MEKINHIBITOR: A Phase I Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor AZD6244 Hydrogen Sulfate in Children with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN).

Why are we doing this research?


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.

Who can participate?

Inclusion Criteria:

Age: greater than or equal to 3 years and less than or equal to 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 AZD6244 hyd-sulfate 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 AZD6244 hyd-sulfate in the pediatric population since it has been well studied in adults.

Diagnosis: Patients with NF1 and inoperable PNs that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, 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 significant cosmetic problems, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Histiologic 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:

  • Six or more café-au-lait macules (greater than or equal to 0.5cm in prepubertal subjects or greater than or equal to 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 as per criteria above.

Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not considered to be feasible without substantial risk or morbidity, or if a patient with a surgical option refuses surgery.

  • 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.
  • Since AZD6244 hyd-sulfate is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimen for PN or other tumor manifestations associated with NF1 such as optic glioma.
  • Patients who have received previous investigational agents or biologic therapy, such as tipifarnib, pirfenidone, Peg-Intron, sorafenib, or other VEGFR inhibitors are eligible for enrollment.
  • Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days.
  • Patients who received prior medical therapy for their PN must have recovered from the toxic effects of all prior therapy before entering this study.
  • At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy.

Performance status: Patients greater than or equal to 16 years of age must

have a Karnofsky performance level of greater than or equal to 70%, and children < 16 years old must have a Lansky performance of greater than or equal to 70%.

Hematologic Function: Patients must have an absolute neutrophil count greater than or equal to 1000/(micro)l, hemoglobin greater than or equal to 9g/dl, and platelet greater than or equal to 100,000/(micro)l.

Hepatic Function: Patients must have bilirubin within 1.5 times the upper limit of normal for age, with the exception of Gilbert syndrome, and ALT within less than or equal to 1.5 times the upper limit of normal.

Renal Function: Patients must have a creatinine clearance or radioisotope GFR greater than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on age described below.

  • Age (years)/Maximum Serum Creatinine(mg/dL):
  • Age less than or equal to 5/Maximum Serum Creatinine 0.8 mg/dL
  • Age 5 and/or less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL
  • Age 10 and/or less than or equal to 15/ Maximum Serum Creatinine 1.2 mg/dL
  • Age greater than 15/ Maximum Serum Creatinine 1.5 mg/dL

Informed Consent: Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients or their legal guardians (if the patient is < 18 years old). When appropriate, pediatric patients will be included in all discussions. This can be accomplished through one of the following mechanisms: a) the NCI, POB screening protocol, b) an IRB-approved institutional screening protocol or c) the study-specific protocol.

Documentation of the informed consent for screening will be maintained in the patient's research chart. Studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed consent was obtained.

Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of age will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.

Exclusion Criteria:

  1. 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 on this study in girls, age 9 or older. 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.
  2. 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.
  3. An investigational agent within the past 30 days.
  4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
  5. Clinically significant uncontrolled unrelated systemic illness such as serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction.
  6. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
  7. Inability to swallow capsules, since capsules cannot be crushed or broken.
  8. 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.
  9. Prior treatment with AZD6244 hyd-sulfate.
  10. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
  11. Presence of greater than or equal to grade 1 cataract, as cataract was observed in preclinical studies with AZD6244 hyd-sulfate.
  12. Supplementation with vitamin E greater than 100% of the daily recommended dose.


  • From 3 to 18 years old


  • Brain Spinal Neurofibromatosis Plexiform Neurofibroma
  • Solid Tumor Neurofibromatosis Plexiform Neurofibroma


Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799