Clinical Trials /

A Study to Compare Treatment With the Drug Selumetinib Alone Versus Selumetinib and Vinblastine in Patients With Recurrent or Progressive Low-Grade Glioma

NCT04576117

Description:

This phase III trial investigates the best dose of vinblastine in combination with selumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinib alone in treating children and young adults with low-grade glioma (a common type of brain cancer) that has come back after prior treatment (recurrent) or does not respond to therapy (progressive). Selumetinib is a drug that works by blocking a protein that lets tumor cells grow without stopping. Vinblastine blocks cell growth by stopping cell division and may kill cancer. Giving selumetinib in combination with vinblastine may work better than selumetinib alone in treating recurrent or progressive low-grade glioma.

Related Conditions:
  • Low Grade Astrocytic Tumor
  • WHO Grade II Glioma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study to Compare Treatment With the Drug Selumetinib Alone Versus Selumetinib and Vinblastine in Patients With Recurrent or Progressive Low-Grade Glioma
  • Official Title: A Phase 3 Study of Selumetinib (NSC# 748727) or Selumetinib in Combination With Vinblastine for Non-NF1, Non-TSC Patients With Recurrent or Progressive Low-Grade Gliomas (LGGs) Lacking BRAFV600E or IDH1 Mutations

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-07549
  • SECONDARY ID: NCI-2020-07549
  • SECONDARY ID: ACNS1931
  • SECONDARY ID: ACNS1931
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT04576117

Conditions

  • Recurrent Low Grade Astrocytoma
  • Recurrent WHO Grade II Glioma

Interventions

DrugSynonymsArms
Selumetinib SulfateAZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Koselugo, Selumetinib SulphateEfficacy Phase Arm II (selumetinib)
Vinblastine Sulfate29060 LE, 29060-LE, Exal, Velban, Velbe, Velsar, VINCALEUKOBLASTINEFeasibility & Efficacy Phase Arm I (selumetinib, vinblastine)

Purpose

This phase III trial investigates the best dose of vinblastine in combination with selumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinib alone in treating children and young adults with low-grade glioma (a common type of brain cancer) that has come back after prior treatment (recurrent) or does not respond to therapy (progressive). Selumetinib is a drug that works by blocking a protein that lets tumor cells grow without stopping. Vinblastine blocks cell growth by stopping cell division and may kill cancer. Giving selumetinib in combination with vinblastine may work better than selumetinib alone in treating recurrent or progressive low-grade glioma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of selumetinib
      sulfate (selumetinib) + vinblastine sulfate (vinblastine) for children with progressive or
      recurrent low-grade gliomas (LGGs).

      II. To determine if selumetinib + vinblastine will lead to improved event-free survival (EFS)
      outcome compared with selumetinib alone for children with progressive or recurrent LGGs.

      SECONDARY OBJECTIVES:

      I. To estimate the objective response rates and overall survival associated with treatment
      with selumetinib + vinblastine versus single-agent selumetinib.

      II. To estimate the difference in EFS and response rate between patients with BRAF rearranged
      LGG and patients with non-BRAF rearranged LGG after treatment with selumetinib + vinblastine
      versus single-agent selumetinib.

      III. To evaluate toxicities associated with selumetinib + vinblastine and single-agent
      selumetinib for children with progressive or recurrent LGGs.

      IV. To compare the quality of life among patients treated with selumetinib + vinblastine and
      single-agent selumetinib.

      V. To examine the vision outcomes among patients with optic pathway gliomas (OPGs) treated
      with selumetinib + vinblastine and single-agent selumetinib.

      EXPLORATORY OBJECTIVE:

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

      OUTLINE: This is a dose-escalation feasibility study of vinblastine sulfate, followed by a
      randomized efficacy study. Patients in the feasibility study are assigned to Arm I, while
      patients in the efficacy study are randomized to Arm I or Arm II.

      ARM I: Patients receive vinblastine sulfate intravenously (IV) over 1 minute or IV infusion
      on days 1, 8, 15, and 22 and selumetinib sulfate orally (PO) twice daily (BID) on days 1-28.
      Treatment repeats every 28 days. Patients receive selumetinib and vinblastine for a total
      duration of 17 cycles followed by 10 additional cycles of selumetinib alone in the absence of
      disease progression or unacceptable toxicity.

      ARM II: Patients 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.

      After completion of study treatment, patients are followed up every 3 months for year 1,
      every 6 months for years 2-3, and annually for years 4-5.
    

Trial Arms

NameTypeDescriptionInterventions
Efficacy Phase Arm II (selumetinib)Active ComparatorPatients 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
Feasibility & Efficacy Phase Arm I (selumetinib, vinblastine)ExperimentalPatients receive vinblastine sulfate IV over 1 minute or IV infusion on days 1, 8, 15, and 22 and selumetinib sulfate PO BID on days 1-28. Treatment repeats every 28 days. Patients receive selumetinib and vinblastine for a total duration of 17 cycles followed by 10 additional cycles of selumetinib alone in the absence of disease progression or unacceptable toxicity.
  • Selumetinib Sulfate
  • Vinblastine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Feasibility phase: patients must be >= 2 years and =< 21 years of age at the time of
             enrollment

          -  Efficacy phase: patients must be >= 2 years and =< 25 years of age at the time of
             enrollment

               -  All patients > 21 years of age at the time of enrollment must have had initial
                  diagnosis of low-grade glioma by 21 years of age

          -  Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment

          -  Patients must have eligibility confirmed by rapid central pathology and central
             molecular screening reviews performed on APEC14B1

               -  Non-neurofibromatosis type 1 (non-NF1), non-tuberous sclerosis complex (non-TSC)
                  low-grade glioma (LGG) without a BRAFV600E or IDH1 mutation

               -  Patients must have progressive or recurrent LGG. Note: Biopsy may be at either
                  initial diagnosis or recurrence

               -  Patients must have measurable disease, defined as having a two-dimensional
                  measurable tumor volume of >= 1 cm^2

                    -  Tumor size will be measured to include both solid and cystic components of
                       the tumor (whether or not tumor is enhancing) + fluid attenuated inversion
                       recovery (FLAIR) signal

               -  Eligible histologies will include all tumors considered low-grade glioma or
                  low-grade astrocytoma (World Health Organization [WHO] Grade 1 and II) by the WHO
                  Classification of Tumors of the Central Nervous System - 4th Edition Revised,
                  with the exception of subependymal giant cell astrocytoma

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

          -  Patients must be progressive or recurrent after having been treated with at least one
             prior tumor-directed therapy before enrollment

          -  Patients must have fully recovered from the acute toxic effects of all prior
             chemotherapy, immunotherapy, or radiotherapy prior to entering this study

               -  Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry
                  onto this study (4 weeks if prior nitrosourea);

               -  Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
                  with a biologic agent;

               -  Radiation therapy (RT): >= 2 weeks (wks) for local palliative RT (small port); >=
                  6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of
                  pelvis; >= 6 wks must have elapsed if other substantial bone marrow (BM)
                  radiation;

               -  Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
                  and toxicity related to prior antibody therapy must be recovered to =< grade 1;

               -  MEK inhibitor or vinblastine: Must not have received treatment with a MEK
                  inhibitor or vinblastine within 6 months of study enrollment

          -  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:

               -  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

               -  Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
                  value of 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 interval (QTc interval) =< 450 msec by electrocardiogram (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

          -  Stable neurological examination for >= 1 week

          -  HYPERTENSION:

               -  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

          -  All patients must have ophthalmology toxicity assessments performed within 4 weeks
             prior to enrollment

          -  For all patients, an 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

               -  Note: If surgical resection or biopsy is performed at the time of progression or
                  recurrence, a post-operative MRI is required

          -  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:

          -  Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following
             exceptions:

               -  Patients must not have had progressive disease while on therapy with vinblastine
                  or a MEK inhibitor;

               -  Patients must not have discontinued vinblastine or selumetinib due to toxicity

          -  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 must not have known hypersensitivity to selumetinib, vinblastine, or similar
             compounds

          -  CYP3A4 agents: Patients must not have received fluconazole or drugs that are strong
             inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment

          -  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

          -  PRE-EXISTING CONDITIONS (CARDIAC):

               -  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

          -  PRE-EXISTING CONDITIONS (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 upper limit of normal (ULN) adjusted by age are
                       not eligible

          -  Any multivitamin containing vitamin E must be stopped prior to study enrollment even
             if it contains less than 100% of the daily recommended dosing for vitamin E

          -  Surgery within 2 weeks prior to enrollment, with the exception of a surgical biopsy,
             placement of a vascular access device or cerebrospinal 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

          -  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

          -  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

          -  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
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose/recommended phase II dose (MTD/RP2D) of selumetinib and vinblastine combination (feasibility)
Time Frame:Up to 17 cycles (cycle = 28 days)
Safety Issue:
Description:The MTD is empirically defined as the highest dose level at which 6 patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic.

Secondary Outcome Measures

Measure:Radiographic tumor response rate (efficacy)
Time Frame:Up to 5 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) (efficacy)
Time Frame:Time from randomization until death from any cause or until the time of last follow-up for patients who are alive at the time of analysis, assessed up to 5 years
Safety Issue:
Description:Will 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:Incidence of adverse events (feasibility)
Time Frame:Up to 5 years
Safety Issue:
Description:Toxicities will be summarized by dose level and by attribution to vinblastine versus selumetinib.
Measure:Incidence of adverse events (efficacy)
Time Frame:Up to 5 years
Safety Issue:
Description:Reported toxicities will be summarized per arm and any dose reductions will also be tabulated.
Measure:Quality of life (QOL)
Time Frame:Baseline to cycle 7 day 1
Safety Issue:
Description:Evaluate and compare change in parent and patient-reported QOL over time and between the 2 treatment arms. QOL will be measured via the validated Pediatric Quality of Life (PedsQL) Generic Module and Brain Tumor Module (for children 2 to 25 years old).

Details

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

Last Updated

January 28, 2021