Phase I Study of MK-1775 With Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients With Recurrent Glioblastoma.
I. To determine the maximum tolerated doses (MTD) of MK-1775 (WEE1 inhibitor MK-1775) in
combination with the current standard of care (radiotherapy/temozolomide for concomitant
therapy and temozolomide for adjuvant therapy) for treating patients with newly diagnosed
II. To define the MTD of MK-1775 in combination with 6 weeks of daily (Monday-Friday [M-F])
radiotherapy (RT) and concomitant temozolomide (TMZ) administered at 75 mg/m^2/day in
patients with newly diagnosed glioblastoma. (Arm 1) III. To define the MTD of MK-1775 in
combination with adjuvant TMZ administered at 150 mg/m^2/day-200 mg/m^2/day for 5 days every
28 days in patients with glioblastoma after concurrent RT/TMZ. (Arm 2)
I. To characterize the safety profile of MK-1775 in combination with RT and concomitant TMZ
(Arm 1) and MK-1775 with adjuvant TMZ (Arm 2) in patients with newly diagnosed glioblastoma.
II. To assess the pharmacokinetic (PK) profile of MK-1775 in combination with upfront
radiation/TMZ and adjuvant TMZ in patients with newly diagnosed glioblastoma.
I. To determine the intratumoral concentration of MK-1775 achieved in patients treated with
the putative MTD.
II. To characterize the time course of MK-1775 in extracellular fluid within brain tumors
following a single oral dose of drug by microdialysis.
III. To characterize O6-methylguanine deoxyribonucleic acid (DNA)-methyltransferase (MGMT)
methylation and tumor protein p53 (P53) pathway status, also P-glycoprotein (P-gp) and wee1
expression levels in patients with newly diagnosed glioblastoma treated with standard
therapy in combination with MK-1775.
OUTLINE: This is a dose-escalation study of WEE1 inhibitor MK-1775. Patients are assigned to
1 of 2 treatment arms.
INITIATION COURSE: Patients receive WEE1 inhibitor MK-1775 orally (PO) on days 1, 3, and 5
or 1-5 weekly and temozolomide PO once daily (QD) for 6 weeks. Patients also undergo
concurrent radiation therapy 5 days per week for 6 weeks.
MAINTENANCE COURSES: Beginning in week 10, patients receive temozolomide PO QD on days 1-5.
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
ARM II: Patients receive WEE1 inhibitor MK-1775 PO QD on days 1, 3, and 5 or 1-5, and
temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 2 months for 2 years and
then every 6 months thereafter.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD of WEE1 inhibitor MK-1775 with 6 weeks of RT and temozolomide, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (Arm I)
Severity and frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experience grade 3 or above toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.
Up to 6 weeks
National Cancer Institute (NCI)
United States: Food and Drug Administration
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