Title
A Phase 3 Study of Selumetinib (NSC# 748727, IND# 77782) 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

Description
A Phase 3 Study of Selumetinib 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

Objective

The overall goals of this study are to:

Find the highest dose of the combination treatment of selumetinib and vinblastine that we can give safely

Compare the effects, good and/or bad, of selumetinib alone versus selumetinib with vinblastine in subjects with progressive or recurrent LGG to find out which is better

Treatment
In Part B of this study you will get 1 of 2 treatment plans. The 2 treatment plans are called Arm 1 and Arm 2, as follows:

Arm 1: Selumetinb and Vinblastine: You will get the combination treatment of selumetinib and vinblastine for the first 17 cycles, then, you will get selumetinib alone for an additional 10 cycles. Each cycle lasts 28 days (4 weeks)

Arm 2: Selumetinb: You will get 27 cycles of selumetinib. Each cycle lasts 28 days (4 weeks)

Key Eligibility
Feasibility Phase: Patients must be greater than or equal to 2 years and less than or equal to 21 years of age

Efficacy Phase: Patients must be greater than or equal to 2 years and less than or equal to 25 years of age

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

Body surface area of greater than or equal to 0.5 m2

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

Progressive or recurrent LGG. Note: Biopsy may be at either initial diagnosis or recurrence

Must have measurable disease, defined as having a two dimensional measurable tumor volume of greater than or equal to 1 cm2

Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (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

Metastatic disease or multiple independent primary LGGs are eligible

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

Must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study as defined by the protocol

Adequate renal, liver, cardiac, bone marrow, and central nervous system function as defined by the protocol

Hypertension and Ophthalmology as defined by the protocol

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

ECOG 0-2, Karnofsky for patients greater than 16 and Lansky for patients less than or equal to 16 as defined by the protocol

Must be able to swallow whole capsules

EXCLUSION

Prior therapy with vinblastine and/or a MEK inhibitor is permitted, with the following exceptions: Must not have had progressive disease while on therapy with vinblastine or a MEK inhibitor and must not have discontinued vinblastine or selumetinib due to toxicity

Concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible

Diffuse intrinsic pontine tumors as seen on MRI (greater than 2/3 of pons involvement on imaging) are not eligible even if biopsy reveals Grade I/II histology

Pre-existing conditions as defined by the protocol

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 CSF diverting procedure such as endoscopic third ventriculostomy (ETV) and ventriculoperitoneal (VP) shunt. Note: Patients must have healed from any prior surgery

Uncontrolled infection are not eligible

Can not be pregnant or breastfeeding

Male and Female of childbearing potential must agree to adequate birth control as defined by the protocol

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 as defined by the protocol

Applicable Disease Sites
Brain/Central Nervous System

Participating Institutions
Gundersen Health System; UW Health University Hospital