Recruiting

Phase 1

Phase 2

Temozolomide & M1774Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness

Sponsor:

National Cancer Institute (NCI)

Code:

NCT05691491

Conditions

Advanced Malignant Solid Neoplasm

Advanced Microsatellite Stable Colorectal Carcinoma

Hematopoietic and Lymphatic System Neoplasm

Metastatic Malignant Solid Neoplasm

Metastatic Microsatellite Stable Colorectal Carcinoma

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Biopsy Procedure

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Temozolomide

Study Details

Brief 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.

Conditions

Advanced Malignant Solid Neoplasm

Advanced Microsatellite Stable Colorectal Carcinoma

Hematopoietic and Lymphatic System Neoplasm

Metastatic Malignant Solid Neoplasm

Metastatic Microsatellite Stable Colorectal Carcinoma

Study ID

NCT05691491

Start date

Sep 28, 2023

Status verified date

Jun, 2026

Completion date

Mar 1, 2027

Anticipated

Primary completion date

Mar 1, 2027

Anticipated

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

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.
For patients with mismatch repair proficient / microsatellite stable colorectal cancer in the phase 2 portion, patients must have received prior therapy with 1 or more systemic therapies in the metastatic setting that includes 5-fluorouracil, irinotecan, and oxaliplatin. Patients with microsatellite stable colorectal cancer (mCRC) need to have had exposure, unless contraindicated, to all 3 of oxaliplatin, irinotecan, and fluoropyrimidine (FP).

The use of 5-fluorouracil and oxaliplatin in the adjuvant setting is acceptable, provided the development of metastatic disease was less than 6 months after the completion of adjuvant therapy.

Patients with a prior hypersensitivity reaction to oxaliplatin in the adjuvant setting do not require retreatment in the metastatic setting.

Age >=18 years. Because no dosing or adverse event data are currently available on the use of M1774 in combination with temozolomide in patients < 18 years of age, children are excluded from this study.
Measurable disease on CT and/or MRI per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%).
Hemoglobin >=10 g/dL (No blood transfusions are allowed within 14 days of cycle 1 day 1 \[C1D1\]).
White blood cells (WBC) > 3 x 10\^9/L.
Absolute neutrophil count >= 1,500/mcL.
Platelets >= 100,000/mcL.
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine-aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) =< 3 x institutional ULN except for when liver metastases are present, in which case they must be =< 5 x institutional ULN.
Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m\^2.
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for 4 weeks.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
The effects of M1774 on the developing human fetus are unknown. For this reason and because ATR inhibitors agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of M1774 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of M1774 administration.
Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

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.
Patients with a prior history of ataxia telangiectasia.
Patients who are not able to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication.
Patients who cannot discontinue proton-pump inhibitors (PPIs) while taking M1774. H-2 receptor antagonists are allowed but should not be taken within 12 hours before or 2 hours after M1774. Antacids are also allowed, but should not be taken 2 hours before 2 hours after M1774.
Extensive RT involving greater than 30% of the bone marrow is not permitted during the study.
A Fridericia's correction formula (QTcF) > 480 ms is exclusionary given the potential for QT.

Study Design

Enrollment

42 participants

Anticipated

Intervention Model

Sequential

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (tuvusertib, temozolomide)

Patients receive tuvusertib PO 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 CT scan and 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 at time of progression.

Interventions

Biopsy Procedure

Undergo biopsy

Biospecimen Collection

Undergo collection of blood samples

Computed Tomography

Undergo CT scan

Magnetic Resonance Imaging

Undergo MRI

Temozolomide

Given orally (PO)

Tuvusertib

Given PO

Primary outcome measure

Dose limiting toxicity and the maximum tolerated dose [ Time Frame: Up to 28 days ]

Central Contacts and Locations

Locations

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Recruiting

Irvine, California, United States, 92612

Contacts

Site Public Contact

877-827-8839 ucstudy@uci.edu

Principal Investigator:

Farshid Dayyani

UC Irvine Health/Chao Family Comprehensive Cancer Center

Recruiting

Orange, California, United States, 92868

Contacts

Site Public Contact

877-827-8839 ucstudy@uci.edu

Principal Investigator:

Farshid Dayyani

Yale University

Recruiting

New Haven, Connecticut, United States, 06520

Contacts

Site Public Contact

203-785-5702 canceranswers@yale.edu

Principal Investigator:

Michael Cecchini

Smilow Cancer Hospital Care Center-Trumbull

Recruiting

Trumbull, Connecticut, United States, 06611

Contacts

Site Public Contact

203-785-5702 canceranswers@yale.edu

Principal Investigator:

Michael Cecchini

University of Kansas Clinical Research Center

Recruiting

Fairway, Kansas, United States, 66205

Contacts

Site Public Contact

913-588-3671 KUCC_Navigation@kumc.edu

Principal Investigator:

Raed Al-Rajabi

University of Kansas Cancer Center

Recruiting

Kansas City, Kansas, United States, 66160

Contacts

Site Public Contact

913-588-3671 KUCC_Navigation@kumc.edu

Principal Investigator:

Raed Al-Rajabi

University of Kansas Cancer Center-Overland Park

Recruiting

Overland Park, Kansas, United States, 66210

Contacts

Site Public Contact

913-588-3671 KUCC_Navigation@kumc.edu

Principal Investigator:

Raed Al-Rajabi

University of Kansas Hospital-Indian Creek Campus

Recruiting

Overland Park, Kansas, United States, 66211

Contacts

Site Public Contact

913-588-3671 KUCC_Navigation@kumc.edu

Principal Investigator:

Raed Al-Rajabi

University of Kansas Hospital-Westwood Cancer Center

Recruiting

Westwood, Kansas, United States, 66205

Contacts

Site Public Contact

913-588-3671 KUCC_Navigation@kumc.edu

Principal Investigator:

Raed Al-Rajabi

National Cancer Institute Developmental Therapeutics Clinic

Recruiting

Bethesda, Maryland, United States, 20892

Contacts

Site Public Contact

800-411-1222

Principal Investigator:

A P. Chen

University of Kansas Cancer Center - North

Recruiting

Kansas City, Missouri, United States, 64154

Contacts

Site Public Contact

913-588-3671 KUCC_Navigation@kumc.edu

Principal Investigator:

Raed Al-Rajabi

University of Kansas Cancer Center - Lee's Summit

Recruiting

Lee's Summit, Missouri, United States, 64064

Contacts

Site Public Contact

913-588-3671 KUCC_Navigation@kumc.edu

Principal Investigator:

Raed Al-Rajabi

University of Oklahoma Health Sciences Center

Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contacts

Site Public Contact

405-271-8777 ou-clinical-trials@ouhsc.edu

Principal Investigator:

Abdul Rafeh Naqash

UPMC Hillman Cancer Center

Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contacts

Site Public Contact

412-647-8073

Principal Investigator:

Janie Y. Zhang

Vanderbilt University/Ingram Cancer Center

Recruiting

Nashville, Tennessee, United States, 37232

Contacts

Site Public Contact

800-811-8480

Principal Investigator:

Elizabeth J. Davis

More Information

Sponsor

National Cancer Institute (NCI)

Last update posted

Jul 31, 2026

Last verified

Jun, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by National Cancer Institute (NCI) on 2026-07-31.