Clinical Trials /

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

NCT04166409

Description:

This trial studies how well selumetinib works in treating patients with low-grade glioma. Selumetinib is a drug that works by blocking a protein (a basic building block of the human body) that lets tumor cells grow without stopping. 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. This trial studies if selumetinib works as well as carboplatin and vincristine for getting rid of or shrinking low-grade gliomas and stopping them from coming back.

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

  • Astrocytoma
  • 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, carboplatin)
SelumetinibARRY-142886, AZD6244, MEK Inhibitor AZD6244Arm II (selumetinib)
Selumetinib SulfateAZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Selumetinib SulphateArm II (selumetinib)
VincristineLeurocristine, VCR, VincrystineArm I (vincristine, carboplatin)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm I (vincristine, carboplatin)

Purpose

This trial studies how well selumetinib works in treating patients with low-grade glioma. Selumetinib is a drug that works by blocking a protein (a basic building block of the human body) that lets tumor cells grow without stopping. 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. This trial studies if selumetinib works as well as carboplatin and vincristine for getting rid of or shrinking low-grade gliomas and stopping them from coming back.

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 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 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 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, carboplatin)Active ComparatorINDUCTION: Patients receive vincristine 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 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
  • Vincristine Sulfate
Arm II (selumetinib)ExperimentalPatients receive selumetinib 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
  • 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 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:

               -  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 (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. For the purpose of this study, the ULN for SGPT is 45 U/L

          -  Albumin >= 2 g/dL

          -  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

          -  Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG)

          -  Absolute neutrophil count >= 1,000/uL (unsupported)

          -  Platelets >= 100,000/uL (unsupported)

          -  Hemoglobin >= 8 g/dL (may be supported)

          -  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)

          -  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

        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

          -  Recent surgery within a minimum of 2 weeks prior to starting study 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:Time from randomization to the first occurrence of clinical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause, assessed up to 10 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Radiographic tumor response rate
Time Frame:Up to 10 years
Safety Issue:
Description:Will summarize the radiologic response rates per arm and test for a difference between the 2 arms using an exact binomial test.
Measure:Overall survival (OS)
Time Frame:Time from randomization until death from any cause or until the time of last follow-up for patients who are alive at time of analysis
Safety Issue:
Description:Will also use the KM methods, log-rank tests, and Cox proportional hazards models to determine whether there is a difference in OS between the 2 arms.
Measure:Proportion of patients who experience an improvement in visual acuity (VA)
Time Frame:After first 12 months of treatment
Safety Issue:
Description:The vision-based analyses will be conducted both on a per-subject and per-eye basis. For the per subject analyses, will use an exact binomial test to compare the difference in the proportion of subjects in each arm that show improvement in VA after 12 months of treatment using a 1-sided test with 10% type 1 error. For the secondary per eye analyses, will use repeated measures approaches to account for within patient correlations. Will consider changes between baseline and 12-month time points for this analysis.
Measure:Motor function assessment
Time Frame:At baseline and after 48 weeks of therapy
Safety Issue:
Description:The Vineland scale will be used to assess motor and coordination deficits. Will compare the magnitudes of change from baseline between the 2 treatment arms and provide a 90% 2-sided confidence interval for this difference.
Measure:Change in parent and patient-reported quality of life (QOL) over time
Time Frame:Baseline and at 9 months after treatment initiation
Safety Issue:
Description:QOL will be measured via the validated PedsQL Generic Module (for children 2-21 years old). Primary analysis will be based on a 2-sample t-test comparing change in the QOL score between 9 months and baseline for the 2 arms, as planned. If the change scores are skewed or do not otherwise meet the t-test assumptions, non-parametric alternatives may be employed for analysis.

Details

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

Last Updated

January 20, 2020