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A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma

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ClinicalTrials.gov Identifier: NCT03871257
Recruitment Status : Not yet recruiting
First Posted : March 12, 2019
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase III trial studies if selumetinib works just as well as the standard treatment with carboplatine/vincristine (CV) for subjects with NF1-associated low grade glioma (LGG), and to see if selumetinib is better than CV in improving vision in subjects with LGG of the optic pathway (vision nerves). Selumetinib is a drug that works by blocking some enzymes that tumor cells need for their growth. This results in killing tumor cells. Drugs used in chemotherapy, such as carboplatin and vincristine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether selumetinib works better in treating patients with NF1 associated low-grade glioma compared to standard therapy with carboplatin and vincristine.

Condition or disease Intervention/treatment Phase
Low Grade Glioma Neurofibromatosis Type 1 Visual Pathway Glioma Drug: Carboplatin Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Selumetinib Drug: Selumetinib Sulfate Drug: Vincristine Drug: Vincristine Sulfate Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 290 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized Study of Selumetinib Versus Carboplatin/Vincristine in Newly Diagnosed or Previously Untreated Neurofibromatosis Type 1 (NF1) Associated Low-Grade Glioma (LGG)
Estimated Study Start Date : October 4, 2019
Estimated Primary Completion Date : May 1, 2027
Estimated Study Completion Date : May 1, 2027


Arm Intervention/treatment
Active Comparator: Arm I (carboplatin, vincristine)

INDUCTION: Patients receive carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 and vincristine IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive carboplatin IV over 60 minutes on days 1, 8, 15, and 22 and vincristine IV on days 1, 8, and 15. Treatment repeats every 6 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Vincristine
Given IV
Other Names:
  • LEUROCRISTINE
  • VCR
  • Vincrystine

Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

Experimental: Arm II (selumetinib sulfate)
Patients receive selumetinib sulfate PO BID on days 1-28. Treatment repeats every 28 days for 27 cycles in the absence of disease progression or unacceptable toxicity.
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Drug: Selumetinib
Given PO
Other Names:
  • ARRY-142886
  • AZD6244
  • MEK inhibitor AZD6244

Drug: Selumetinib Sulfate
Given PO
Other Names:
  • AZD-6244 Hydrogen Sulfate
  • AZD6244 Hydrogen Sulfate
  • AZD6244 Hydrogen Sulphate
  • Selumetinib Sulphate




Primary Outcome Measures :
  1. Event-free survival [ Time Frame: From randomization to the first occurrence of any of the following events: clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, assessed up to 10 years ]
    Will estimate the hazard ratio based on a stratified Cox proportional hazards model and use Kaplan-Meier (KM) methods to visualize and summarize the data.

  2. Visual acuity (VA) [ Time Frame: From pre-treatment baseline up to 12 cycles ]
    Defined as the difference in proportion of randomized patients in each arm who experience an improvement in VA within the first 12 cycles of treatment (approximately 1 year). Assessed using Teller acuity cards (TAC). The primary analysis will be based on per subject outcome (rather than per eye). For the per subject analysis, will use an exact binomial test to compare the difference in the proportion of subjects in each arm that show improvement in VA within 12 months of treatment using a 1 sided test with 5% type 1 error.


Secondary Outcome Measures :
  1. Radiographic tumor response rate [ Time Frame: Up to 10 years ]
    Will summarize the radiologic response rates per arm and test for a difference between the two arms using an exact binomial test.

  2. Overall survival (OS) [ Time Frame: From randomization until death from any cause or till the time of last follow-up for patients who are alive at the time of analysis, assessed up to 10 years ]
    We will use the KM methods, log-rank tests, and Cox proportional hazards models to determine whether there is a difference in OS between the two arms.

  3. Change in motor function [ Time Frame: Baseline up to 12 cycles ]
    Will compare the magnitudes of change from baseline between the two treatment arms and provide a 90% 2-sided confidence interval for this difference.

  4. Change in quality of life (QOL) [ Time Frame: Baseline up to 12 months ]
    Assessed by Pediatric Quality of Life (PedsQL) Generic and Brain Tumor modules. The primary analysis will be based on a 2-sample t-test comparing change in the QOL score for the two arms, as planned.

  5. Change in neurocognitive function [ Time Frame: From pre-treatment (Baseline) up to 24 months ]
    Will be evaluated in patients with a computerized battery (Cogstate) and the Children's Oncology Group Standardized Neuropsychological & Behavioral Battery. The primary analysis will be based on a 2-sample t-test comparing change in the designated neurocognitive score for the two arms, as planned.


Other Outcome Measures:
  1. Change in circumpapillary retinal nerve fiber layer (cpRNFL) and ganglion cell inner plexiform layer (GCIPL) thickness [ Time Frame: Baseline to 12 months ]
    Will compare changes cpRNFL/GCIPL thickness from baseline to month 12 between treatment groups. A generalized estimating equation will be applied to all optical coherence tomography (OCT) data to account for known inter-eye correlations of both VA and OCT metrics. cpRNFL thickness and GCIPL measures are both continuous variables. Ordinary least squares will assess the rate of change in OCT measures between baseline and subsequent visits.

  2. Effect of change in cpRNFL and GCIPL thickness on treatment response [ Time Frame: Baseline to 12 months ]
    Determine if cpRNFL/GCIPL thickness measures prior to treatment initiation can predict treatment response in children with optic pathway gliomas. A generalized estimating equation will be applied to all OCT data to account for known inter-eye correlations of both VA and OCT metrics. cpRNFL thickness and GCIPL measures are both continuous variables. Ordinary least squares will assess the rate of change in OCT measures between baseline and subsequent visits.

  3. Effect of change in cpRNFL and GCIPL thickness on visual acuity [ Time Frame: Baseline to 12 months ]
    Determine if changes in cpRNFL/GCIPL thickness measures over time are associated with VA loss. A generalized estimating equation will be applied to all OCT data to account for known inter-eye correlations of both VA and OCT metrics. cpRNFL thickness and GCIPL measures are both continuous variables. Ordinary least squares will assess the rate of change in OCT measures between baseline and subsequent visits.

  4. Novel semi-automated volumetric magnetic resonance imaging measurements [ Time Frame: Up to 10 years ]
    Tumors will be classified into progressive disease, stable disease, and partial response (PR) using volumetric measurements and same thresholds as the ones for used for 2-dimensional (2D) measurements (e.g. ,50% reduction in tumor size for PR) and these assessments will be compared to the ones obtained based on 2D measurements. Will summarize the results using descriptive statistics. We will also compare the absolute percent change in tumor size between 2D and 3-dimensional measurements in a descriptive fashion as well as using longitudinal approaches.

  5. Tumor and blood banking [ Time Frame: Up to 10 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
  • Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or germline genetic testing
  • Patients must have a LGG (newly diagnosed or previously diagnosed) that has never previously been treated with chemotherapy or radiation
  • For patients with optic pathway gliomas (OPGs):

    • Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms (including visual dysfunction, as defined below) or other exam findings associated with the tumor
    • Previously-diagnosed patients with OPG are eligible if they have new or worsening neurologic symptoms (including visual dysfunction, as defined below) or have tumor growth
    • For both newly-diagnosed and previously-diagnosed OPG, the patient may be eligible, irrespective of whether there has been tumor growth or other neurological symptoms or worsening, if they meet at least one of the following visual criteria:

      • Visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year (by examination or history); OR
      • Significant visual dysfunction (defined as VA worse than normal for age by 0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)
  • For patients with LGG in other locations (i.e., not OPGs):

    • Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms or other exam findings associated with the tumor

      • NOTE: Newly-diagnosed patients with LGG without associated neurologic symptoms or exam findings are not eligible
    • Previously-diagnosed patients with LGG are eligible if they have new or worsening neurologic symptoms or have tumor growth
  • Although not required, if a biopsy/tumor resection is performed, eligible histologies will include all tumors considered LGG or low-grade astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO classification of central nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma

    • Patients who have undergone tumor resection must have two-dimensional measurable residual tumor >= 1 cm^2
  • Patients with metastatic disease or multiple independent primary LGGs are allowed on study
  • Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender within 7 days prior to enrollment as follows:

    • Age; maximum serum creatinine (mg/dL)
    • 2 to < 6 years; 0.8 (male) and 0.8 (female)
    • 6 to < 10 years; 1 (male) and 1 (female)
    • 10 to < 13 years; 1.2 (male) and 1.2 (female)
    • 13 to < 16 years; 1.5 (male) and 1.4 (female)
    • >= 16 years; 1.7 (male) and 1.4 (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 glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN) = 135 U/L within 7 days prior to enrollment. For the purpose of this study, the ULN for SGPT is 45 U/L
  • Albumin >= 2 g/dL 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 7 days prior to enrollment
  • Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) within 7 days 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 have not experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
  • 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. Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of antihypertensive medications).

    • Note: Adequate blood pressure can be achieved using medication for the treatment of hypertension
  • All patients must have an ophthalmology examination performed within 4 weeks prior to enrollment
  • For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors) with and without contrast must be performed within 4 weeks prior to enrollment
  • For patients who undergo a surgery on the target tumor (not required), a pre- and post-operative MRI of the brain (with orbital cuts for optic pathway tumors) with and without contrast and a pre- or post-operative MRI of the spine (if clinically indicated) with and without contrast must also be performed within 4 weeks prior to enrollment

    • The post-operative MRIs should be performed ideally within 48 hours after surgery if possible
  • 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
  • Patients must have receptive and expressive language skills in English or Spanish to complete the quality of life (QOL) and neurocognitive assessments
  • 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.

Exclusion Criteria:

  • Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted
  • Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
  • Patients may not be receiving any other investigational agents
  • Patients with any serious medical or psychiatric illness/ condition, including substance use disorders likely in the judgement of the investigator to interfere or limit compliance with study requirements/treatment are not eligible
  • Patients who, in the opinion of the investigator, are not able to comply with the study procedures 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 are not eligible
  • 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
  • Cardiac conditions:

    • Known inherited coronary artery disease
    • Symptomatic heart failure
    • New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
    • Severe valvular heart disease
    • History of atrial fibrillation
  • 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 ULN adjusted by age are not eligible
    • Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN, such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
  • Treatments and/or medications patient is receiving that would make her/him ineligible, such as:

    • Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment
    • Recent surgery within a minimum of 2 weeks prior to starting study enrollment, with the exception of surgical placement for vascular access or cerebrospinal fluid (CSF) diverting procedures such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP) shunt.

      • Note: Patients must have healed from any prior surgery prior to enrollment
  • Patients who have an uncontrolled infection are not eligible

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03871257


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jason R Fangusaro Children's Oncology Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03871257     History of Changes
Other Study ID Numbers: NCI-2019-01396
NCI-2019-01396 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACNS1831 ( Other Identifier: Childrens Oncology Group )
ACNS1831 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: March 12, 2019    Key Record Dates
Last Update Posted: September 4, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioma
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nerve Sheath Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Carboplatin
Vincristine
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action