Description:
This phase III trial studies if selumetinib works just as well as the standard treatment with
carboplatin/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
low-grade glioma tumor cells need for their growth. This results in killing tumor cells.
Drugs used as 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.
Title
- Brief Title: A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma
- 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)
Clinical Trial IDs
- ORG STUDY ID:
NCI-2019-01396
- SECONDARY ID:
NCI-2019-01396
- SECONDARY ID:
ACNS1831
- SECONDARY ID:
ACNS1831
- SECONDARY ID:
U10CA180886
- NCT ID:
NCT03871257
Conditions
- Low Grade Glioma
- Neurofibromatosis Type 1
- Visual Pathway Glioma
Interventions
Drug | Synonyms | Arms |
---|
Carboplatin | Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo | Arm I (carboplatin, vincristine) |
Selumetinib Sulfate | AZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Koselugo, Selumetinib Sulphate | Arm II (selumetinib sulfate) |
Vincristine Sulfate | Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate | Arm I (carboplatin, vincristine) |
Purpose
This phase III trial studies if selumetinib works just as well as the standard treatment with
carboplatin/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
low-grade glioma tumor cells need for their growth. This results in killing tumor cells.
Drugs used as 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.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine whether the efficacy of treatment with selumetinib sulfate (selumetinib) as
measured by event-free survival (EFS) is non-inferior to treatment with
carboplatin/vincristine sulfate (vincristine) (CV) in previously untreated neurofibromatosis
type 1 (NF1)-associated low-grade glioma (LGG).
II. To determine whether visual acuity (VA) using Teller acuity cards (TAC), in patients with
NF1-associated LGG within the optic pathway, is better in those treated with selumetinib
compared to CV.
SECONDARY OBJECTIVES:
I. To estimate tumor response rates and overall survival (OS) in each treatment regimen in
previously untreated NF1-associated LGG.
II. To evaluate VA outcomes utilizing HOTV letter acuity testing in previously untreated
NF1-associated LGG within the optic pathway in patients who are old enough to perform visual
acuity testing utilizing HOTV (a recognition acuity measure).
III. To describe the improvement in motor function as measured by the Vineland scale in
patients with previously untreated NF1-associated LGG that have documented motor deficits at
enrollment.
IV. To prospectively evaluate and compare the quality of life among patients treated with
selumetinib or CV.
V. To prospectively evaluate and compare the cognitive, social, emotional, and behavioral
functioning of patients with NF1-associated LGG treated with either selumetinib or CV.
EXPLORATORY OBJECTIVES:
I. To evaluate optical coherence tomography (OCT) measures of retinal axon and ganglion cell
thickness as a marker of treatment response in previously untreated NF1-associated LGG within
the optic pathway.
II. To compare novel, semi-automated volumetric magnetic resonance imaging (MRI) measures to
traditional measurements of treatment response (bi-dimensional MRI measurements) in
NF1-associated optic pathway tumors.
III. To obtain paired blood and tumor tissue to be banked for future NF1-LGG biology studies
involving comprehensive molecular analysis, including but not limited to whole exome and
ribonucleic acid (RNA) sequencing.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I:
INDUCTION: Patients receive carboplatin intravenously (IV) over 60 minutes on days 1, 8, 15,
22, 43, 50, 57, and 64 and vincristine IV or IV push over 1 minute 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 or IV push over 1 minute on days 1, 8, and 15. Treatment repeats every 6 weeks
for 8 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28.
Treatment is continuous and repeats every 28 days for 27 cycles in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up with MRIs and physical exams
every 3 months for 1 year, every 6 months for 2 years, and then once yearly for up to 10
years.
Trial Arms
Name | Type | Description | Interventions |
---|
Arm I (carboplatin, vincristine) | Active Comparator | INDUCTION: Patients receive carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 and vincristine IV or IV push over 1 minute 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 or IV push over 1 minute on days 1, 8, and 15. Treatment repeats every 6 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. | - Carboplatin
- Vincristine Sulfate
|
Arm II (selumetinib sulfate) | Experimental | Patients receive selumetinib sulfate PO BID on days 1-28. Treatment is continuous and repeats every 28 days for 27 cycles in the absence of disease progression or unacceptable toxicity. | |
Eligibility 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 be newly diagnosed or have previously diagnosed NF-1 associated LGG that
has not been treated with any modality other than surgery
- 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 must have two-dimensional measurable 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 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
- 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) or spine
(depending on the site(s) of primary disease) 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 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
- 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
even if less than 100% of the daily recommended dosing for vitamin E
- Surgery within 2 weeks prior to 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
Maximum Eligible Age: | 21 Years |
Minimum Eligible Age: | 2 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Event-free survival (EFS) |
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 3 years after accrual completion |
Safety Issue: | |
Description: | EFS is defined as time 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. Patients who are event-free will be censored at the time of last follow-up. Hazard ratio based on a stratified Cox proportional hazards model will be reported, along with a 90% confidence interval. |
Secondary Outcome Measures
Measure: | Radiographic tumor response rate |
Time Frame: | Assessed up to 3 years after accrual completion |
Safety Issue: | |
Description: | Tumors will be classified into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Radiologic response rates will be summarized per arm and be tested for a difference between the two arms using an exact binomial test. |
Measure: | 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 3 years after accrual completion |
Safety Issue: | |
Description: | OS is defined as the time 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. Hazard ratio will be reported, along with a 90% confidence interval. |
Measure: | Change in VA using HOTV letter acuity testing |
Time Frame: | Baseline and end of about 12 months of treatment |
Safety Issue: | |
Description: | HOTV is a recognition acuity measure. It will be conducted on patients who are developmentally able to perform this testing. |
Measure: | Change in motor function |
Time Frame: | Baseline and approximately 12 months of treatment |
Safety Issue: | |
Description: | The Vineland-3 Motor Scale from the Comprehensive Parent Rating Form will be used to assess motor deficits. Change in Vineland motor scale from baseline to about 12 months of treatment will be compared between two treatment arms. |
Measure: | Change in quality of life (QOL) |
Time Frame: | Baseline and 12 months of treatment |
Safety Issue: | |
Description: | Will be measured by Pain and Hurt subscale score. QOL will be assessed by Pediatric Quality of Life (PedsQL) Generic and Brain Tumor modules. Analysis will be based on a 2-sample t-test comparing change in Pain and Hurt subscale score from baseline to 12 months for the two arms. |
Measure: | Change in quality of life (QOL) |
Time Frame: | Baseline and 12 months of treatment |
Safety Issue: | |
Description: | Will be measured by Movement and Balance subscale score. QOL will be assessed by Pediatric Quality of Life (PedsQL) Generic and Brain Tumor modules. Analysis will be based on a 2-sample t-test comparing change in Movement and Balance subscale score from baseline to 12 months for the two arms. |
Measure: | Change in executive function |
Time Frame: | Baseline and 24 months of treatment |
Safety Issue: | |
Description: | Will be measured by BRIEF Cognitive Regulation Index (CRI). Executive function will be measured by age-appropriate Behavior Rating Inventory of Executive Function (BRIEF) questionnaire. Analysis will be based on a 2-sample t-test comparing change in the designated score from baseline to 24 months for the two arms. |
Measure: | Change in neurocognitive function |
Time Frame: | Baseline and 24 months of treatment |
Safety Issue: | |
Description: | Will be measured by Cogstate composite score. Neurocognitive function will be measured by a computerized battery (Cogstate) testing. Analysis will be based on a 2-sample t-test comparing change in Cogstate composite score from baseline to 24 months for the two arms. |
Details
Phase: | Phase 3 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
August 25, 2021