MEK Inhibitor PD-0325901 Trial in Adolescents and Adults With NF1

Inclusion Criteria:

• All studies to determine eligibility must be performed within 2 weeks prior toenrollment unless otherwise indicated below. All clinical and laboratory data requiredfor eligibility of a subject must be available in the subject's medical or researchrecord.

• All subjects must have EITHER the clinical diagnosis of NF1 using the NIH ConsensusConference criteria OR have a constitutional NF1 mutation documented in a CLIA/CAPcertified lab.

• Subjects must have plexiform neurofibroma(s) that are progressive OR are causingsignificant morbidity, such as (but not limited to) head and neck lesions that arecompromising the airway or great vessels, brachial or lumbar plexus lesions that arecausing nerve compression and loss of function, lesions causing major deformity (e.g.,orbital lesions) or are significantly disfiguring lesions of the extremity that causelimb hypertrophy or loss of function, and painful lesions. Subjects with paraspinalplexiform neurofibromas will be eligible for this trial. Histologic confirmation oftumor is not necessary in the presence of consistent clinical and radiographicfindings

• For subjects enrolled for tumor progression, progression is defined as:

• Presence of new plexiform neurofibroma on MRI or CT (documented by comparisonwith prior MRI or CT), OR

• A measurable increase in plexiform neurofibroma size (≥ 20% increase in thevolume, or a ≥ 13% increase in the product of the two longest perpendiculardiameters, or a ≥ 6% increase in the longest diameter) documented by comparisonof two scans (MRI or CT) approximately one year or less prior to evaluation forthis 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 areasof the body that are unable to be concealed by standard garments. In order to enroll aplexiform neurofibroma for these indications, the Study Chair or Co-Chair must becontacted to review subject eligibility prior to enrollment.

• Measurable disease: Subjects must have measurable plexiform neurofibroma(s) amenableto volumetric MRI analysis. The target lesion must be seen on at least 3 consecutiveMRI slices and the field of view must contain the entire tumor of interest. Tumorsmust be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet thiscriteria). If the tumor is <3 cm in longest diameter, the subject may still beeligible. Central review of the MRI of the target plexiform is required prior toenrollment 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 study entry.

• Durable Power of Attorney: Adults who are unable to provide informed consent will NOTbe enrolled on this study.

• Performance Level: Karnofsky greater than or equal to 50% Note: Subjects who areunable to walk because of paralysis, but who are up in a wheelchair, will beconsidered ambulatory for the purpose of assessing the performance score.

• Prior Therapy: Subjects are only eligible if complete resection of a plexiformneurofibroma with acceptable morbidity is not feasible, or if a subject with surgicaloption refuses surgery.

• Subjects who underwent surgery for a progressive plexiform neurofibroma will beeligible to enter the study after the surgery, provided the plexiform neurofibroma wasincompletely resected and is evaluable by volumetric analysis.

• Subjects may have been previously treated for a plexiform neurofibroma or othertumor/malignancy, but must have fully recovered from the acute toxic effects of allprior chemotherapy or radiotherapy prior to entering this study.

• Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry ontothis study.

• Hematopoietic growth factors: At least 7 days since the completion of therapy with agrowth factor that supports platelet, red or white cell number or function.

• Biologic (anti-neoplastic agent): At least 14 days since the completion of therapywith a biologic agent. These subjects must be discussed with the Study Chair on acase-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 orstress doses of steroids if necessary.

• 6 months from involved field radiation to index plexiform neurofibroma(s); 6 weeksmust have elapsed if subject has received radiation to areas outside index plexiformneurofibroma(s). Subjects who have received radiation to the orbit at any time areexcluded.

• Surgery: At least 2 weeks since undergoing any major surgery and must be recoveredfrom effects of surgery.

• Organ Function Requirements

• Adequate Bone Marrow Function

• Adequate Renal Function

• Adequate Liver Function

Exclusion Criteria:

• Chronic treatment with systemic steroids or another immunosuppressive agent. Subjectswith endocrine deficiencies are allowed to receive physiologic or stress doses ofsteroids if necessary.

• Evidence of an active optic glioma or other low-grade glioma, requiring treatment withchemotherapy or radiation therapy. Subjects not requiring treatment are eligible forthis protocol.

• Patients with malignant glioma, malignant peripheral nerve sheath tumor, or othermalignancy requiring treatment in the last 12 months.

• Subjects who have received radiation to the orbit at any time previously

• Subjects with glaucoma, intraocular pressure >21 mmHg, or any other significantabnormality on ophthalmic examination (performed by an ophthalmologist).

• Ophthalmological findings secondary to long-standing Optic Pathway Glioma such asoptic nerve pallor or strabismus will NOT be considered significant for the purposesof the study.

• Tumor not able to be reliably evaluated by volumetric analysis.

• Other concurrent severe and/or uncontrolled medical disease, which could compromiseparticipation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension,severe infection, severe malnutrition, chronic liver or renal disease, active upper GItract ulceration, congestive heart failure, etc.)

• Subjects who have an uncontrolled infection.

• Impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter the absorption of PD-0325901 (e.g. ulcerative disease,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowelresection). 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 agreedto use an effective contraceptive method during the period they are receiving thestudy drug and for 3 months thereafter. Abstinence is an acceptable method of birthcontrol. Women of childbearing potential will be given a pregnancy test within 7 daysprior to administration of PD-0325901 and must have a negative urine or serumpregnancy test.

• History of noncompliance to medical regimens.

• Subjects unwilling to or unable to comply with the protocol, or who in the opinion ofthe investigator may not be able to comply with the safety monitoring requirements ofthe study.

• Prior treatment with a MEK inhibitor of any kind