Introduction

This family protocol summary provides a general overview of the Children’s Oncology Group (COG) study ACNS0822. It tells who is eligible and gives basic information about the study. More details about the study are in the consent form and protocol. You can get these from your oncologist.

ACNS0822 is a Phase II/III clinical trial. A trial is another word for a study. This study (clinical trial) is a therapeutic clinical trial. The purpose of a Phase II trial is to learn if a new treatment works in treating a type of cancer and how it affects the body. In a Phase II trial, patients with a specific type of cancer receive a new treatment using a dose that was found to be safe in a Phase I trial. Patients are checked for side effects of the treatment and to see whether the cancer shrinks or goes away.

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?

ACNS0822 compares 3 treatments. 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 is 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 followed for several years. If one of the treatments is found to be better or safer than the others while the trial is still on-going, 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

ACNS0822

Official Title

A Randomized Phase II/III Study of Vorinostat and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children with Newly Diagnosed High-Grade Gliomas

Trial Opening Date

ACNS0822 opened in November 2010. The ACNS0822 committee hopes to enroll 108 patients in the phase II portion of the study, and 128 patients in the phase III portion of the study. It is expected to take 6½ years to enroll this number of patients, although there is no set date for study enrollment to end.

General Patient Eligibility

• Age: 3 - 21 years of age at the time of diagnosis
• Diagnosis: newly diagnosed high grade glioma including anaplastic astrocytoma, glioblastoma multiforme, and gliosarcoma
• No prior chemotherapy or radiation therapy

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

General Background and Study Goal

The outcome for children with high grade gliomas (HGG) is not good despite the use of surgery, radiation therapy and chemotherapy. New therapies are needed to improve the outcome for children with newly diagnosed HGG.

Surgery to remove the tumor and radiation therapy are considered the standard treatment for HGG. A drug called temozolomide, which is a radiosensitizer, has been used as part of HGG treatment in many studies. A radiosensitizer is a drug that makes tumor cells more sensitive to radiation therapy. ACNS0822 will compare the effect of temozolomide against two other radiosensitizer drugs.

This study will be done in three phases: the first phase (which was completed in August 2011) determined the dose of the drug Vorinostat that is safe and tolerable in combination with radiation therapy for children and adolescents.

The second phase of the study (currently open) will randomize patients to one of 3 different radiosensitizers during the “chemoradiation” segment of treatment. Patients will be randomized to receive:

• Arm A - Vorinostat and radiation therapy
• Arm B - Temozolomide and radiation therapy
• Arm C- Bevacizumab and radiation therapy

Temozolomide is considered the standard drug for treatment of HGG, (meaning Arm A and C are considered the experimental arms). Vorinostat and bevacizumab have been studied in adults with HGG, and patients who had these drugs added to their treatment did better than those who didn’t.

Following the chemoradiation portion of therapy, all patients will receive identical maintenance therapy which includes up to 12 cycles of Bevacizumab and Temozolomide therapy. This maintenance therapy is also considered experimental, although this part of the treatment is offered to all patients.

The 3rd phase of the study (currently not open to enrollment) will compare the 2 best treatment arms from the 2nd phase of the study. Following enrollment and evaluation of 108 patients on the phase II part of the study, the study committee will determine the best 2 treatment arms of the 3 tested. During the 3rd phase of the study, patient will be randomly assigned to receive one of these two treatment arms. Patients on Phase 2 of the study will not be in phase 3.

The main aims of this study are:

• To identify the safe, effective dose of Vorinostat when given in combination with radiotherapy (RT) in patients with newly diagnosed high-grade gliomas (HGG). This aim has been completed.
• To learn if either Vorinostat or bevacizumab gives a more promising outcome compared to temozolomide, when given in combination with radiotherapy (RT) followed by maintenance chemotherapy with bevacizumab and temozolomide in patients with newly diagnosed high-grade gliomas (HGG).

Summary of the Treatment

This is a randomized study comparing 3 different treatment arms assigned randomly to patients by computer. In this study all patients get standard radiation therapy along with one of 3 possible radiosensitizer chemotherapy drugs. All patients will receive an identical maintenance phase of therapy.

Chemoradiation: The chemoradiation phase lasts about 10 weeks: 6 weeks of radiation therapy + radiosensitizer followed by 4 week rest.

• Patients on Arm A will receive vorinostat in liquid or pill form Monday-Friday. Patients on Arm B will receive temozolomide in liquid or pill form daily for 42 days.
• Patients on Arm C will receive an IV dose of bevacizumab twice during the 6 week period.

Maintenance: All patients start maintenance at week 10. Maintenance therapy is identical for all patients, and consists of 12 cycles, 28 days long. During maintenance therapy, patients receive:

• bevacizumab IV every 14 days and
• temozolomide pills or liquid daily for 5 days every 28 days

Special Considerations

• Patients must be enrolled on the study before starting treatment, but must start treatment within 14 days once enrolled and within 31 days of the diagnostic surgery.
• Vorinostat and bevacizumab are provided at no cost to the patient.

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

Study Chair

• Dr. Maryam Fouladi MD
  Cincinnati Children’s Hospital Medical Center

FAMILY PROTOCOL SUMMARY REVIEW/APPROVALS