Clinical Trials /

A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma

NCT04166409

Description:

This phase 3 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 BRAFV600E mutation 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 tumor cells, either by killing the cells or by stopping them from dividing. The overall goal of this study is to see if selumetinib works just as well as the standard treatment of CV for patients with 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 also examine if treatment with selumetinib improves the quality of life for subjects who take it.

Related Conditions:
  • Low Grade Glioma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma
  • Official Title: A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine Versus Selumetinib (NSC# 748727) in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) Not Associated With BRAFV600E Mutations or Systemic Neurofibromatosis Type 1 (NF1)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-07600
  • SECONDARY ID: NCI-2019-07600
  • SECONDARY ID: ACNS1833
  • SECONDARY ID: ACNS1833
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT04166409

Conditions

  • Low Grade Astrocytoma
  • Low Grade Glioma
  • Metastatic Low Grade Astrocytoma
  • Metastatic Low Grade Glioma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (vincristine sulfate, carboplatin)
Selumetinib SulfateAZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Koselugo, Selumetinib SulphateArm II (selumetinib sulfate)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm I (vincristine sulfate, carboplatin)

Purpose

This phase 3 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 BRAFV600E mutation 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 tumor cells, either by killing the cells or by stopping them from dividing. The overall goal of this study is to see if selumetinib works just as well as the standard treatment of CV for patients with 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 also examine if treatment with selumetinib improves the quality of life for subjects who take it.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To demonstrate that the efficacy of treatment with selumetinib as measured by event-free
      survival (EFS) is non-inferior compared to treatment with carboplatin/vincristine (CV) in
      previously-untreated low-grade glioma (LGG) not associated with BRAFV600E mutations or
      systemic neurofibromatosis type 1 (NF1).

      SECONDARY OBJECTIVES:

      I. To estimate tumor response rates to each regimen of chemotherapy. II. To evaluate visual
      acuity (VA) outcomes utilizing Teller Acuity Cards (TAC) and HOTV letter acuity testing in
      previously-untreated optic pathway gliomas (OPGs).

      III. To describe the improvement in motor function as measured by the Vineland Scale in
      children with previously-untreated LGG that have motor deficits at enrollment.

      IV. To estimate the difference in EFS and tumor response rate between BRAF rearranged and
      non-BRAF 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 of
      children with LGG not associated with BRAFV600E or systemic NF1 treated with either CV or
      selumetinib.

      EXPLORATORY OBJECTIVE:

      I. To obtain paired blood and tumor specimens for future biology studies, including studies
      to correlate genomic 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.

      MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15, and
      carboplatin 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.

      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.

      After completion of study treatment, patients are followed up every 3 months for year 1,
      every 6 months for years 2-3, and then annually for years 4-10.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (vincristine sulfate, carboplatin)Active ComparatorINDUCTION: Patients receive vincristine sulfate 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. MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15, and carboplatin 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.
  • Carboplatin
  • Vincristine Sulfate
Arm II (selumetinib sulfate)ExperimentalPatients 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.
  • Selumetinib Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  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 Molecular
             Screening Reviews performed on APEC14B1 (NCT02402244) and that has not been treated
             with any modality besides surgery. Note: Patients may be newly-diagnosed OR previously
             diagnosed, and there is no required time frame between biopsy/surgery and treatment
             initiation.

               -  Patients with residual tumor after resection or progressive tumor after initial
                  diagnosis (with or without surgery) who have not received treatment (chemotherapy
                  and/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 WHO
             classification of central nervous system (CNS) tumors with the exception of
             subependymal giant cell astrocytoma

          -  Patients with metastatic disease or multiple independent primary LGG are eligible

          -  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 (performed within
             7 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 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
             (performed within 7 days prior to enrollment). For the purpose of this study, the ULN
             for SGPT 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 LVEF
             result is given as a range of values, then the upper value of the range will be used)
             by echocardiogram (performed within 7 days prior to enrollment)

          -  Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (performed within
             7 days prior to enrollment)

          -  Absolute neutrophil count >= 1,000/uL (unsupported) (performed within 7 days prior to
             enrollment)

          -  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 have
             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 (with or without the use of
             anti-hypertensive medications)

          -  All patients must have ophthalmology toxicity assessments performed within 4 weeks
             prior to 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 anti-hypertensive medications)

          -  Note for patients of all ages: Adequate blood pressure can be achieved using
             medication for the treatment of hypertension

          -  For all patients, a magnetic resonance imaging (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

          -  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

          -  All patients have signed an appropriate consent form and Health Insurance Portability
             and Accountability Act (HIPAA) authorization form (if applicable)

          -  All patients and/or their parents or legal guardians must sign a written informed
             consent

          -  All patients have been consented and enrolled on APEC14B1 (NCT02402244) followed by
             enrollment on the ACNS1833 Pre-Enrollment Eligibility Screening (Step 0) on the same
             day 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 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 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 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

          -  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

          -  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 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 if
             less than 100% of the daily recommended dosing for vitamin E

          -  Surgery within 2 weeks prior to enrollment, with the exception of surgical biopsy,
             placement of a vascular access device or cerebral spinal 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
      
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:Up to 10 years from date of randomization
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate EFS which is defined as the interval from randomization to first occurrence of clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, or to the date of last follow-up. Estimates with 95% confidence intervals will be reported by treatment arm. The hazard ratio with a confidence interval will also be reported to compare treatment arms based on a Cox proportional hazards model stratified by BRAF status, tumor location and size of residual tumor.

Secondary Outcome Measures

Measure:Radiographic tumor response rate
Time Frame:Up to 10 years
Safety Issue:
Description:Percentages of patients with responses (complete or partial response) will be reported by treatment arm with 95% confidence intervals. The result of an exact binomial test to test for the difference in response rates between treatment arm will also be reported.
Measure:Overall survival (OS)
Time Frame:Up to 10 years from date of randomization
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate OS by treatment arm, defined as the interval from randomization to death from any cause, or to the date of last follow-up. Estimates with confidence intervals will be reported by treatment arm.
Measure:Number of patients who experience an improvement in visual acuity (VA)
Time Frame:After the first 12 months of treatment
Safety Issue:
Description:Numbers of patients that show improvement in VA after 12 months of treatment will be reported by treatment arm. Patients with at least 1 impaired eye are evaluable. In a patient with a unilateral optic nerve glioma, only the affected eye is considered. In patients with bilateral visual impairment, if VA improves in 1 eye but worsens in the other, the patient will be coded as a treatment failure, whereas if 1 eye improves and the other is at least stable, the patient will be coded as a success.
Measure:Change in motor function
Time Frame:After 48 weeks of therapy
Safety Issue:
Description:Motor function is measured using the Vineland-3 Motor Scale. Only patients with motor function deficits at baseline are included. Magnitudes of change for each patient after 48 weeks of therapy from baseline will be calculated and medians (with ranges) by treatment arm will be reported.
Measure:Change in quality of life (QOL)
Time Frame:Baseline and 9 months after treatment initiation
Safety Issue:
Description:QOL will be measured using the PedsQL Total Scale Score as measured from the validated PedsQL Generic Module (for children 2-21 years old). Mean differences in the total scale score between 9 months and baseline will be reported by treatment arm. The results of 2-sample t-test comparing differences in the QOL scores between the 2 arms will also be reported. If change scores do not follow normal distributions, non-parametric alternatives may be employed for analysis.
Measure:Processing speed function
Time Frame:Up to 9 months post-treatment initiation
Safety Issue:
Description:Measured by Wechsler Processing Speed Index (standard score). Scores at 9 months will be summarized by treatment arm and reported as means (with standard deviations) or medians (with ranges) depending on the data distribution.
Measure:Change in executive function
Time Frame:Baseline and 9-months
Safety Issue:
Description:Executive function will be measured by the BRIEF-2 Cognitive Regulation Index (CRI). Summary statistics for the differences in scores from baseline to 9 months will be reported by treatment arm.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

June 29, 2021