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

S
Sandeep Batra, MD

Primary Investigator

Enrolling By Invitation
2 years - 25 years
All
Phase 3
300 participants needed
2 Locations

Brief description of study

What is the purpose of this study?
This phase III trial investigates the best dose of vinblastine in combination withumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinibg children and young adults with low-grade glioma (a common type of brain) 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. Giving selumetinib in combination with vinblastine may work better thanumetinib alone in treating recurrent or progressive low-grade glioma.
 
THIS STUDY IS ENROLLING BY INVITATION ONLY - Consistent with most oncology trials, patients are not actively “recruited,” but are screened by their physician for appropriate clinical trial(s) at the time of their routine clinic visit. Occasionally, a patient may be a self-referral or physician referral, but are still screened for appropriate clinical trials at the time of their routine clinic visit. PI and staff may send copies of relevant consent forms to these patients to look over prior to actually consenting or enrolling them. This may take place at the patient's visit at which the consent is presented or the patient's next visit to the outpatient hematology/oncology clinic. 
 
Interested in participating? For more information about this research study or other cancer-related clinical trials at IU Simon Comprehensive Cancer Center, please contact:
IU Clinical Trials Office 
Phone: (317) 278-5632

Detailed description of study

What will happen during the study?
  • This is a dose-escalation feasibility study of vinblastine sulfate in combination with selumetinib, followed by a randomized efficacy study. Patients in the feasibility studygned to Arm I, while patients in the efficacy study are randomized to Arm I or Arm.
  • ARM I: Patients receive vinblastine sulfate intravenously (IV) over 1 minute or IV infusiondays 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. Patients undergo magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood sample collection during screeningd on study.
  • 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. Patients undergo MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.
  • After completion of study treatment, patients are followed up every 3 months for year 1,very 6 months for years 2-3, and annually for years 4-5.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Riley, Recurrent Low Grade Astrocytoma, Recurrent WHO Grade 2 Glioma, Refractory Low Grade Astrocytoma, Refractory Low Grade Glioma, Refractory WHO Grade 1 Glioma
  • Age: 2 years - 25 years
  • Gender: All

Inclusion Criteria:
  • Feasibility phase: patients must be >= 2 years and =< 21 years of age at the time of
  • Efficacy phase: patients must be >= 2 years and =< 25 years of age at the time of
    • All patients > 21 years of age at the time of enrollment must have had initialdiagnosis 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 centralular screening reviews performed on APEC14B1
    • Non-neurofibromatosis type 1 (non-NF1), non-tuberous sclerosis complex (non-TSC)w-grade glioma (LGG) without a BRAFV600E or IDH1 mutation
    • Patients must have progressive or recurrent LGG. Note: Biopsy may be at eitherdiagnosis or recurrence
    • Patients must have measurable disease, defined as having a two-dimensionalurable tumor volume of >= 1 cm^2
      • Tumor size will be measured to include both solid and cystic components ofhe tumor (whether or not tumor is enhancing) + fluid attenuated inversionvery (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 WHOClassification 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 aregible

  • 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 priorhemotherapy, immunotherapy, or radiotherapy prior to entering this study
    • Myelosuppressive chemotherapy: Must not have received within 2 weeks of entryhis study (4 weeks if prior nitrosourea);
    • Biologic (anti-neoplastic agent): At least 7 days since the completion of therapywith 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 ofvis; >= 6 wks must have elapsed if other substantial bone marrow (BM)diation;
    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,d toxicity related to prior antibody therapy must be recovered to =< grade 1;
    • MEK inhibitor or vinblastine: Must not have received treatment with a MEKhibitor 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 (within 7 days):
    • 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 (within 7 days prior to

    enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on studygardless of their total and indirect [unconjugated] bilirubin levels as long asheir direct [conjugated] bilirubin is < 3.1 mg/dL)
  • Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L(within 7 days prior to enrollment)
    • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to thevalue of 45 U/L
  • Albumin >= 2 g/L (within 7 days prior to enrollment)
  • Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEFult is given as a range of values, then the upper value of the range will be used)by echocardiogram (within 4 weeks prior to enrollment)
  • Corrected QT interval (QTc interval) =< 450 msec by electrocardiogram (EKG) (within 4weeks prior to enrollment)
  • Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to)
  • 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 not haved a significant increase in seizure frequency within 2 weeks prior to
  • Stable neurological examination for >= 1 week
  • HYPERTENSION:
    • Patients 2-17 years of age must have a blood pressure that is =< 95th percentilege, height, and gender at the time of enrollment (with or without the use ofhypertensive medications);
    • Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time(with or without the use of anti-hypertensive medications)
    • Note for patients of all ages: Adequate blood pressure can be achieved usingdication 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)d/or spine (depending on the site[s] of primary disease) with and without contrastust be performed within 4 weeks prior to enrollment
    • Note: If surgical resection or biopsy is performed at the time of progression orurrence, 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 andLansky 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
    • Patients must not have had progressive disease while on therapy with vinblastineK 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 ponsvolvement 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 similarunds
  • CYP3A4 agents: Patients must not have received fluconazole or drugs that are strongducers or inhibitors of CYP3A4 within 7 days prior to study enrollment
  • Patients with any serious medical or psychiatric illness/condition, includingubstance use disorders or ophthalmological conditions, likely in the judgment of thevestigator to interfere or limit compliance with study requirements/treatment
  • Patients who, in the opinion of the investigator, are not able to comply with theudy procedures are not eligible
  • PRE-EXISTING CONDITIONS (CARDIAC):
    • Known genetic disorder that increases risk for coronary artery disease. Note: Thedyslipidemia in a family with a history of myocardial infarction isusion unless there is a known genetic disorder documented;
      • Symptomatic heart failure
      • New York Heart Association (NYHA) class II-IV prior or currentdiomyopathy
      • 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 intraocularure (IOP) > 22 mmHg or upper limit of normal (ULN) adjusted by age aregible

  • 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,vascular access device or cerebrospinal fluid (CSF) diverting procedureuch 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 andgenic effects have been noted for several of the study drugs. A pregnancy testquired 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 anve contraceptive method for the duration of their study participation and for12 weeks after stopping study therapy are not eligible
    • Note: Women of child-bearing potential and males with sexual partners who aregnant or who could become pregnant (i.e., women of child-bearing potential)hould use effective methods of contraception for the duration of the study and12 weeks after stopping study therapy to avoid pregnancy and/or potentialdverse 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

Updated on 11 Dec 2024. Study ID: NCI-2020-07549, PHO-COG-ACNS1931, 11075
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