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.
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, and then every 3 months for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
58
Undergo biopsy
Undergo collection of blood samples
Undergo CT scan
Undergo MRI
Given orally (PO)
Given PO
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
RECRUITINGUC San Diego Moores Cancer Center
La Jolla, California, United States
ACTIVE_NOT_RECRUITINGUC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
RECRUITINGYale University
New Haven, Connecticut, United States
Dose limiting toxicity and the maximum tolerated dose
Defined as adverse events meeting the criteria that are at least "possibly related" to TMZ or M1774. Dose limiting toxicity for temozolomide in combination with M1774 and the maximum tolerated dose or maximum safe dose. Will consider ten dose levels (dose level -2, -1, 1, 2, 3, 4, 5, 6, 7, 8). The Bayesian Optimal Interval (BOIN) design based on the cumulative number of patients who experience a dose-limiting toxicity (DLT) at the current dose level will be used to guide dose escalation.
Time frame: Up to 28 days
Objective response rate (ORR)
Will report the ORR and corresponding 2-sided 90% exact confidence intervals using the Clopper-Pearson method.
Time frame: Up to 2 years
Progression free survival (PFS)
Will be estimated using Kaplan-Meier method. Median survival times will be estimated. The confidence intervals for the median will be calculated. Log-rank test will be used to compare the PFS between the MGMT+ and MGMT- group.
Time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Overall survival (OS)
Will be estimated using Kaplan-Meier method. Median survival times will be estimated. The confidence intervals for the median will be calculated. Log rank test will be used to compare the OS between the MGMT+ and MGMT- group.
Time frame: Up to 2 years
Rate of >= grade 3 adverse events (AE)
The revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.
Time frame: Up to 2 years
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Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, United States
RECRUITINGMemorial Hospital East
Shiloh, Illinois, United States
RECRUITINGUniversity of Kansas Clinical Research Center
Fairway, Kansas, United States
RECRUITINGUniversity of Kansas Cancer Center
Kansas City, Kansas, United States
RECRUITINGUniversity of Kansas Cancer Center-Overland Park
Overland Park, Kansas, United States
RECRUITINGUniversity of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, United States
RECRUITING...and 13 more locations