Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness

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. 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) once daily (QD) on days 1-7 and temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan and magnetic resonance imaging (MRI) as well as collection of blood samples throughout the trial. Patients also undergo a biopsy at baseline and may undergo one on study and/or time of progression. After completion of study treatment, patients are followed up at 4 weeks (if clinically indicated), and then every 3 months for up to 2 years.