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A Phase 1 Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor AZD6244 Hydrogen Sulfate (Selumetinib Sulfate) in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)

Phase 1
3 Years
18 Years
Open (Enrolling)
Neurofibromatosis 1, Neurofibromatosis Type 1, NF 1, Neurofibroma, Plexiform

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Trial Information

A Phase 1 Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor AZD6244 Hydrogen Sulfate (Selumetinib Sulfate) in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)


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

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 AZD6244 hyd sulfate administered daily
to pediatric patients with NF1 and inoperable PN.

To define the acute and chronic toxicities, pharmacokinetics (PK), and pharmacodynamics (PD)
of AZD6244 hyd sulfate.

To determine the effect of AZD6244 hyd sulfate on the growth rate of PN.


Pediatric Patients (3 to 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


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.

Inclusion Criteria


1. 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.

2. 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 caf -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

3. 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.

4. 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.

5. Performance status: Patients greater than or equal to 16 years of age must have a
Karnofsky performance level of greater than or equal to70%, and children < 16 years
old must have a Lansky performance of greater than or equal to 70%.

6. 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.

7. 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.

8. 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

9. 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.

10. 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


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

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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the maximum tolerated dose (MTD), tolerability, and recommended Phase II dose AZD6244 hyd sulfate administered PO Q 12H daily for 28 days/cycle with no rest period between cycles.

Principal Investigator

Brigitte C Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

May 2011

Completion Date:

July 2013

Related Keywords:

  • Neurofibromatosis 1
  • Neurofibromatosis Type 1
  • NF 1
  • Neurofibroma, Plexiform
  • Dose Limited Toxicity
  • Maximum Tolerated Dose
  • Pharmacokinetics
  • Pharmacodynamics
  • Dose Escalation
  • Neurofibromatosis Type 1
  • NF1
  • Plexiform Neurofibroma
  • Nervous System Neoplasms
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Childrens National Medical CenterWashington, District of Columbia  
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039