What is the purpose of this study?
phase II open label study will evaluate adolescents (≥ 16 years of age) and
adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated
with the MEK inhibitor PD-0325901. The primary aim of the study will be to
assess quantitative radiographic response in a target lesion. Subjects will
receive PD-0325901 by mouth on a bid dosing schedule of 2 mg/m2/dose with a
maximum dose of 4 mg bid. Each course is 4 weeks duration, and subjects will
receive drug on a 3 week on/1 week off schedule. Subjects may receive
additional courses beyond course 8 only if there is at least 15% reduction in
volume of the target tumor. Subjects who have a 20% or greater reduction in
target tumor volume at the end of 12 courses can continue on therapy for up to
an additional year (maximum of 24 total courses). However, subjects who do not
achieve at least 15% reduction in volume of the target tumor after 8 courses
(~8 months) will be considered treatment failures and taken off study.
The Primary purpose of this protocol is to determine whether PD-0325901
results in objective radiographic responses based on volumetric MRI
measurements in adolescents and adults with NF1 and growing or symptomatic
There are several secondary aims of this protocol:
To evaluate the feasibility and toxicity of chronic PD-0325901
administration in this patient population
To estimate the objective response rate of up to 2 non-target plexiform
neurofibromas to PD-0325901by MRI
To characterize the pharmacokinetic profile of PD-0325901 when administered
to this patient population
To characterize the pharmacodynamic profile of PD-0325901 when administered
to this patient population using dermal neurofibromas as a surrogate for
plexiform neurofibroma cells
To characterize the activity of PD-0325901 on neurofibroma cell gene
To characterize the activity of PD-0325901 on plasma cytokines and growth
To correlate pERK levels to pharmacokinetic data and response
To evaluate quality of life and pain during treatment with PD-0325901
To validate the PedsQL NF1 QOL Module, a disease specific QOL scale, for
use in this patient population, and
To determine whether subjects who respond (≥20% objective radiographic
response of target lesion by 12 courses) to PD-0325901 will maintain that
response for 1 year one they come off therapy
Who can participate?
All studies to determine eligibility must be performed
within 2 weeks prior to enrollment unless otherwise indicated below. All
clinical and laboratory data required for eligibility of a subject must be
available in the subject's medical or research record.
All subjects must have EITHER the clinical diagnosis of
NF1 using the NIH Consensus Conference criteria OR have a constitutional NF1
mutation documented in a CLIA/CAP certified lab.
Subjects must have plexiform neurofibroma(s) that are
progressive OR are causing significant morbidity, such as (but not limited to)
head and neck lesions that are compromising the airway or great vessels,
brachial or lumbar plexus lesions that are causing nerve compression and loss
of function, lesions causing 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. Subjects with paraspinal plexiform
neurofibromas will be eligible for this trial. Histologic confirmation of tumor
is not necessary in the presence of consistent clinical and radiographic
· For subjects enrolled for tumor progression, progression
is defined as:
Presence of new plexiform neurofibroma on MRI or CT
(documented by comparison with prior MRI or CT), OR
A measurable increase in plexiform neurofibroma size (≥
20% increase in the volume, or a ≥ 13% increase in the product of the two
longest perpendicular diameters, or a ≥ 6% increase in the longest diameter)
documented by comparison of two scans (MRI or CT) approximately one year or
less prior to evaluation for this study.
For subjects enrolled for a "major deformity"
or "significantly disfiguring" tumor, eligible tumors will be limited
to tumors of the head & neck or those on other areas of the body that are
unable to be concealed by standard garments. In order to enroll a plexiform
neurofibroma for these indications, the Study Chair or Co-Chair must be
contacted to review subject eligibility prior to enrollment.
Measurable disease: Subjects must have measurable
plexiform neurofibroma(s) amenable to volumetric MRI analysis. The target
lesion must be seen on at least 3 consecutive MRI slices and the field of view
must contain the entire tumor of interest. Tumors must be at least 3 mL in
volume (most PNs 3 cm in longest diameter will meet this criteria). If the
tumor is <3 cm in longest diameter, the subject may still be eligible.
Central review of the MRI of the target plexiform is required prior to
enrollment to ensure that the tumor is measurable and amenable to volumetric
analysis. After consenting, images will be sent for Central review
Age: Subjects must be ≥ 16 years of age at the time of
Durable Power of Attorney: Adults who are unable to
provide informed consent will NOT be enrolled on this study.
Performance Level: Karnofsky greater than or equal to 50%
Note: Subjects who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the
Prior Therapy: Subjects are only eligible if complete
resection of a plexiform neurofibroma with acceptable morbidity is not
feasible, or if a subject with surgical option refuses surgery.
Subjects who underwent surgery for a progressive
plexiform neurofibroma will be eligible to enter the study after the surgery,
provided the plexiform neurofibroma was incompletely resected and is evaluable
by volumetric analysis.
Subjects may have been previously treated for a plexiform
neurofibroma or other tumor/malignancy, but must have fully recovered from the
acute toxic effects of all prior chemotherapy or radiotherapy prior to entering
Myelosuppressive chemotherapy: Must not have received
within 4 weeks of entry onto this study.
Hematopoietic growth factors: At least 7 days since the
completion of therapy with a growth factor that supports platelet, red or white
cell number or function.
Biologic (anti-neoplastic agent): At least 14 days since
the completion of therapy with a biologic agent. These subjects must be discussed
with the Study Chair on a case-by-case basis.
Investigational Drugs: Subjects must not have received an
investigational drug within 4 weeks.
Steroids: Subjects with endocrine deficiencies are
allowed to receive physiologic or stress doses of steroids if necessary.
6 months from involved field radiation to index plexiform
neurofibroma(s); 6 weeks must have elapsed if subject has received radiation to
areas outside index plexiform neurofibroma(s). Subjects who have received
radiation to the orbit at any time are excluded.
Surgery: At least 2 weeks since undergoing any major
surgery and must be recovered from effects of surgery.
Organ Function Requirements
Adequate Bone Marrow Function
Adequate Renal Function
Adequate Liver Function
Chronic treatment with systemic steroids or another
immunosuppressive agent. Subjects with endocrine deficiencies are allowed to
receive physiologic or stress doses of steroids if necessary.
Evidence of an active optic glioma or other low-grade
glioma, requiring treatment with chemotherapy or radiation therapy. Subjects
not requiring treatment are eligible for this protocol.
Patients with malignant glioma, malignant peripheral
nerve sheath tumor, or other malignancy requiring treatment in the last 12
Subjects who have received radiation to the orbit at any
Subjects with glaucoma, intraocular pressure >21 mmHg,
or any other significant abnormality on ophthalmic examination (performed by an
Ophthalmological findings secondary to long-standing
Optic Pathway Glioma such as optic nerve pallor or strabismus will NOT be
considered significant for the purposes of the study.
Tumor not able to be reliably evaluated by volumetric
Other concurrent severe and/or uncontrolled medical
disease, which could compromise participation in the study (e.g. uncontrolled
diabetes, uncontrolled hypertension, severe infection, severe malnutrition,
chronic liver or renal disease, active upper GI tract ulceration, congestive
heart failure, etc.)
Subjects who have an uncontrolled infection.
Impairment of gastrointestinal function or
gastrointestinal disease that may significantly alter the absorption of
PD-0325901 (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome or small bowel resection). A nasogastric tube (NG tube)
or gastric tube (G tube) is allowed.
Women who are pregnant or breast feeding.
Males or females of reproductive potential may not
participate unless they have agreed to use an effective contraceptive method
during the period they are receiving the study drug and for 3 months
thereafter. Abstinence is an acceptable method of birth control. Women of
childbearing potential will be given a pregnancy test within 7 days prior to
administration of PD-0325901 and must have a negative urine or serum pregnancy
History of noncompliance to medical regimens.
Subjects unwilling to or unable to comply with the
protocol or who in the opinion of the investigator may not be able to comply
with the safety monitoring requirements of the study.
Prior treatment with a MEK inhibitor of any kind