A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine versus Selumetinib in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) not associated with BRAFV600E Mutations or Systemic Neurofibromatosis Type 1 (NF1)
Study of Investigational Treatment for Slow-Growing Brain Tumors in Children and Young Adults
Sandeep Batra, MD
Primary Investigator
Brief description of study
Detailed description of study
Eligibility of study
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, Cancer, Riley
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Age: 2 years - 21 years
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Gender: All
- 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
- 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
This study investigates treatment options for children and young adults with low-grade glioma (LGG), a type of brain tumor. The purpose of this study is to compare the effects of an investigational medication with standard chemotherapy treatments, carboplatin and vincristine, in patients who do not have a specific genetic mutation called BRAFV600E and do not have neurofibromatosis type 1. LGG is a slow-growing tumor that affects the brain and nervous system.
Participants in this study will be assigned to one of two study arms. In the first arm, participants will receive standard chemotherapy treatments with carboplatin and vincristine, along with regular blood tests and MRI scans. In the second arm, participants will receive the investigational medication, selumetinib, taken orally twice a day, with similar monitoring through blood tests and MRI scans. The goal is to determine if the investigational medication is as effective as the standard treatment.
- Who can participate: Participants must be between 2 and 21 years old with a body surface area of at least 0.5 m², have low-grade glioma without a BRAFV600E mutation, and not be associated with neurofibromatosis type 1.
- Study details: Participants will receive either standard chemotherapy with carboplatin and vincristine or an investigational medication, selumetinib. The investigational medication is taken orally, while chemotherapy is given intravenously.