A Phase 1/2 Trial Evaluating the Combination of Temozolomide and the Ataxia Telangiectasia and Rad3-Related Inhibitor M1774
Summary
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.
Detailed description
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.
Arms & interventions
- ProcedureBiopsy Procedure
Undergo biopsy
- ProcedureBiospecimen Collection
Undergo collection of blood samples
- ProcedureComputed Tomography
Undergo CT scan
- ProcedureMagnetic Resonance Imaging
Undergo MRI
- DrugTemozolomide
Given orally (PO)
- DrugTuvusertib
Given PO
Outcome measures
Primary
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
Secondary
Objective response rate (ORR)
Time frame: Up to 2 years after completion of study treatment
Progression free survival (PFS)
Time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years after completion of study treatment
Overall survival (OS)
Time frame: Up to 2 years after completion of study treatment
Rate of >= grade 3 adverse events (AE)
Time frame: Up to 2 years after completion of study treatment
Eligibility criteria
Study locations (23)
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612
UC San Diego Moores Cancer Center
La Jolla, California, 92093
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
Yale University
New Haven, Connecticut, 06520
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, 06611
Memorial Hospital East
Shiloh, Illinois, 62269
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
University of Kansas Cancer Center
Kansas City, Kansas, 66160
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City, Missouri, 64116
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232