PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of selumetinib sulfate (selumetinib) + vinblastine sulfate (vinblastine) for children with progressive or recurrent low-grade gliomas (LGGs).
II. To determine if selumetinib + vinblastine will lead to improved event-free survival (EFS) outcome compared with selumetinib alone for children with progressive or recurrent LGGs.
SECONDARY OBJECTIVES:
I. To estimate the objective response rates and overall survival associated with treatment with selumetinib + vinblastine versus single-agent selumetinib.
II. To estimate the difference in EFS and response rate between patients with BRAF rearranged LGG and patients with non-BRAF rearranged LGG after treatment with selumetinib + vinblastine versus single-agent selumetinib.
III. To evaluate toxicities associated with selumetinib + vinblastine and single-agent selumetinib for children with progressive or recurrent LGGs.
IV. To compare the quality of life among patients treated with selumetinib + vinblastine and single-agent selumetinib.
V. To examine the vision outcomes among patients with optic pathway gliomas (OPGs) treated with selumetinib + vinblastine and single-agent selumetinib.
EXPLORATORY OBJECTIVE:
I. To obtain paired blood and tumor specimens for future biology studies, including studies to correlate genomic drivers to response.
OUTLINE: This is a dose-escalation feasibility study of vinblastine sulfate in combination with selumetinib, followed by a randomized efficacy study. Patients in the feasibility study are assigned to Arm I, while patients in the efficacy study are randomized to Arm I or Arm II.
ARM I: Patients receive vinblastine sulfate intravenously (IV) over 1 minute or IV infusion on days 1, 8, 15, and 22 and selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days. Patients receive selumetinib and vinblastine for a total duration of 17 cycles followed by 10 additional cycles of selumetinib alone in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood sample collection during screening and on study.
ARM II: Patients receive selumetinib sulfate PO BID on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.
After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and annually for years 4-5.
Inclusion Criteria:
- Feasibility phase: patients must be >= 2 years and =< 21 years of age at the time of
enrollment
- Efficacy phase: patients must be >= 2 years and =< 25 years of age at the time of
enrollment
- 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
eligible
- 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)
radiation;
- 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
enrollment)
- 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
enrollment
- Stable neurological examination for >= 1 week
- HYPERTENSION:
- 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
exceptions:
- 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
compounds
- 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
- PRE-EXISTING CONDITIONS (CARDIAC):
- 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
cardiomyopathy
- Severe valvular heart disease
- History of atrial fibrillation
- PRE-EXISTING CONDITIONS (OPHTHALMOLOGIC CONDITIONS):
- 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
consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
