This phase I trial investigates the side effects and best dose of nedisertib, and to see how
well it works in combination with radiation therapy in treating patients with newly diagnosed
MGMT unmethylated glioblastoma or gliosarcoma. Radiation therapy uses high energy x-rays to
kill tumor cells and shrink tumors. Nedisertib may further stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as
temozolomide, 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. Giving nedisertib
with radiation therapy may work better than radiation therapy alone in treating patients with
glioblastoma or gliosarcoma.
I. To determine the maximum tolerated dose (MTD) of nedisertib (M3814) in combination with
standard of care radiation dose (60 Gy, 2 Gy/fraction over 6 weeks) in patients with newly
diagnosed MGMT unmethylated glioblastoma (GBM). (Stage I) II. To determine the ability of
M3814 to cross the blood brain barrier and to evaluate their pharmacodynamic properties in
resected tissue. (Stage II)
SECONDARY AND EXPLORATORY OBJECTIVES:
I. To evaluate the dose limiting toxicities (DLT). (Stage I) (Secondary Objective) II. To
determine the overall response rate (ORR), median progression free survival (mPFS) and median
overall survival (mOS) of M3814 in combination with radiation. (Stage I) (Secondary
Objective) II. To determine the overall response rate (ORR), median progression free survival
(mPFS) and median overall survival (mOS) of M3814 in combination with radiation. (Stage II)
I. To evaluate pharmacodynamic properties of M3814. II. To assess the alterations in tumor
immune microenvironment as a result of deoxyribonucleic acid (DNA)-dependent protein kinase
OUTLINE: This is a dose-escalation study of nedisertib. Patients are assigned to 1 of 2
STAGE I (CONCURRENT): Patients undergo standard of care radiation therapy daily
(Monday-Friday) for 30 fractions. Patients also receive nedisertib orally (PO) on each day of
radiation therapy and given 1-2 hours before each treatment fraction. Treatment continues for
6 weeks in the absence of disease progression or unacceptable toxicity.
STAGE I (ADJUVANT): Patients receive temozolomide PO once daily (QD) on days 1-5. Treatment
repeats every 28 days for up to 6 cycles in the absence of disease progression or
STAGE II (CONCURRENT): Patients receive nedisertib and undergo standard of care radiation
therapy as in Stage I. Within 1-14 days after the completion of radiation therapy, patients
undergo surgical resection.
STAGE II (ADJUVANT): Patients receive temozolomide as in Stage I.
After completion of study treatment, patients are followed up every 3 months.
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.
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