A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma
S
Sandeep Batra, MD
Primary Investigator
Overview
This phase III trial compares the effect of selumetinib versus the standard of care treatment
with carboplatin and vincristine (CV) in treating patients with newly diagnosed or previously
untreated low-grade glioma (LGG) that does not have a genetic abnormality called BRAFV600Eutation and is not associated with systemic neurofibromatosis type 1. Selumetinib works by
blocking some of the enzymes needed for cell growth and may kill tumor cells. Carboplatin and
vincristine are chemotherapy drugs that work in different ways to stop the growth of tumorher by killing the cells or by stopping them from dividing. The overall goal ofhis study is to see if selumetinib works just as well as the standard treatment of CV forwith LGG. Another goal of this study is to compare the effects of selumetinib versus
CV in subjects with LGG to find out which is better. Additionally, this trial will alsowith selumetinib improves the quality of life for subjects who take it.
Description
PRIMARY OBJECTIVE:
I. To demonstrate that the efficacy of treatment with selumetinib as measured by event-freeurvival (EFS) is non-inferior compared to treatment with carboplatin/vincristine (CV) inviously-untreated low-grade glioma (LGG) not associated with BRAFV600E mutations orystemic neurofibromatosis type 1 (NF1).
SECONDARY OBJECTIVES:
I. To estimate tumor response rates to each regimen of chemotherapy. II. To evaluate visualuity (VA) outcomes utilizing Teller Acuity Cards (TAC) and HOTV letter acuity testing inviously-untreated optic pathway gliomas (OPGs).
III. To describe the improvement in motor function as measured by the Vineland Scale inhildren with previously-untreated LGG that have motor deficits at enrollment.
IV. To estimate the difference in EFS and tumor response rate between BRAF rearranged andBRAF rearranged patients treated on each chemotherapy regimen.
V. To prospectively evaluate the quality of life of children with LGG not associated with
BRAFV600E or systemic NF1 treated with either CV or selumetinib.
VI. To prospectively evaluate the cognitive, social, emotional, and behavioral functioning ofhildren with LGG not associated with BRAFV600E or systemic NF1 treated with either CV orumetinib.
EXPLORATORY OBJECTIVE:
I. To obtain paired blood and tumor specimens for future biology studies, including studiesgenomic drivers to response.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I:
INDUCTION: Patients receive vincristine sulfate intravenously (IV) over 1 minute on days 1,
8, 15, 22, 29, 36, 43, 50, 57, and 64, and carboplatin IV over 60 minutes on days 1, 8, 15,
22, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity.
Patients also undergo collection of blood and magnetic resonance imaging (MRI) at baselined end of induction.
MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15, andboplatin IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 42 days for
up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also
undergo collection of blood and undergo MRI at baseline, throughout the trial, and duringw up.
ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (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 also undergo collection of blood and undergo MRI at baseline,hroughout the trial, and during follow up.
After completion of study treatment, patients are followed up every 3 months for year 1,very 6 months for years 2-3, and then annually for years 4-10.
Eligibility
You may be eligible for this study if you meet the following criteria:
-
Conditions:
Low Grade Astrocytoma, Low Grade Glioma, Metastatic Low Grade Astrocytoma, Metastatic Low Grade Glioma
-
Age: Between 2 Years - 21 Years
-
Gender: All
Inclusion Criteria:
- Patients must be >= 2 years and =< 21 years at the time of enrollment
- Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
- Patients must have non-neurofibromatosis type 1 (non-NF1) low-grade glioma (LGG)without a BRAFV600E mutation as confirmed by Rapid Central Pathology and Molecularg Reviews performed on APEC14B1 (NCT02402244) and that has not been treatedwith any modality besides surgery. Note: Patients may be newly-diagnosed OR previouslydiagnosed, and there is no required time frame between biopsy/surgery and treatment.
- Patients with residual tumor after resection or progressive tumor after initialdiagnosis (with or without surgery) who have not received treatment (chemotherapyd/or radiation) are eligible
- Patients must have two-dimensional measurable tumor >= 1 cm^2 to be eligible
- Eligible histologies will include all tumors considered low-grade glioma or low-grade
astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHOvous system (CNS) tumors with the exception ofubependymal giant cell astrocytoma
- Patients with metastatic disease or multiple independent primary LGG are eligible
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70L/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (performed within7 days prior to enrollment):
- Age: Maximum Serum Creatinine (mg/dL)
- 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 (performed within 7 days
prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowedudy regardless of their total and indirect [unconjugated] bilirubin levels asg as their direct [conjugated] bilirubin is < 3.1 mg/dL)
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L(performed within 7 days prior to enrollment). For the purpose of this study, the ULNGPT is 45 U/L
- Albumin >= 2 g/dL (performed within 7 days prior to enrollment)
- Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEFult is given as a range of values, then the upper value of the range will be used)by echocardiogram (performed within 4 weeks prior to enrollment)
- Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performed withinweeks prior to enrollment)
- Absolute neutrophil count >= 1,000/uL (unsupported) (performed within 7 days prior to)
- Platelets >= 100,000/uL (unsupported) (performed within 7 days prior to enrollment)
- Hemoglobin >= 8 g/dL (may be supported) (performed within 7 days prior to enrollment)
- Patients with a known seizure disorder should be stable and should not haved a significant increase in seizure frequency within 2 weeks prior to
- Patients 2-17 years of age must have a blood pressure that is =< 95th percentile forge, height, and gender at the time of enrollment (with or without the use ofhypertensive medications)
- Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of(with or without the use of anti-hypertensive medications)
- Note for patients of all ages: Adequate blood pressure can be achieved usingdication for the treatment of hypertension
- All patients must have ophthalmology toxicity assessments performed within 4 weeks
- For all patients, a magnetic resonance imaging (MRI) of the brain (with orbital cutshway 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
- Patients must have a performance status corresponding to Eastern Cooperative OncologyGroup (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age andLansky for patients =< 16 years of age
- Patients must have the ability to swallow whole capsules
- All patients have signed an appropriate consent form and Health Insurance Portabilityd Accountability Act (HIPAA) authorization form (if applicable)
- All patients and/or their parents or legal guardians must sign a written informed
- All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed byhe ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the sameday to complete the Rapid Central Review
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute(NCI) requirements for human studies must be met
Exclusion Criteria:
- Patients must not have received any prior tumor-directed therapy includinghemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Priorurgical intervention is permitted
- Patients with a concurrent malignancy or history of treatment (other than surgery) forher tumor within the last year are ineligible
- Patients with diffuse intrinsic pontine tumors as seen on MRI (> 2/3 of ponsvolvement on imaging) are not eligible even if biopsy reveals grade I/II histology
- Patients may not be receiving any other investigational agents
- Patients with any serious medical or psychiatric illness/condition, includingubstance use disorders or ophthalmological conditions, likely in the judgment of thevestigator to interfere or limit compliance with study requirements/treatment
- Patients who, in the opinion of the investigator, are not able to comply with theudy procedures are not eligible
- Female patients who are pregnant are not eligible since fetal toxicities andgenic effects have been noted for several of the study drugs. A pregnancy testquired for female patients of childbearing potential
- Lactating females who plan to breastfeed their infants are not eligible
- Sexually active patients of reproductive potential who have not agreed to use anve contraceptive method for the duration of their study participation and for12 weeks after stopping study therapy are not eligible.
- Note: Women of child-bearing potential and males with sexual partners who aregnant or who could become pregnant (i.e., women of child-bearing potential)hould use effective methods of contraception for the duration of the study and12 weeks after stopping study therapy to avoid pregnancy and/or potentialdverse effects on the developing embryo
- 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 inusion unless there is a known genetic disorder documented
- Symptomatic heart failure
- New York Health Association (NYHA) class II-IV prior or current cardiomyopathy
- 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 ULN adjusted by age are not eligible
- Supplementation with vitamin E greater than 100% of the daily recommended dose. Any
multivitamin containing vitamin E must be stopped prior to study enrollment even ifhan 100% of the daily recommended dosing for vitamin E
- Surgery within 2 weeks prior to enrollment, with the exception of surgical biopsy,vascular access device or cerebral spinal fluid (CSF) divertingdure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP)hunt.
- Note: Patients must have healed from any prior surgery
- Patients who have an uncontrolled infection are not eligible
Updated on
01 May 2024.
Study ID: NCI-2019-07600
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