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

  • STATUS
    Recruiting
  • End date
    Dec 30, 2026
  • participants needed
    18
  • sponsor
    National Cancer Institute (NCI)
Updated on 11 October 2022

Summary

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 cells. Giving selumetinib in combination with vinblastine may work better than selumetinib alone in treating recurrent or progressive low-grade glioma.

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 in combination with selumetinib, 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.

Details
Condition Recurrent Low Grade Astrocytoma, Recurrent WHO Grade 2 Glioma, Refractory Low Grade Astrocytoma, Refractory Low Grade Glioma, Refractory WHO Grade 1 Glioma
Treatment questionnaire administration, quality-of-life assessment, vinblastine sulfate, Selumetinib Sulfate
Clinical Study IdentifierNCT04576117
SponsorNational Cancer Institute (NCI)
Last Modified on11 October 2022

Eligibility

Yes No Not Sure

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
Patients with metastatic disease or multiple independent primary LGGs are eligible
WHO Classification of Tumors of the Central Nervous System - 4th Edition
Revised, with the exception of subependymal giant cell astrocytoma
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
Patients must be progressive or recurrent after having been treated with at least one
prior tumor-directed therapy before enrollment
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
to < 6 years: 0.8 mg/dL (male) 0.8 mg/dL (female)
to < 10 years: 1 mg/dL (male) 1 mg/dL (female)
to < 13 years: 1.2 mg/dL (male) 1.2 mg/dL (female)
to < 16 years: 1.5 mg/dL (male) 1.4 mg/dL (female)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
>= 16 years: 1.7 mg/dL (male) 1.4 mg/dL (female)
mL/min/1.73 m^ 2 or a serum creatinine based on age/gender as follows
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)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (children with a
Absolute neutrophil count >= 1,000/uL (unsupported)
diagnosis of Gilbert's syndrome will be allowed on study regardless of their
Platelets >= 100,000/uL (unsupported)
total and indirect [unconjugated] bilirubin levels as long as their direct
Hemoglobin >= 8 g/dL (may be supported)
[conjugated] bilirubin is < 3.1 mg/dL)
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
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 the ability to swallow whole capsules
All patients must have ophthalmology toxicity assessments 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

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 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
Patients with a concurrent malignancy or history of treatment (other than surgery) for
Severe valvular heart disease
another tumor within the last year are ineligible
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
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 institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
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
All patients and/or their parents or legal guardians must sign a written informed
consent
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer  to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note