Clinical Trials /

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

NCT03871257

Description:

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 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.

Related Conditions:
  • Low Grade Glioma
  • Neurofibromatosis Type 1
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

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

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (carboplatin, vincristine)
SelumetinibARRY-142886, AZD6244, MEK Inhibitor AZD6244Arm II (selumetinib sulfate)
Selumetinib SulfateAZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Selumetinib SulphateArm II (selumetinib sulfate)
VincristineLeurocristine, VCR, VincrystineArm I (carboplatin, vincristine)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm I (carboplatin, vincristine)

Purpose

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.

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 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.

      ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28.
      Treatment 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 every 3 months for 1 year,
      every 6 months for 2 years, and then once yearly for up to 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (carboplatin, vincristine)Active ComparatorINDUCTION: 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.
  • Carboplatin
  • Vincristine
  • Vincristine Sulfate
Arm II (selumetinib sulfate)ExperimentalPatients 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.
  • 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 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

               -  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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
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 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 10 years
Safety Issue:
Description: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.
Measure:Change in motor function
Time Frame:Baseline up to 12 cycles
Safety Issue:
Description:Will compare the magnitudes of change from baseline between the two treatment arms and provide a 90% 2-sided confidence interval for this difference.
Measure:Change in quality of life (QOL)
Time Frame:Baseline up to 12 months
Safety Issue:
Description: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.
Measure:Change in neurocognitive function
Time Frame:From pre-treatment (Baseline) up to 24 months
Safety Issue:
Description: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.

Details

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

Last Updated

November 22, 2019