PRIMARY OBJECTIVE:~I. To determine the maximum tolerated dose of the combination of temozolomide (TMZ) and tuvusertib (M1774).~SECONDARY OBJECTIVES:~I. To observe and record anti-tumor activity. II. To determine the overall response rate. III. To estimate progression free survival. IV. To estimate overall survival. V. To determine the recommended phase 2 dose of the combination of TMZ and M1774.~VI. To determine the response rate in O6-methylguanine DNA methyltransferase (MGMT) methylated tumors compared to non-methylated tumors.~EXPLORATORY OBJECTIVES:~I. Correlate MGMT promoter hypermethylation, MGMT expression and tumor-infiltrating lymphocytes (TILs) with efficacy endpoints of response rate, progression free survival, and overall survival.~II. Assess pre and post treatment tumor biopsies for changes in tumor mutational burden, tumor associated neo-antigens and microsatellite status by whole exome sequencing.~III. Measure changes in peripheral blood mononuclear cell populations with treatment.~IV. Assess liquid biopsies by circulating tumor (ct)DNA for changes in tumor mutational burden and microsatellite status by whole exome sequencing.~OUTLINE: This is a phase I, dose-escalation study of temozolomide and tuvusertib followed by a phase II study.~Patients receive tuvusertib orally (PO) and temozolomide PO on study. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), biopsy, and collection of blood samples on study.
This phase I/II trial studies the side effects and best dose of temozolomide and M1774 and how well they works in treating patients with cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and may have spread to nearby tissue, lymph nodes, or distant parts of the body (advanced). Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells and slow down or stop tumor growth. M1774 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Adding M1774 to temozolomide may shrink or stabilize cancer for longer than temozolomide alone.