Neurofibromatosis 1Phase 1/2NCT01362803
AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors
A Phase 1/2 study testing AZD6244 in people with Neurofibromatosis 1 and Neurofibromatosis Type 1, run by National Cancer Institute (NCI) at 4 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 18 years
- Conditions the study is for
- Neurofibromatosis 1, Neurofibromatosis Type 1, NF1
- What is being tested?
- AZD6244
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 99 participants
- Where
- 4 sitesUnited States
- Study dates
- 21 Sep 2011to 1 Jan 2032
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
None listed.
Who cannot join
- 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.
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- 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
- Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease)
- Prior or current cardiomyopathy
- Severe valvular heart disease
- History of atrial fibrillation
- Ophthalmologic conditions:
- Current or past history of central serous retinopathy
- Current or past history of retinal vein occlusion
- Known intraocular pressure (IOP) >= 21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP). Patients with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair.
- Subjects with any other significant abnormality on ophthalmic examination should be discussed with the Study Chair for potential eligibility
- Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
- Known severe hypersensitivity to selumetinib or any excipient of selumetinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib.
- Recent major surgery within a minimum of 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access.
- Any unresolved chronic toxicity with CTC AE grade >= 2 from previous anti-NF1 therapy, except for alopecia.
- Clinical judgement by the investigator that the patient should not participate in the study.
- While not an exclusion criterion, unless considered clinically indicated, patients should avoid taking other additional non-study medications that may interfere with the study medications. In particular, patients should avoid medications that are known to either induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19 and CYP3A4, as this may interfere with the metabolism of selumetinib.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229-3039
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
Official title: A Phase I/II Study of the Mitogen Activated Protein Kinase (MEK) 1 Inhibitor Selumetinib (AZD6244; Hydrogen Sulfate in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
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.
Read more
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.
Read the detailed description
Background
- 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. Surgery is the only standard treatment option available for PN. However, this is often difficult due to the encasement of vital structures, and extensive and invasive PN growth.
- PN are composed of neoplastic Schwann cells that lack NF1 gene expression. This results in upregulation of Ras, which initiates several signaling cascades regulating cell proliferation.
- Selumetinib (AZD6244 hyd sulfate), a novel orally bioavailable mitogen activated protein kinase inhibitor, is a specific inhibitor of MEK 1, which may mediate anti-tumor effects in PN by inhibition of downstream signaling of Ras. Selumetinib is currently undergoing evaluation in adult cancers and children with brain tumors.
- In this phase I study of selumetinib directed at NF1 PN, we have observed a degree of activity which has not been observed previously; therefore a phase II evaluation will be conducted.
Objectives
Phase I:
- 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 pediatric dosing, an additional dose level of 25 mg/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/m^2/dose.
- To define the acute and chronic toxicities and pharmacokinetics (PK) of selumetinib. Completed with amendment H.
Phase II:
-Primary objectives: To evaluate the confirmed partial and complete response rate of selumetinib using volumetric MRI analysis in children and young adults with NF1 and inoperable PN with PN related morbidity at the time of enrollment.
Eligibility
Pediatric Patients (>= 2 and <=18 years) who are able to swallow intact capsules, with NF1 and inoperable measurable PN that cause or have the potential to cause significant morbidity.
Design
- Selumetinib will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment cycle). In the phase I portion, limited dose escalations will be performed to define the MTD based on tolerability of selumetinib during the first three treatment cycles. In the phase II portion, the recommended phase II dose level (RP2D) will be administered.
- Phase II: Patients will be enrolled on one of two strata:
- Stratum 1: PN related morbidity present at enrollment ---PN related pain, disfigurement, or difficulty in physical functioning
- Stratum 2: No significant PN related morbidity present at enrollment, but potential for development of PN morbidity
- Patient reported and functional outcomes will be evaluated at regular intervals.
- Disease status will be evaluated using volumetric MRI analysis at regular intervals.
- The day 1 and steady state plasma PK and PD of selumetinib will be evaluated.
- Being tested
- AZD6244
- Keywords
- Maximum Tolerated Dose, Pharmacokinetics, Pharmacodynamics, Response Rate, pain, quality of life and physical functioning
- Medical subject headings
- Neurofibromatosis 1, Neurofibroma, Plexiform, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD6244Drug
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
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | Phase 1: AZD6244 PO BID x 28 DAYS Receives: Drug: AZD6244 |
| Arm 2 | Experimental | Phase 2: AZD6244 PO BID x 28 DAYS Receives: Drug: AZD6244 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 3 treatment cycles
Secondary outcomes (7)
Study PK
pharmacokinetics (PK) of selumetinib at baseline and steady state
Measured: first course
Ph2: Evaluate effect of selumetinib on bone mineral density, pain, quality of life and physical functioning.
DEXA, survey responses and functional evaluations
Measured: before cycles 3,5,9,13 and then every 12 cycles
Ph2: Evaluate confirmed partial and complete response rate, and duration of response.
Objective response rate
Measured: at each response evaluation
Ph2: determine long term tolerability, and safety
Detailed clinical evaluation and laboratory studies
Measured: at each response evaluation
Measure adherence of chronic dosing
level of adherence to selumetinib
Measured: at each response evaluation
determine effect on growth rate of PN
Percent PN volume increase per year
Measured: at time of PD
Define toxicities
describe and define the toxicities in pediatric patients on chronic dosing of selumetinib
Measured: at each response evaluation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 May 2011 (estimated)
- Study start21 Sep 2011
- Primary completion1 Jan 2027 (estimated)
- Study completion1 Jan 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Neurofibromatosis 1Studies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 99 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Brigitte C Widemann, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01362803
- Sponsor's protocol ID
- 110161
- Other IDs
- 11-C-0161
- Status last verified
- 18 Sep 2026
- First submitted
- 27 May 2011
- Last updated
- 8 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All IPD recorded in the medical record will be shared with intramural investigators upon request.
Publications
Gross AM, Rhodes SD, Dufek A, Dombi E, Baldwin A, Shern JF, Sundby RT, Zhang X, Pekmezci M, Clapp DW, Pressey JG, Weiss BD, Bornhorst M, Kim A, Fisher MJ, Widemann BC. Malignant peripheral nerve sheath tumor development during MEK inhibitor treatment: A pre-clinical study and a clinical case series. Neurooncol Adv. 2026 Jul 11;8(1):vdag180. doi: 10.1093/noajnl/vdag180. eCollection 2026 Jan-Dec.
PubMed 42540436Adeyemi 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.
PubMed 40709016Gross 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.
PubMed 38869947Gross 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.
PubMed 37115514Gross 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.
PubMed 35467749Gross 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.
PubMed 32187457Dombi 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.
PubMed 28029918