AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors
- Plexiform neurofibromas are tumors that grow in and around nerves. The only way to treat them is with surgery. Some of these tumors cannot be completely removed. The tumors may be too large, too numerous, or in a bad location for surgery. An experimental drug called AZD6244 hydrogen sulfate may be able to prevent the tumors from growing, slow down their growth, or shrink them. This drug has been tested in adults with cancer and in children with some types of brain cancer. This study will test how well this drug works with these types of tumors.
- To study the safety and effectiveness of AZD6244 hydrogen sulfate in children and young adults with plexiform neurofibromas that cannot be completely removed by surgery.
- Children and young adults between 12 and 18 years of age who have plexiform neurofibromas that cannot be completely removed by surgery.
- Patients will be screened with a physical exam, medical history, blood tests, and imaging studies.
- They will take the study drug twice a day with 8 ounces of water, every day for 28-day cycles of treatment. During study visits, participants will have blood and urine tests and physical exams. They will also have imaging studies to examine the tumor sizes and locations. They will answer questions about their health. They may have other tests as needed.
- Participants will continue to receive the study drug as long as they have no severe side effects and the disease is not getting worse.
Neurofibromatosis Type 1
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1/2 Study of the Mitogen Activated Protein Kinase Kinase(MEK) 1 Inhibitor Selumetinib (AZD6244, Hydrogen Sulfate) in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)|
- Determine MTD and extended tolerability [ Time Frame: 3 treatment cycles ] [ Designated as safety issue: Yes ]
- Determine effect on growth rate of PN [ Time Frame: At time of PD ] [ Designated as safety issue: No ]
- Study PK [ Time Frame: First course ] [ Designated as safety issue: No ]
- Measure adherence of chronic dosing [ Time Frame: At each response evaluation ] [ Designated as safety issue: No ]
- Define toxicities [ Time Frame: At each response evaluation ] [ Designated as safety issue: Yes ]
|Study Start Date:||May 2011|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||December 2017 (Final data collection date for primary outcome measure)|
Experimental: Arm 1
AZD6244 PO BID
AZD6244 orally every 12 hours on continuous daily schedule for cycles of 28 days until unacceptable PD
Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. PN may be congenital and appear to have the fastest growth rate in young children. There are no standard treatment options for PN other than surgery, which is often difficult due to the encasement of vital structures, and extensive and invasive growth.
PN are composed of neoplastic Schwann cells that lack NF1 gene expression resulting in upregulation of Ras, which initiates several signaling cascades regulating cell proliferation.
AZD6244 hyd sulfate, a novel orally bioavailable mitogen activated protein kinase inhibitor, is a specific inhibitor of MEK 1, which is currently undergoing evaluation in adult cancers and children with brain tumors, and may mediate anti-tumor effects in PN by inhibition of downstream signaling of Ras.
To determine the maximum tolerated dose (MTD) of oral selumetinib administered daily to pediatric patients with NF1 and inoperable PN. Based on the results of the dose escalation in this study, the current MTD has been determined as 20 mg/m2/dose. To be consistent in pedriatric dosing, an additional dose level of 25mg/m2/dose was added, which is the MTD recently determined in a study conducted by the Pediatric Brain Tumor Consortium (PBTC). Amendment H (November 2014). The MTD has been determined to be 25 mg/m2/dose.
To determine the effect of selumetinib on the growth rate of PN.
Pediatric Patients (3 less than or equal to 18 years) who are able to swallow intact capsules, with NF1 and inoperable measurable PN that have the potential to cause significant morbidity.
AZD6244 hyd sulfate will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment cycle). Limited dose escalations will be performed to define the MTD based on tolerability of AZD6244 hyd sulfate during the first three treatment cycles.
Disease status will be evaluated using volumetric MRI analysis at regular intervals.
The plasma PK and PD of AZD6244 hyd sulfate will be evaluated.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01362803
|Contact: Brigitte C Widemann, M.D.||(301) email@example.com|
|United States, District of Columbia|
|Childrens National Medical Center||Recruiting|
|Washington, District of Columbia, United States|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937|
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center||Recruiting|
|Cincinnati, Ohio, United States, 45229-3039|
|United States, Pennsylvania|
|Childrens Hospital, Philadelphia||Recruiting|
|Philadelphia, Pennsylvania, United States, 19104|
|Principal Investigator:||Brigitte C Widemann, M.D.||National Cancer Institute (NCI)|