AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

NCT01362803 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 11016111-C-0161
• Study Type: interventional
• Target: 99
• Locations: 1 country
• Sites: 4

Brief Summary

Background: \- 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. Objectives: \- 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. Eligibility: \- Children and young adults between 12 and 18 years of age who have plexiform neurofibromas that cannot be completely removed by surgery. Design:

• 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.

Conditions

Neurofibromatosis 1; Neurofibromatosis Type 1; NF1; Neurofibroma, Plexiform

Keywords

Maximum Tolerated Dose; Pharmacokinetics; Pharmacodynamics; Response Rate; pain, quality of life and physical functioning

Outcome Measures

Primary Outcomes (2)

• Ph2: Evaluate the confirmed partial and complete response rate of selumetinib in children and young adults with NF1 and inoperable PN.

  Evaluate the confirmed partial and complete response rate of selumetinib in children and young adults with NF1 and inoperable PN.

  prior to cycles 5,6,13,17,21,25 and then every 6 cycles

• Ph1: Determine MTD and extended tolerability

  Determine MTD and extended tolerability

  3 treatment cycles

Secondary Outcomes (7)

• Study PK

  first course

• Ph2: Evaluate effect of selumetinib on bone mineral density, pain, quality of life and physical functioning.

  before cycles 3,5,9,13 and then every 12 cycles

• Ph2: Evaluate confirmed partial and complete response rate, and duration of response.

  at each response evaluation

• Ph2: determine long term tolerability, and safety

  at each response evaluation

• Measure adherence of chronic dosing

  at each response evaluation

Study Arms (2)

Arm 1

EXPERIMENTAL

Phase 1: AZD6244 PO BID x 28 DAYS

Drug: AZD6244

Arm 2

EXPERIMENTAL

Phase 2: AZD6244 PO BID x 28 DAYS

Drug: AZD6244

Interventions

AZD6244 DRUG

AZD6244 orally (at recommended Ph2 dose) every 12 hours on continuous daily schedule for cycles of 28 days until unacceptable toxicity, patient withdrawal or PD

Arm 1; Arm 2

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age Phase I: \>=3 years and \<=18 years of age at the time of study enrollment, if able to swallow whole capsules. The age limits including young children were chosen because early childhood and puberty are considered to be the greatest risk for disease progression, and selumetinib may provide the most benefit to this young group of patients. In addition, an important objective of this study is to characterize the pharmacokinetics of selumetinib in the pediatric population since it has been well studied in adults.
• Age Phase II: \>=2 and \<= 18 years. BSA \>= 0.55 m\^2, and able to swallow whole capsules.
• Diagnosis: Patients with NF1 and inoperable PN, defined as PN that cannot be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. The PN has to cause (stratum 1) or have the potential to cause (stratum 2) significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, paraspinal lesions that can cause myelopathy brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Patients will be enrolled into stratum 1 or 2 based on PN related morbidity.
• Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected.
• A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve. In addition to PN, all study subjects must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below: (NIH Consensus conference):
• Six or more cafe-au-lait macules (\>=0.5cm in prepubertal subjects or \>=1.5 cm in post pubertal subjects)
• Freckling in axilla or groin
• Optic glioma
• Two or more Lisch nodules
• A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
• A first-degree relative with NF1
• Measurable disease: Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable.
• Phase II: Measurability and suitability for volumetric MRI analysis of the target PN must be confirmed with the NCI POB prior to enrolling a patient. The target PN will be defined as the clinically most relevant PN, which has to be amenable to volumetric MRI analysis. PN will be classified as "typical PN" versus "nodular PN" versus "solitary nodular PN" prior to enrollment
• Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not considered to be feasible without substantial risk or morbidity.
• Since there is no standard effective chemotherapy for patients with NF1 and PN, patients may be treated on this trial without having received prior medical therapy directed at their PN.

You may not qualify if:

• Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrollment for all females of childbearing potential as per institutional standards (at NIH subjects 9 years and older or those showing pubertal development). Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
• Phase I: Patients who anticipate the need for surgical intervention within the first three cycles (3 months), as surgical intervention during the period of DLT evaluation may affect analysis of adherence and/or make the subject inevaluable.
• Use of an investigational agent within the past 30 days.
• Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
• Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any patient known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded. Patients with HIV who have adequate CD4 count, not requiring antiretroviral medication, may be enrolled.
• Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
• Inability to swallow capsules, since capsules cannot be crushed or broken.
• Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
• Prior treatment with selumetinib or another specific MEK1/2 inhibitor (unless the subject meets criteria for re-treatment).
• Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to initiation of therapy.
• Patients not achieving adequate blood pressure in spite of antihypertensive therapy for control of blood pressure.
• Cardiac Function:
• Known inherited coronary disease

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (6)

• Adeyemi A, Gross AM, Baldwin A, Dombi E, Widemann BC, Sint KJ. Selumetinib in pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma: Propensity score analysis of SPRINT vs. natural history control arm. Neurooncol Adv. 2025 May 17;7(1):vdaf101. doi: 10.1093/noajnl/vdaf101. eCollection 2025 Jan-Dec.

  PMID: 40709016 DERIVED

• Gross AM, Achee C, Hart SE, Brewer L, Baldwin A, Wolters PL, Widemann BC; SPRINT study team. Selumetinib for children with neurofibromatosis type 1 and plexiform neurofibromas: A plain language summary of SPRINT. Future Oncol. 2024 May;20(14):877-890. doi: 10.2217/fon-2023-0565. Epub 2024 Feb 22.

  PMID: 38869947 DERIVED

• Gross AM, Dombi E, Wolters PL, Baldwin A, Dufek A, Herrera K, Martin S, Derdak J, Heisey KS, Whitcomb PM, Steinberg SM, Venzon DJ, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Smith MA, Widemann BC. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro Oncol. 2023 Oct 3;25(10):1883-1894. doi: 10.1093/neuonc/noad086.

  PMID: 37115514 DERIVED

• Gross AM, Glassberg B, Wolters PL, Dombi E, Baldwin A, Fisher MJ, Kim A, Bornhorst M, Weiss BD, Blakeley JO, Whitcomb P, Paul SM, Steinberg SM, Venzon DJ, Martin S, Carbonell A, Heisey K, Therrien J, Kapustina O, Dufek A, Derdak J, Smith MA, Widemann BC. Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity. Neuro Oncol. 2022 Nov 2;24(11):1978-1988. doi: 10.1093/neuonc/noac109.

  PMID: 35467749 DERIVED

• Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18.

  PMID: 32187457 DERIVED

• Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943.

  PMID: 28029918 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform; Pain

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Brigitte C Widemann, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 27, 2011
• First Posted: May 30, 2011
• Study Start: September 21, 2011
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2032
• Last Updated: April 24, 2026

Record last verified: 2026-02-26

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (4)