Advanced Malignant Solid NeoplasmPhase 1/2NCT05691491
Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness
A Phase 1/2 study testing Biopsy Procedure, Biospecimen Collection and Computed Tomography in people with Advanced Malignant Solid Neoplasm and Advanced Microsatellite Stable Colorectal Carcinoma, run by National Cancer Institute (NCI) at 23 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Malignant Solid Neoplasm, Advanced Microsatellite Stable Colorectal Carcinoma, Hematopoietic and Lymphatic System Neoplasm
- What is being tested?
- Biopsy Procedure, Biospecimen Collection and Computed Tomography
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 42 participants
- Where
- 23 sitesUnited States
- Study dates
- 28 Sep 2023to 1 Mar 2027
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
23 sites in 1 country. Contact the study team or a site near you to ask about taking part.
23 sites in 1 country
United States23 sites, 15 recruiting
- Recruiting
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892
Site Public Contact, 800-411-1222
A P. Chen
- Active, not recruiting
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
- Active, not recruiting
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
- Recruiting
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Raed Al-Rajabi
- Recruiting
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612
Site Public Contact, 877-827-8839, ucstudy@uci.edu
Farshid Dayyani
- Recruiting
University of Kansas Cancer Center
Kansas City, Kansas, 66160
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Raed Al-Rajabi
- Recruiting
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Raed Al-Rajabi
- Active, not recruiting
UC San Diego Moores Cancer Center
La Jolla, California, 92093
- Recruiting
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Raed Al-Rajabi
- Recruiting
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
Site Public Contact, 800-811-8480
Elizabeth J. Davis
- Recruiting
Yale University
New Haven, Connecticut, 06520
Site Public Contact, 203-785-5702, canceranswers@yale.edu
Michael Cecchini
- Suspended
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City, Missouri, 64116
- Recruiting
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Site Public Contact, 405-271-8777, ou-clinical-trials@ouhsc.edu
Abdul Rafeh Naqash
- Recruiting
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
Site Public Contact, 877-827-8839, ucstudy@uci.edu
Farshid Dayyani
- Recruiting
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Raed Al-Rajabi
- Recruiting
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Raed Al-Rajabi
- Recruiting
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
Site Public Contact, 412-647-8073
Janie Y. Zhang
- Active, not recruiting
Memorial Hospital East
Shiloh, Illinois, 62269
- Active, not recruiting
Washington University School of Medicine
St Louis, Missouri, 63110
- Active, not recruiting
Siteman Cancer Center-South County
St Louis, Missouri, 63129
- Active, not recruiting
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
- Recruiting
Smilow Cancer Hospital Care Center-Trumbull
Trumbull, Connecticut, 06611
Site Public Contact, 203-785-5702, canceranswers@yale.edu
Michael Cecchini
- Recruiting
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
Site Public Contact, 913-588-3671, KUCC_Navigation@kumc.edu
Raed Al-Rajabi
About this study
Official title: A Phase 1/2 Trial Evaluating the Combination of Temozolomide and the Ataxia Telangiectasia and Rad3-Related Inhibitor M1774
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.
Read the detailed description
PRIMARY OBJECTIVE:
- To determine the maximum tolerated dose of the combination of temozolomide (TMZ) and tuvusertib (M1774).
SECONDARY OBJECTIVES:
- 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:
- 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.
- Conditions
- Advanced Malignant Solid Neoplasm, Advanced Microsatellite Stable Colorectal Carcinoma, Hematopoietic and Lymphatic System Neoplasm, Metastatic Malignant Solid Neoplasm, Metastatic Microsatellite Stable Colorectal Carcinoma, Stage III Colorectal Cancer AJCC v8
- Being tested
- Biopsy Procedure, Biospecimen Collection, Computed Tomography, Magnetic Resonance Imaging, Temozolomide
- Medical subject headings
- Neoplasm Metastasis, Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo collection of blood samples
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT scan
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
TemozolomideDrug
Also called CCRG-81045, Gliotem, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831
Given orally (PO)
TuvusertibDrug
Also called ATR Kinase Inhibitor M1774, M 1774, M-1774, M1774
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Treatment (tuvusertib, temozolomide) | Experimental | 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. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Temozolomide; Drug: Tuvusertib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 28 days
Secondary outcomes (4)
Objective response rate (ORR)
Will report the ORR and corresponding 2-sided 90% exact confidence intervals using the Clopper-Pearson method.
Measured: Up to 2 years after completion of study treatment
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.
Measured: 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)
Will be estimated using Kaplan-Meier method. Median survival times will be estimated. The confidence intervals for the median will be calculated.
Measured: Up to 2 years after completion of study treatment
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.
Measured: Up to 2 years after completion of study treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2023
- Study start28 Sep 2023
- Primary completion1 Mar 2027 (estimated)
- Study completion1 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Malignant Solid NeoplasmStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 42 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Michael Cecchini, Principal investigator, Yale University Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05691491
- Sponsor's protocol ID
- NCI-2022-10211
- Other IDs
- NCI-2022-10211, 2000034441, 10572, 10572, UM1CA186689
- Status last verified
- Jun 2026
- First submitted
- 18 Jan 2023
- Last updated
- 31 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.