MEK Inhibitor PD-0325901 Trial in Adolescents and Adults With NF1
Condition: Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma
Intervention: PD-0325901
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Neurofibromatosis Type 1 (Neurofibromas); PD-0325901; Radiographic Response; Inoperable Plexiform Neurofibromas

Summary:

      This 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 inoperable PN.

      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-0325901 by MRI

      To characterize the pharmacokinetic profile of PD-0325901 when administered to this patient
      population

      To evaluate quality of life and pain during treatment with PD-0325901
    

Eligibility criteria:

        Inclusion Criteria:

          -  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
             findings

          -  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 study entry.

          -  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 performance score.

          -  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 this study.

          -  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

        Exclusion Criteria:

          -  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 months.

          -  Subjects who have received radiation to the orbit at any time previously

          -  Subjects with glaucoma, intraocular pressure >21 mmHg, or any other significant
             abnormality on ophthalmic examination (performed by an ophthalmologist).

          -  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 analysis.

          -  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 test.

          -  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