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.
Eligibility criteria
This trial does not accept healthy volunteers
Qualifiers
Patients must have histologically or cytologically confirmed diagnosis of metastatic advanced cancer.
In dose escalation, any solid tumor patients with either O6-methylguanine DNA methyltransferase (MGMT) promoter hypermethylation positivity on testing / pre-screening of archival tissue OR an extracranial solid tumor where TMZ is considered a standard of care per National Comprehensive Cancer Network (NCCN) guidelines (neuroendocrine tumor, small cell lung cancer, melanoma or soft tissue sarcoma). The tumor lesion must be safely accessible to a mandatory biopsy. Patients with MGMT promoter hypermethylated colorectal cancer must be mismatch repair proficient / microsatellite stable.
In phase 2, only patients with mismatch repair proficient / microsatellite stable colorectal cancer that have MGMT promoter hypermethylation positivity on pre-screening of archival tissue will be eligible.
In dose escalation, patients must have progressed after treatment with all available therapies including immunotherapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment. Patients may not have previously received temozolomide or an ataxia telangiectasia and rad3-related (ATR) inhibitor.
Disqualifiers
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy, which may be =< grade 2.
History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to M1774 or temozolomide, including dacarbazine.
Patients with uncontrolled intercurrent illness.
Pregnant women are excluded from this study because M1774 is an ATR inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M1774 breastfeeding should be discontinued if the mother is treated with M1774. These potential risks also apply to temozolomide.
Trial design
Design model
Sequential
Treatments tested in this trial
Biopsy Procedure
Procedure/Surgery
Undergo biopsy
Biospecimen Collection
Procedure/Surgery
Undergo collection of blood samples
Computed Tomography
Procedure/Surgery
Undergo CT scan
Magnetic Resonance Imaging
Procedure/Surgery
Undergo MRI
Temozolomide
Drug
Given orally (PO)
Tuvusertib
Drug
Given PO
Treatment groups
42 Participants
are divided into 1 treatment group
Group A: Treatment (tuvusertib, temozolomide)Experimental treatment 6 interventions
Trial outcomes
Primary outcomes
1
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 outcomes
1
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 after completion of study treatment
2
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.
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
3
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.
Time frame
Up to 2 years after completion of study treatment
4
Rate of >= grade 3 adverse events (AE)
The revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for AE reporting.
Time frame
Up to 2 years after completion of study treatment
Other outcomes
Sponsors and contacts
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