Neurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PN Clinical Trial
Official title:
A Phase 2 Trial of the MEK Inhibitor PD-0325901 in Adolescents and Adults With NF1-Associated Morbid Plexiform Neurofibromas
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.
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