A Phase 3 Study of Selumetinib (NSC# 748727, IND# 77782) or Selumetinib in Combination with Vinblastine for non-NF1, non-TSC Patients with Recurrent or Progressive Low-Grade Gliomas (LGGs) Lacking BRAFV600E or IDH1 Mutations

Protocol # :
Recurrent Low Grade Astrocytoma
Recurrent WHO Grade 2 Glioma
Refractory Low Grade Astrocytoma
Refractory Low Grade Glioma
Refractory WHO Grade 1 Glioma
Disease Sites
Brain and Nervous System
Principal Investigator
Chi, Susan, N
Site Research Nurses
Gouthro, Michelle, S.
Strachan, Marylynne

Trial Description

This phase III trial investigates the best dose of vinblastine in combination with
selumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinib
alone in treating children and young adults with low-grade glioma (a common type of brain
cancer) that has come back after prior treatment (recurrent) or does not respond to therapy
(progressive). Selumetinib is a drug that works by blocking a protein that lets tumor cells
grow without stopping. Vinblastine blocks cell growth by stopping cell division and may kill
cancer cells. Giving selumetinib in combination with vinblastine may work better than
selumetinib alone in treating recurrent or progressive low-grade glioma.

Eligibility Requirements

Inclusion Criteria:

- Feasibility phase: patients must be >= 2 years and =< 21 years of age at the time of

- Efficacy phase: patients must be >= 2 years and =< 25 years of age at the time of

- All patients > 21 years of age at the time of enrollment must have had initial
diagnosis of low-grade glioma by 21 years of age

- Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment

- Patients must have eligibility confirmed by rapid central pathology and central
molecular screening reviews performed on APEC14B1

- Non-neurofibromatosis type 1 (non-NF1), non-tuberous sclerosis complex (non-TSC)
low-grade glioma (LGG) without a BRAFV600E or IDH1 mutation

- Patients must have progressive or recurrent LGG. Note: Biopsy may be at either
initial diagnosis or recurrence

- Patients must have measurable disease, defined as having a two-dimensional
measurable tumor volume of >= 1 cm^2

- Tumor size will be measured to include both solid and cystic components of
the tumor (whether or not tumor is enhancing) + fluid attenuated inversion
recovery (FLAIR) signal

- Eligible histologies will include all tumors considered low-grade glioma or
low-grade astrocytoma (World Health Organization [WHO] grade 1 and II) by the WHO
Classification of Tumors of the Central Nervous System - 4th Edition Revised,
with the exception of subependymal giant cell astrocytoma

- Patients with metastatic disease or multiple independent primary LGGs are

- Patients must be progressive or recurrent after having been treated with at least one
prior tumor-directed therapy before enrollment

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study

- Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry
onto this study (4 weeks if prior nitrosourea);

- Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
with a biologic agent;

- Radiation therapy (RT): >= 2 weeks (wks) for local palliative RT (small port); >=
6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of
pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM)

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to =< grade 1;

- MEK inhibitor or vinblastine: Must not have received treatment with a MEK
inhibitor or vinblastine within 6 months of study enrollment

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^ 2 or a serum creatinine based on age/gender as follows (within 7 days
prior to enrollment):

- 2 to < 6 years: 0.8 mg/dL (male) 0.8 mg/dL (female)

- 6 to < 10 years: 1 mg/dL (male) 1 mg/dL (female)

- 10 to < 13 years: 1.2 mg/dL (male) 1.2 mg/dL (female)

- 13 to < 16 years: 1.5 mg/dL (male) 1.4 mg/dL (female)

- >= 16 years: 1.7 mg/dL (male) 1.4 mg/dL (female)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study
regardless of their total and indirect [unconjugated] bilirubin levels as long as
their direct [conjugated] bilirubin is < 3.1 mg/dL)

- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(within 7 days prior to enrollment)

- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L

- Albumin >= 2 g/L (within 7 days prior to enrollment)

- Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF
result is given as a range of values, then the upper value of the range will be used)
by echocardiogram (within 4 weeks prior to enrollment)

- Corrected QT interval (QTc interval) =< 450 msec by electrocardiogram (EKG) (within 4
weeks prior to enrollment)

- Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to

- Platelets >= 100,000/uL (unsupported) (within 7 days prior to enrollment)

- Hemoglobin >= 8 g/dL (may be supported) (within 7 days prior to enrollment)

- Patients with a known seizure disorder should be stable and should not have
experienced a significant increase in seizure frequency within 2 weeks prior to

- Stable neurological examination for >= 1 week


- Patients 2-17 years of age must have a blood pressure that is =< 95th percentile
for age, height, and gender at the time of enrollment (with or without the use of
anti-hypertensive medications);

- Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time
of enrollment (with or without the use of anti-hypertensive medications)

- Note for patients of all ages: Adequate blood pressure can be achieved using
medication for the treatment of hypertension

- All patients must have ophthalmology toxicity assessments performed within 4 weeks
prior to enrollment

- For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors)
and/or spine (depending on the site[s] of primary disease) with and without contrast
must be performed within 4 weeks prior to enrollment

- Note: If surgical resection or biopsy is performed at the time of progression or
recurrence, a post-operative MRI is required

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age

- Patients must have the ability to swallow whole capsules

Exclusion Criteria:

- Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following

- Patients must not have had progressive disease while on therapy with vinblastine
or a MEK inhibitor;

- Patients must not have discontinued vinblastine or selumetinib due to toxicity

- Patients with a concurrent malignancy or history of treatment (other than surgery) for
another tumor within the last year are ineligible

- Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of pons
involvement on imaging) are not eligible even if biopsy reveals grade I/II histology

- Patients may not be receiving any other investigational agents

- Patients must not have known hypersensitivity to selumetinib, vinblastine, or similar

- CYP3A4 agents: Patients must not have received fluconazole or drugs that are strong
inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment

- Patients with any serious medical or psychiatric illness/condition, including
substance use disorders or ophthalmological conditions, likely in the judgment of the
investigator to interfere or limit compliance with study requirements/treatment

- Patients who, in the opinion of the investigator, are not able to comply with the
study procedures are not eligible


- Known genetic disorder that increases risk for coronary artery disease. Note: The
presence of dyslipidemia in a family with a history of myocardial infarction is
not in itself an exclusion unless there is a known genetic disorder documented;

- Symptomatic heart failure

- New York Heart Association (NYHA) class II-IV prior or current

- Severe valvular heart disease

- History of atrial fibrillation


- Current or past history of central serous retinopathy

- Current or past history of retinal vein occlusion or retinal detachment

- Patients with uncontrolled glaucoma

- If checking pressure is clinically indicated, patients with intraocular
pressure (IOP) > 22 mmHg or upper limit of normal (ULN) adjusted by age are
not eligible

- Any multivitamin containing vitamin E must be stopped prior to study enrollment even
if it contains less than 100% of the daily recommended dosing for vitamin E

- Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy,
placement of a vascular access device or cerebrospinal fluid (CSF) diverting procedure
such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt

- Note: Patients must have healed from any prior surgery

- Patients who have an uncontrolled infection are not eligible

- Female patients who are pregnant are not eligible since fetal toxicities and
teratogenic effects have been noted for several of the study drugs. A pregnancy test
is required for female patients of childbearing potential

- Lactating females who plan to breastfeed their infants

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
12 weeks after stopping study therapy are not eligible

- Note: Women of child-bearing potential and males with sexual partners who are
pregnant or who could become pregnant (i.e., women of child-bearing potential)
should use effective methods of contraception for the duration of the study and
for 12 weeks after stopping study therapy to avoid pregnancy and/or potential
adverse effects on the developing embryo

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

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met