Diagnosed High-Risk B-ALL; Risk Adapted Post-Induction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and Disseminated B-LLy

Study Opening Date

AALL1732 opened on October 28, 2019. The AALL1732 committee plans to enroll 3,698 patients over the next 5 years. It is expected that this study will remain open until 2024.

General Patient Eligibility

  • Age: 1-25 years old
  • Diagnosis: newly diagnosed high risk B-lymphoblastic leukemia (B-ALL), mixed phenotype acute leukemia (MPAL), or stage 3 or 4 B-lymphoblastic lymphoma (B-LLy) or B-LLy with steroid pretreatment
  • Patients with Down Syndrome will not be eligible for this study

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

General Background and Study Goal

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Survival rates for this type of leukemia range from 80-85%. While overall cure rates for ALL have greatly improved over the past few decades, there are still specific groups of patients that have lower survival rates. Previous clinical trials have tried to improve these survival rates by adding different chemotherapy agents to the standard chemotherapy regimen, or by increasing the frequencies and dosages of known chemotherapy agents. Unfortunately, these changes have been unable to increase survival rates, and have also caused increased toxicities in patients.

However, targeted immunotherapies have had impressive response results in patients with relapsed ALL. Targeted immunotherapies are drugs that use the immune system to target the cancer. Inotuzumab is one of these agents. AALL1732 will look to see if adding inotuzumab to the standard chemotherapy regimen can increase overall cure rates for high risk patients without increasing toxicities.

Standard therapy uses a variety of chemotherapy drugs given at different doses, schedules or intensity, depending on the risk group. Treatment is administered in 5 distinct phases, or periods of time, called:

  • Induction
  • Consolidation
  • Interim maintenance (one or two phases depending on diagnosis and risk group)
  • Delayed intensification
  • Maintenance

The term “risk” in “risk group” means the “risk” of the leukemia cells coming back. Knowing the patient’s risk group helps determine what treatment is best. Patients with B-ALL are assigned to risk groups based on their age and white blood cell count at diagnosis, leukemia cell characteristics, and response to initial treatment. If a patient has features that put them at a lower risk for relapse, they are called “favorable” characteristics. If a patient has features that put them at a higher risk for relapse, they are called “unfavorable” characteristics. Some patients will not have any specific features, and they are called “neutral” characteristics. Leukemia cell characteristics include information about the genetics or biology of a patient’s leukemia. Response to treatment is determined by a laboratory measurement that is able to detect very small amounts of leukemia cells in the blood or bone marrow. This laboratory test is called minimal residual disease, or MRD.

Patients with B-LLy will be placed into risk groups based on whether and how long steroid treatment was used prior to diagnosis, and the presence of lymphoma cells in various parts of the body, including in the bone marrow or central nervous system.

B-ALL
In AALL1732, patients with B-ALL are assigned to one of two risk groups:

  • High Risk with favorable features (HR-Fav)
    • Age less than 10 years old but white blood cell count greater than 50,000 at diagnosis
    • No leukemia in the brain/spinal cord or testes
    • Favorable genetic characteristics
    • MRD level less than 0.01% in the bone marrow by end of Induction
  • High Risk (HR)
    • Standard risk (SR) (age less than 10 years and white blood cell count less than 50,000 at diagnosis) but with leukemia in the brain or spinal fluid; steroid treatment 2 weeks prior to diagnosis; and/or leukemia in the testes with MRD less than 1% in the bone marrow by end of Consolidation
    • HR (age greater than 10 years or white blood cell count greater than 50,000 at diagnosis) who do not meet criteria of HR-Fav and with MRD level less than 0.01% in the bone marrow by the end of Consolidation

Patients with HR-Fav B-ALL on AALL1732 will be assigned to the standard arm of treatment.

Patients with HR B-ALL on AALL1732 will be randomly assigned to receive the standard arm of treatment, or the standard arm of treatment with the addition of 2 cycles of inotuzumab. The goal is to maintain or improve cure rates, without increasing side effects.

To ensure safety when giving inotuzumab to newly diagnosed patients, there will be an initial safety period to monitor inotuzumab’s effects on the liver and blood counts.

B-LLy
Patients with B-LLy are treated with "leukemia type" treatment with excellent outcomes. Patients with B-LLy will be assigned to the standard arm of treatment, with the goal of learning more about lymphoma biology and response to treatment.

MPAL
Patients with MPAL have leukemia that has both lymphoblastic (ALL) and myeloblastic (AML) features. Recently research has indicated that these patients do better when treated with "ALL type" treatment rather than “AML type” treatment. Patients with MPAL will be assigned to the standard arm of treatment, with the goal of learning more about MPAL biology and response to treatment.

Summary of the Treatment

AALL1732 will divide patients with B-ALL into two groups, those with favorable characteristics, and those with neutral or unfavorable characteristics. Patients with neutral or unfavorable characteristics will be randomized into another two groups. One group will receive standard chemotherapy, and the other group will receive standard chemotherapy with the addition of two cycles of inotuzumab.

Patients who have measurable MRD in the bone marrow at the end of Consolidation will not be able to continue on study but may be eligible for another study, AALL1721.

Patients with B-ALL and favorable characteristics, MPAL, and B-LLy will not undergo a randomization, but will receive standard chemotherapy.

AALL1732 will decrease the duration of therapy to about 2 ½ years for both girls and boys. Historically, total treatment duration was 1 year longer for boys.

Special Considerations

  • Inotuzumab infusions are given at the hospital and may require more outpatient visits
  • There may be an increased risk of liver toxicity
  • There may be an increased need for blood and/or platelet transfusions

 

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. Your treatment team will explain all risks and side effects 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.

Adherence Study

AALL1732 will have an additional study available for patients who meet the following eligibility requirements:

  • Diagnosed with B-ALL (not B-LLy or MPAL)
  • Age at diagnosis: 10 years or greater and less than 25 years old
  • English or Spanish speaking
  • Receiving the chemotherapy agent mercaptopurine (6-MP) during the maintenance phase
  • Able and willing to use a special tracking pill bottle, also known as the MEMS TrackCap
  • Willing to use a smartphone to receive medication reminders
  • Has a designated parent/caregiver to participate in a daily supervised routine

This additional study is known as an adherence study. Adherence can be defined as how well someone follows directions. This study will examine whether specific reminders can increase the chance of the 6-MP medication being taken as prescribed in the home. These specific reminders are known as interventions. It will also look to see if personal characteristics and/or understanding about your child’s health will have any effect on adherence.

All patients who are enrolled in this study will take part in the following interventions:

  • MEMS TrackCap is a special pill bottle used to track 6MP adherence. Patients and caregivers will be educated on how to use the MEMS TrackCap and will receive these bottles at the start of Maintenance Cycles 1 and 3.
  • Multimedia Interactive Patient/Parent Education (MIPE) is an interactive education program that uses video clips to discuss 6-MP adherence. MIPE provides a flexible and individualized way to learn about the importance of adherence and will be viewed by the patient and designated caregiver at the start of Maintenance Cycle 2.
  • Customized printed medication schedules are individualized 6-MP schedules that are printed and provided by the healthcare provider every four weeks during Maintenance Cycles 2-4. They will be available in English or Spanish.
  • Directly supervised therapy will involve training the designated caregiver to remind the patient to take 6-MP every day and to supervise the patient swallowing the medication. Training for the caregiver will be done at the start of Maintenance Cycle 2.

In addition, all patients will be randomized into one of three possible groups with an intervention of varying intensity. The three possible groups are as follows:

  • Group IP will receive daily electronic reminders by smartphone from their healthcare provider to take their 6-MP.
  • Group iIP will receive daily electronic reminders by smartphone from their healthcare provider with real-time feedback and extra reminders to take their 6-MP if necessary.
  • Group pIP will be trained along with their designated caregiver to make their own personal electronic reminders by smartphone to take their 6-MP.

Patients will have additional blood draws at specific times to determine the amount of measurable 6-MP in the body. There will also be questionnaires that must be completed by the patients/caregivers at specific times looking at personal characteristics and understanding related to adherence.

Contact Information

Your (or your child’s) oncologist and nurses are the best source for further information

Study Co-Chairs

  • Jennifer McNeer, MD, MS
    University of Chicago Comprehensive Cancer Center
  • Maureen O’Brien, MD, MS
    Cincinnati Children’s Hospital Medical Center

 

FAMILY PROTOCOL SUMMARY REVIEW/APPROVALS

Initial development Name Date
Written by (protocol nurse) Lauren Guidry, NP
Christine Yun, NP
August 30, 2019
Reviewed/approved by (PI) Maureen O’Brien October 24, 2019
Ongoing review
Reviewed and updated by