Introduction

This family protocol summary provides a general overview of the Children's Oncology Group (COG) study AAML1331. 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.

AAML1331 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?

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 the new treatment is found to not be safer, or is less effective than the standard treatment 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

AAML1331

Official Title

A Phase III Study for Patients with Newly Diagnosed Acute Promyelocytic Leukemia (APL) using Arsenic Trioxide and All Trans-Retinoic Acid

Study Opening Date

AAML1331 opened on June 29, 2015. The AAML1331 committee hopes to enroll 158 patients. It is expected that this study will remain open for approximately 5 years.

General Patient Eligibility

• Age: 1 year - 21 years
• Diagnosis: Newly diagnosed acute promyelocytic leukemia

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

General Background and Study Goal

Acute promyelocytic leukemia (APL) is a sub-type of acute myeloid leukemia (AML). Standard treatment for APL, meaning what has been used most successfully in the past, includes 3 phases of treatment. The 1^st phase of treatment, called Induction, uses chemotherapy including medications called anthracyclines along with another drug, all-trans retinoic acid (ATRA). The 2^nd phase of treatment, called Consolidation, uses a combination of chemotherapy medications including anthracyclines. The 3^rd phase, called Maintenance, uses ongoing medication, usually at a lower dose, and lasts 1-2 years.

Anthracycline therapy is part of the standard treatment of APL, but it may cause long term side effects, especially to the heart. Exposure to high cumulative doses of anthracycline used during standard treatment of APL is also associated with increased risk for infection and secondary cancers.

Arsenic Trioxide (ATO) is a drug that has been effective for treatment of patients with relapsed APL. ATO appears to have better anti-cancer activity than ATRA for treating APL, and it appears that combining ATRA with ATO may be more effective in reducing the risk of relapse than ATO alone. Several large adult clinical trials using little or no chemotherapy have shown that APL may be cured with ATRA and ATO alone. Further study of ATO in newly diagnosed patients is needed.

The main goal of this study, AAML1331, is to find out if eliminating or decreasing the amount of anthracycline chemotherapy used in standard APL treatment, adding arsenic trioxide, and eliminating the maintenance phase of therapy will reduce some of the long term side effects while maintaining a good cure rate in patients with newly diagnosed APL.

Summary of the Treatment

All patients will be assigned to a treatment group based on the white blood cell (WBC) count at diagnosis.

• standard risk group = patients with WBC count less than 10,000
• high risk group = patients with WBC count 10,000 or more

Both the standard risk group and the high risk group will receive an IV infusion of ATO every day and take ATRA capsules twice a day for at least 28 days.

In addition, patients who are in the high risk group will also receive IV infusions of idarubicin (an anthracycline chemotherapy) and oral dexamethasone (a steroid drug) during Induction. Patients in the standard risk group will not receive either of these drugs.

Consolidation phase therapy is identical for both groups. Consolidation lasts a total of 28 weeks and is divided into 4 cycles. During Consolidation, patients take ATRA pills twice a day for 2 weeks followed by 2 weeks without taking pills. This is repeated every 4 weeks. Patients will also receive infusions of ATO every Monday-Friday for 4 weeks, followed by 4 weeks without infusions, repeated every 8 weeks.

This clinical trial does not include Maintenance phase therapy. Study treatment ends after Consolidation is complete. The total time of therapy is approximately 8-9 months.

Special Consideration

A bone marrow study will be done on day 29 to check for disease status. If there are APL cells still visible under a microscope, the Induction therapy of daily ATO infusions and twice a day ATRA pills will continue for 2 more weeks, followed by another bone marrow study. Induction may last as long as 70 days (10 weeks), with bone marrow studies every 2 weeks, until there are no APL cells visible. This is called remission.

ATO infusions are given over 2 hours. After the initial weeks of therapy, it may be possible to have infusions performed at home; however, not all patients live in areas where this is possible. Infusions may need to be continued in the hospital clinic setting.

ATRA capsules are most effective when swallowed whole. Parents of young children who cannot swallow pills will be given instructions on the best way to give this medication.

There are many medications and supplements that interfere with ATRA and ATO. Your medical team will let you know what should be avoided while taking these medications.

Minimal residual disease (MRD) testing detects very small amounts of APL in the bone marrow using special laboratory tests. It is possible for MRD to be positive even when doctors cannot see APL cells in a sample of bone marrow. Patients who have positive MRD after the 2^nd cycle of Consolidation (Day 43) will receive a cycle of different chemotherapy medications, including mitoxantrone and cytarabine, along with ATRA.

Patients who are known to have APL cells in the brain or spinal cord (central nervous system or CNS disease) or bleeding in the brain (CNS bleed), will receive additional drugs during Induction and Consolidation. These are standard therapy drugs that would be given even if you did not take part in this study.

Study doctors want to better understand how cancer treatments affect learning and thinking after treatment has ended. Patients who are 18 years old or younger have the option of participating in neurocognitive testing which will be scheduled at several time points.

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 sources for further information.

FAMILY PROTOCOL SUMMARY REVIEW/APPROVALS

Study Chair

Matthew A. Kutny, MD

Children's Hospital of Alabama