Mitogen Activated Protein Kinase Kinase (MEK1/2) Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in People With Neurofibromatosis Type 1 (NF1) Mutated Gastrointestinal Stromal Tumors (GIST)

BACKGROUND:

- Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the
gastrointestinal tract, and traditional cytotoxic chemotherapy is not effective.
Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing GIST, and
surgery remains the only standard treatment option for NF1-related GIST. While the
tyrosine kinase inhibitors (TKIs) imatinib and sunitinib prolong survival in patients
with KIT/PDGFRA mutated GIST, they have no documented efficacy in patients with NF1
related GISTs, which lack KIT/PDGFRA mutations. Radiation therapy also seems to be
ineffective. Therefore, new therapies are needed.

- Selumetinib (AZD6244 hyd sulfate), a novel orally bioavailable mitogen activated protein
kinase inhibitor, is a specific inhibitor of MEK 1/2, which is currently undergoing
evaluation in adults with refractory cancers, in adults and children with NF1 and
plexiform neurofibromas (PN) and children with brain tumors. Evaluation of selumetinib
in children and young adults with NF1 related plexiform neurofibromas (PN) has
demonstrated activity with most patients demonstrating some PN shrinkage, and a partial
response rate of 71%. Selumetinib has also demonstrated activity in children with NF1
and low-grade gliomas. It is thus possible that selumetinib may mediate anti-tumor
effects in NF1 GIST by inhibition of downstream signaling of Ras.

OBJECTIVES:

- To estimate the response rate (radiologic response as defined by RECIST v1.1) of
selumetinib in children and adults with measurable NF1-mutated GIST which is unresectable,
progressive or metastatic.

ELIGIBILITY:

- Patients who are greater than or equal to 3 years of age and able to swallow capsules,
with a histologically or cytologically confirmed measurable GIST without Kit or PDGFRA
mutation, who have a clinical diagnosis of NF1 or a mutation of NF1 in the GIST.

- Patients tumors must demonstrate progression within the past 12 months or be metastatic;
patients who do not meet this criterion will be followed, on the NF1 Natural History
Study if appropriate; in the event that they demonstrate subsequent progression they may
be enrolled.

- Patients must have adequate major organ function, adequate performance status, and
normal LVEF by ECHO.

- No prior medical therapy is required; patients should have surgical resection if this is
deemed feasible without unacceptable morbidity. Patients must meet the time requirements
since prior therapy and have recovered from prior therapy toxicities.

- No prior treatment with selumetinib or another specific MEK1/2 inhibitor is permitted.

DESIGN:

- Selumetinib will be administered at a starting dose of 50 mg/dose orally in patients 18
years or older and 25 mg/m^2/dose in children < 18 years of age; drug will be given
twice daily continuously in the absence of toxicity or disease progression, using 28-day
cycles. The pediatric dose is the recommended phase II dose of selumetinib determined in
a CTEP sponsored phase I trial of selumetinib for children and young adults with NF1 and
inoperable plexiform neurofibromas, and the adult dose is equal to that used in our
phase II study of adults with NF1 and inoperable PN. Adults will be allowed a one-time
intrapatient dose escalation to 75mg BID provided the drug is well tolerated during the
first cycle. Patients will be asked to co-enroll on POB protocol 10-C-0086:
"Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a
Repository for Related Biological Studies and 08-C-0079: Natural History Study and
Longitudinal Assessment of Children, Adolescents, and Adults with Neurofibromatosis Type
1".

- Patients will be monitored for toxicity and response.

- Response will be assessed on a regular schedule. FDG-PET will be obtained at baseline
prior to therapy, on day 11 (+/- 3 days) to assess for early FDG-PET response
(optional), after 3 cycles and as clinically indicated.

- This study will use a Simon optimal two-stage phase II design with a target response
rate of 25%, enrolling a minimum of 7 and a maximum of 16 evaluable patients. A maximum
accrual of 20 patients may be accrued allowing for a small number (4) of inevaluable
patients.

- ELIGIBILITY CRITERIA:

- Age: greater than or equal to 3 years of age, BSA greater than or equal to 0.55 m^2,
and able to swallow intact capsules.

- Diagnosis: must have either a clinical diagnosis of NF1 or a germline NF1 mutation, or
in patients without the NF1 syndrome, demonstrate an NF1 mutation in the GIST verified
in a CLIA certified laboratory. In patients without the NF1 syndrome, confirmation of
the NF1 mutation in the GIST is required for enrollment.

- a) For a clinical diagnosis of NF1 patients must have at least two of the
diagnostic criteria for NF1 listed below

- Six or more cafe-au-lait macules (greater or equal to 0.5cm in prepubertal
subjects or greater than or equal to 1.5 cm in post pubertal subjects)

- Freckling in axilla or groin

- A neurofibroma or plexiform neurofibroma

- Optic glioma

- Two or more Lisch nodules

- A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
thinning of long bone cortex)

- A first-degree relative with NF1

- Patients must have a histologically or cytologically confirmed measurable GIST without
PDGFRA or KIT mutations. GIST may be newly diagnosed or recurrent provided that it
meets criteria for progressive or metastatic disease. Metastatic disease refers to
disease outside the GI tract, not simply a multifocal primary tumor. Testing performed
by the Laboratory of Pathology, NCI, unless previously conducted by a CLIA/CAP
external laboratory; analysis will include evaluation of 4 exons of KIT (9, 11, 13,
17) and 3 exons of PDGFRA (12, 14, 18).

- Measurable Disease:

- Patients must have measurable GIST as defined by RECIST v 1.1 as at least one
lesion not previously irradiated, that can be accurately measured at baseline
greater than or equal to 10 mm in the longest diameter (except lymph nodes which
must have short axis greater than or equal to 15 mm) with computed tomography
(CT) or magnetic resonance imaging (MRI) and which is suitable for accurate
repeated measurements.

- Progressive disease: GIST has demonstrated progression as defined by RECIST v1.1
within the past 12 months. Patients whose tumors do not meet this criterion, and
have a diagnosis of NF1, may enroll on the NF1 Natural History study.

- Performance Status: ECOG less than or equal to 2 (Patients greater than or equal to 16
years of age must have a Karnofsky performance level of greater than or equal to 70%
(or ECOG less than or equal to 2), and children less than or equal to 16 years old
must have a Lansky performance of greater than or equal to 70%

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,000/mcL

- platelets greater than or equal to 100,000/mcL

- hemoglobin (Hgb) greater than or equal to 9.0 g/dL

- total bilirubin < 1.5(SqrRoot) institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) < 3.0 (SqrRoot) institutional upper limit of normal

- creatinine clearance or radioisotope GFR > 60 mL/min/1.73 m^2 by either
Cockcroft- Gault formula or analysis normal serum creatinine based on age
described below:

- Age (years): less than or equal to 5; Maximum Serum Creatinine (mg/dL): 0.8

- Age (years): 5 or less or equal to 10; Maximum Serum Creatinine (mg/dL): 1.0

- Age (years): 10 or less than or equal to 15; Maximum Serum Creatinine
(mg/dL): 1.2

- Age (years): >15; Maximum Serum Creatinine (mg/dL): 1.5

- Prior Therapy: Patients will be eligible if tumor is metastatic, unresectable,
progressive, or if complete tumor resection is not considered to be feasible without
substantial risk or morbidity.

- Since there is no standard effective chemotherapy for patients with NF1 and GIST,
patients may be treated on this trial without having received prior medical
therapy directed at their GIST. Patients who have had prior GIST-directed surgery
may enroll provided they have measurable disease.

- Since selumetinib is not expected to cause substantial myelosuppression, there
will be no limit to number of prior myelosuppressive regimen for GIST or other
tumor manifestations associated with NF1.

- Patients who have received previous investigational agents or biologic therapy,
such as tipifarnib, pirfenidone, Peg-Intron, sorafenib, imatinib or other
targeted therapies are eligible for enrollment. At least 4 weeks must have
elapsed since receiving medical therapy directed at the PN and patients who
received previous GIST-directed therapy must either demonstrate progression as
defined by RECIST, or be unable to tolerate their previous therapy. Patients who
received effects of all prior therapy to less than or equal to grade 1 before
entering this study.

- Cytotoxic chemotherapy last dose must have been received at least 28 days prior
to enrollment, their last dose of biological therapy, immunomodulatory agents,
vaccines, differentiating agents, used to treat their cancer at least 7 days
prior to enrollment, their last dose of a monoclonal antibody at least 30 days
prior to enrollment, and their last dose of any investigational agent at least 30
days prior

to enrollment.

- Growth factors that support platelet or white cell number or function must not have
been administered within the 7 days prior to enrollment.

- At least 6 weeks must have elapsed prior to enrollment since the patient received any
prior radiation therapy.

- At least 4 weeks must have elapsed since any surgeries, with evidence of good wound
healing.

- The effects of selumetinib on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason, women of child-bearing potential
and men must agree to use adequate contraception (hormonal or barrier method of
birth control; abstinence) prior to study entry, for the duration of study
participation, and for 4 weeks after dosing with selumetinib ceases. Women of
child-bearing potential must have a negative pregnancy test prior to entry.
Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, the patient should inform her treating
physician immediately. Please note that the selumetinib

manufacturer recommends that adequate contraception for male patients should be used for 16
weeks post-last dose due to sperm life cycle.

- All patients and/or their parents or legal guardians must sign a written informed
consent.

- Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
sun exposure is anticipated.

- Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other
products containing these fruits, e.g. grapefruit juice or marmalade) during the
study, as these may affect selumetinib metabolism.

- Although not a requirement, participants will be asked to also participate in protocol
10-C-0086 Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of
a Repository for Related Biological Studies. Patients with NF1 will be asked to
coenroll

on the NF1 Natural History Study and 08-C-0079: Natural History Study and Longitudinal
Assessment of Children, Adolescents, and Adults with Neurofibromatosis Type 1.

EXCLUSION CRITERIA:

- Patients with evidence of another malignancy or benign tumor requiring chemotherapy or
radiation therapy are excluded; however, those patients with a plexiform neurofibroma
requiring treatment will be eligible as selumetinib has documented activity in
plexiform neurofibromas.

- Patients with a diagnosis of NF1 and GIST who do not meet other eligibility criteria
may enroll on the NF1 Natural History Study, and will be followed on this study.
Should they require therapy for GIST based on evidence of progression, they may then
enroll on study.

- Patients who are receiving any other investigational agents.

- Prior therapy with selumetinib or another specific MEK inhibitor is not permitted.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to selumetinib or other agents used in study.

- Previous MEK, RAS, or RAF inhibitor use.

- Patients who anticipate the need for surgical intervention within the first three
cycles (3 months), as surgical intervention during the period of DLT evaluation may
affect analysis of adherence and/or make the subject inevaluable.

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- Patients with the following cardiac conditions are excluded:

- Uncontrolled hypertension (Adults: blood pressure [BP] of greater than or equal
to 150/95 despite medical support/management. Participants 18 years of age and
younger should have a blood pressure less than or equal to 95th percentile for
age, height and gender. Preexisting hypertension in adults should be controlled
(either with pharmacological or nonpharmacological methods) at the time of
enrollment.)

- Acute coronary syndrome within 6 months prior to starting treatment

- Uncontrolled angina - Canadian Cardiovascular Society grade II-IV despite medical
support/management

- Heart failure NYHA Class II or above

- Prior or current cardiomyopathy including but not limited to the following: Known
hypertrophic cardiomyopathy

- Known arrhythmogenic right ventricular cardiomyopathy

- Baseline left ventricular ejection fraction (LVEF) less than or equal to 55%

- Previous moderate or severe impairment of left ventricular systolic function
(LVEF less than 50% on echocardiography or equivalent on Multi-Gated Acquisition
Scan [MUGA]) even if full recovery has occurred.

- Severe valvular heart disease

- Atrial fibrillation with a ventricular rate greater than 100 bpm on ECG at rest

- Ophthalmological conditions as follows:

- Current or past history of retinal pigment epithelial detachment (RPED)/central
serous retinopathy (CSR) or retinal vein occlusion

- Intraocular pressure (IOP) greater than 21 mmHg or uncontrolled glaucoma
(irrespective of IOP).

- Evidence of optic glioma, malignant glioma, malignant peripheral nerve sheath
tumor,

- Ophthalmological findings secondary to long-standing optic pathway glioma (such
as visual loss, optic nerve pallor or strabismus) or long-standing orbitotemporal
PN (such as visual loss, strabismus) will NOT be considered a significant
abnormality for the purposes of the study

- Subjects with any other significant abnormality on ophthalmic examination
(performed by an ophthalmologist) should be discussed with the Study Chair for
potential eligibility.

- Inability to swallow capsules, since capsules cannot be crushed or broken.

- Patients with refractory nausea and vomiting, chronic gastrointestinal (GI) diseases
(e.g., inflammatory bowel disease) or significant bowel resection that may
significantly alter the absorption of study agent

- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP 1A2, 2C8, 2C9, 2C19, 3A4/5 and UGT 1A1 and 1A3, P-glycoprotein, or
BCRP are ineligible. Because the lists of these agents are constantly changing, it is
important to regularly consult a frequently-updated medical reference. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product.

- No supplementation with vitamin E is permitted because the selumetinib capsules
contain vitamin E

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because the effects of selumetinib on the
developing human fetus at the recommended therapeutic dose are unknown. Because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother, breastfeeding should be discontinued if the mother is treated
with selumetinib.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with selumetinib. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated.

- Ongoing radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or biologic
therapy directed at the tumor. Those patients with a plexiform neurofibroma requiring
treatment will be eligible, as selumetinib has documented activity in plexiform
neurofibromas.

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study.