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
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.
Subjects will have retinal screening performed before starting PD-0325901 and regularly while
on study drug. Patients with glaucoma, intraocular pressure >21 mmHg, or any other
significant abnormality (excluding chronic, stable ophthalmological findings secondary to
Optic Pathway Glioma) on ophthalmic examination (performed by an ophthalmologist) will not be
eligible. Patients who have received radiation or cytotoxic therapy within 4 weeks of study
entry and patients who have received radiation to the orbit at any time previously, will not
be eligible for the study. Patients with other concurrent severe and/or uncontrolled medical
disease will also be excluded. In addition, pregnant women will not be eligible for
enrollment and subjects of reproductive age will be required to practice birth control while
on treatment.
Subjects entered on the trial will be carefully monitored for the development of PD-0325901
associated toxicities.
In all consenting subjects entered on this trial, a complete pharmacokinetic profile of
PD-0325901 after administration will be evaluated during course 1. Involvement with this part
of the study will be required.
Consenting subjects with dermal neurofibromas will have punch biopsies of dermal
neurofibromas at two time points to determine if the PD-0325901 is affecting the biologic
target. Involvement with this part of the study will be optional.
Since plexiform neurofibromas may significantly impact the lives of patients with NF1, this
study will evaluate the effects of the disease and treatment with PD-0325901 on the quality
of life (QOL) of adolescents and adults. Involvement in this part of the study will be
required. The Pediatric Quality of Life Inventory (PedsQL) Neurofibromatosis Type 1 Module
will be used to assess the QOL of subjects. The PedsQL NF1 Module is a self-reported
disease-specific QOL scale developed for adolescents and adults with NF1. It assesses 16
domains of functioning including physical functioning, emotional functioning, social
functioning, cognitive functioning, physical appearance, worry, pain and hurt, fatigue, and
daily activities. Preliminary data collected on this scale indicates good reliability and
validity in adults. The preliminary data in a small sample of adolescents also looks
promising. Data collected from this trial may be used toward validating this instrument since
no disease specific QOL measure for NF1 currently exists, but such a tool is critically
needed. Pain will be assessed using the Numeric Rating Scale-11 (NRS-11), which is an
11-point self-report scale of pain intensity. In addition, the Brief Pain Inventory Pain
Interference Scale is a 7-item self-report questionnaire that measures the extent to which
pain interferes with daily functioning. Both of these brief measures have been recommended to
assess different aspects of pain in clinical trials.
For subjects who respond to PD-0325901 (≥20% tumor volume reduction of target lesion by 12
courses), an MRI scan of the target lesion is requested (but not required) at 4 and 12 months
after stopping drug (as long as the subject is still on protocol) in order to determine
whether response is maintained post-therapy. These studies will not be requested from
subjects who experience disease progression while on study drug.
Before the subject can be enrolled, the responsible institutional investigator must sign and
date the completed eligibility checklist. The completed eligibility checklist should be faxed
to the NF Operations Center to confirm eligibility prior to subject enrollment.
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
