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Advanced Malignant Solid NeoplasmPhase 1NCT05687136

Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and Tuvusertib (M1774) for Advanced Solid Tumors

A Phase 1 study testing Biopsy Procedure, Biospecimen Collection and Computed Tomography in people with Advanced Malignant Solid Neoplasm and Metastatic Malignant Solid Neoplasm, run by National Cancer Institute (NCI) at 7 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in combination with tuvusertib (M1774) in treating patients with solid tumors that have spread to other places in the body (advanced). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biopsy Procedure, Biospecimen Collection and Computed Tomography
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
66 participants
Where
7 sitesUnited States
Study dates
7 Jun 2024to 31 Aug 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

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 confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective, or if the treating investigator deems the study appropriate.
  • For the dose escalation and dose expansion phases, patients must have genomic (tumor next-generation sequencing [NGS], circulating tumor deoxyribonucleic acid [ctDNA], fluorescence in situ hybridization [FISH], etc.) or immunohistochemical evidence (e.g., loss of expression) of inactivating ATM mutations, MYC amplification, mutation of FBXW7, CCNE1 amplification, SWI/SNF member mutation (ARID1A, PBRM1, SMARCA4, ARID2, ARID1b, SMARCB1, SMARCA2, SS18) and mutation or loss of expression of ATRX/DAXX. Mutations may be germline or somatic. All mutations/alterations must be approved by the overall principal investigator (PI). Other SWI/SNF mutations may be considered after discussion with the overall PI.
  • Progression on at least one prior standard therapy (if no standard therapy exists, the patient may be allowed if the treating investigator deems appropriate).
  • Age >= 18 years. Because no dosing or adverse event data are currently available on the use of peposertib (M3814) in combination with tuvusertib (M1774) in patients < 18 years of age, children are excluded from this study.
  • Life expectancy > 3 months.
  • Eastern cooperative oncology group (ECOG) performance status =< 2 (Karnofsky >= 60%).
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  • Measurable disease by response evaluation criteria in solid tumors (RECIST) 1.1 (RECIST 1.1 non-measurable disease permitted for the dose escalation portion).
  • Hemoglobin >= 9 g/dL.
  • 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 × institutional ULN or =< 5.0X the ULN if liver metastases are present.
  • Glomerular filtration rate (GFR) >= 60 mL/min/1.73m^2.
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Anti-retroviral therapy agents must be considered for potential drug-drug interactions per exclusion.
  • 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 or have evidence of clearance of HCV (i.e., undetectable HCV viral load). For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
  • 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.
  • Able to swallow whole capsules or tablets.
  • Willing to undergo paired biopsies (expansion arm); if a biopsy is not feasible or safe, the patient may be allowed to participate after discussion with the overall PI.
  • Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Female patients of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 6 months after the last dose of study medication.
  • Male patients of reproductive potential must agree to avoid impregnating a partner while receiving study drug and for 3 months after the last dose of study drug by complying with adequate methods of contraception.
  • Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

Who cannot join

  • Patients who have received immunotherapy within 21 days of Cycle 1 Day 1.
  • Patients who have received therapeutic radiation therapy within 21 days, or palliative radiation therapy within 7 days, of Cycle 1 Day 1.
  • Patients who have undergone major surgery within 21 days of Cycle 1 Day 1.
  • 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, controlled endocrine toxicity (e.g., hypothyroidism), and cutaneous toxicity which will be permitted at Grade 2.
  • Patients who are receiving any other investigational agents.
  • Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy.
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  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to peposertib (M3814) and tuvusertib (M1774).
  • Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes, CYP1A2, CYP3A4/5, CYP2C19, and CYP2C9. Concomitant use of substrates hMATE1, hMATE2, and CYP3A4/5 substrates with a narrow therapeutic index are also excluded. Opioids may interact with these enzymes; use of opioids while on study is allowed but should be closely monitored. Concomitant administration of sensitive substrates of P-gp, BCRP, OCT1, OATP1B1, and OATP1B3 should be avoided (if the use is unavoidable, carefully monitor patients for signs of increased toxicity). Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time before the patient can be treated:
  • Strong inducers of CYP1A2, CYP3A4/5, CYP2C19, and CYP2C9: >= 3 weeks prior to study treatment.
  • Strong inhibitors of CYP1A2, CYP3A4/5, CYP2C19, and CYP2C9: >= 1 week prior to study treatment.
  • Substrates of hMATE1, hMATE2, CYP3A4/5, P-gp, BCRP, OCT1, OATP1B1, and OATP1B3 with a narrow therapeutic index: >= 1 day prior to study treatment.
  • Patients who cannot discontinue proton-pump inhibitors (PPIs). H-2-receptor antagonist should be held during the 2 weeks of concurrent dosing with peposertib (M3814). There is no H-2-receptor antagonist restriction during the off weeks without peposertib (M3814) dosing. H-2-receptor antagonists should not be taken within 12 hours before or 2 hours after tuvusertib (M1774). Antacids should not be taken within 2 hours before or 2 hours after tuvusertib (M1774).
  • Patients who received hematopoietic growth factor (e.g., granulocyte colony-stimulating factor, erythropoietin) within 14 days prior to the first dose of study intervention.
  • Patients with uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
  • QTcF (using the Fridericia correction calculation) of >= 470 msec
  • Pregnant women and women who are breastfeeding are excluded from this study because the effects of the study drugs on the developing fetus are unknown.
  • 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 as assessed by the treating investigator may be included with the approval of the sponsor-investigator.

Trial locations and contacts

7 sites in 1 country. Contact the study team or a site near you to ask about taking part.

7 sites in 1 country

United States7 sites, 6 recruiting

  • National Cancer Institute Developmental Therapeutics Clinic

    Bethesda, Maryland, 20892

    Site Public Contact, 800-411-1222

    A P. Chen

    Recruiting

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

    Active, not recruiting

  • Massachusetts General Hospital Cancer Center

    Boston, Massachusetts, 02114

    Site Public Contact, 877-726-5130

    Gregory M. Cote

    Recruiting

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

    Site Public Contact, 877-442-3324

    Candace L. Haddox

    Recruiting

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

    Site Public Contact, 800-293-5066, Jamesline@osumc.edu

    Gabriel R. Tinoco Suarez

    Recruiting

  • NYU Langone Hospital - Long Island

    Mineola, New York, 11501

    Site Public Contact, 212-263-4432, cancertrials@nyulangone.org

    Nancy Chan

    Recruiting

  • Laura and Isaac Perlmutter Cancer Center at NYU Langone

    New York, New York, 10016

    Site Public Contact, CancerTrials@nyulangone.org

    Nancy Chan

    Recruiting

Other trials in United States

About this study

Official title: A Molecularly Driven Phase 1b Dose Escalation and Dose Expansion Study of the DNA-PK Inhibitor Peposertib (M3814) in Combination With the ATR Inhibitor Tuvusertib (M1774)

This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in combination with tuvusertib (M1774) in treating patients with solid tumors that have spread to other places in the body (advanced). Peposertib and tuvusertib stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the safety and tolerability of peposertib (M3814) in combination with tuvusertib (M1774). (DOSE ESCALATION AND EXPANSION COHORT) II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of peposertib (M3814) and tuvusertib (M1774). (DOSE ESCALATION COHORT)

SECONDARY OBJECTIVES:

  1. To observe and record anti-tumor activity. II. To determine the pharmacokinetic (PK) profiles of peposertib (M3814) and tuvusertib (M1774) when administered in combination.

EXPLORATORY OBJECTIVES:

  1. To explore correlations between pharmacodynamic (PD) and predictive biomarkers (gammaH2AX, phospho-KAP1 and phospho-RPA) with clinical outcomes.

II. To explore correlations between baseline genomic alterations of ataxia-telangiectasia mutated (ATM) or markers of replicative stress, ATM expression by immunohistochemistry (IHC), RAD5' foci formation with clinical outcomes.

III. To determine metrics of anticancer activity including the objective response rate (ORR) and progression-free survival (PFS).

OUTLINE: This a dose-escalation study of peposertib and tuvusertib, followed by a dose-expansion study.

Patients receive peposertib orally (PO) once (QD) or twice (BID) daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients are followed up for 30 days after removal from treatment or until initiating a new anticancer therapy or until death, whichever occurs first.

Being tested
Biopsy Procedure, Biospecimen Collection, Computed Tomography, Magnetic Resonance Imaging, Peposertib
Medical subject headings
Neoplasm Metastasis

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 tissue biopsy

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

    Undergo blood sample collection

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo CT

  • Magnetic Resonance ImagingProcedure or surgery

    Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan

    Undergo MRI

  • PeposertibDrug

    Also called 3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-, M 3814, M-3814, M3814

    Given PO

  • Positron Emission TomographyProcedure or surgery

    Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)

    Undergo PET

  • TuvusertibDrug

    Also called ATR Kinase Inhibitor M1774, M 1774, M-1774, M1774

    Given PO

Study groups in NCT05687136
Study groupRoleWhat they receive
Treatment (peposertib, tuvusertib)ExperimentalPatients receive peposertib PO QD or BID daily on days 2-14 of cycle 1 and days 1-14 of subsequent cycles in combination with tuvusertib PO QD daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of the study or the study drug is no longer available. Patients also undergo tumor biopsy, blood sample collection, PET, CT, and MRI throughout the study.
Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Peposertib; Procedure: Positron Emission Tomography; Drug: Tuvusertib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of dose limiting toxicity

    Measured: Up to 28 days

  2. Incidence of adverse events

    Descriptive statistics will be used for safety in the Phase 1b escalation study. Patients will be included in this analysis if they receive at least one dose of any study treatment. For toxicity reporting, all adverse events will be graded and analyzed using Common Terminology Criteria for Adverse Events (CTCAE). Type of adverse events, intensity (grading), and attribution will be provided in a listing. All adverse events resulting in discontinuation, dose modification, and/or dosing interruption, and/or treatment delay of drug will also be summarized. Laboratory test results will be classified according to CTCAE.

    Measured: Up to week 12

Secondary outcomes (1)

  1. Pharmacokinetic (PK) analysis

    Peposertib (M3814) and tuvusertib (M1774) concentrations in these samples will be quantitatively measured using a liquid chromatography/tandem mass spectrometric method. The individual PK parameters will be derived: maximum concentration (Cmax), time to maximum concentration (Tmax), are under the curve (AUC), half life (T1/2), apparent oral clearance (Cl/F), and apparent volume of distribution in steady state (Vss/F) using non-compartmental methods with the software WinNonlin, as feasible. Advanced population PK methods may be employed to assess the link between drug exposure and biological effects and efficacy. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. PK parameters (e.g., T1/2, Cmax, Cl, and AUC) will be compared across dose level using nonparametric statistical testing techniques.

    Measured: Pre, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hour (h) post dose on cycle (C)1 day (D)1, pre, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h post dose on C1D10 (dose-escalation); pre, 0.5, 1,1.5, 2, and 3 h post dose on C1D1 and C1D10 (dose-expansion)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jan 2023
  2. Study start7 Jun 2024
  3. Primary completion31 Aug 2027 (estimated)
  4. Study completion31 Aug 2027 (estimated)

Resources

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
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
66 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05687136
Sponsor's protocol ID
NCI-2022-10210
Other IDs
NCI-2022-10210, 24-169, 10527, 10527, UM1CA186709
Status last verified
Aug 2026
First submitted
14 Jan 2023
Last updated
24 Aug 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."

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Biopsy Procedure, Biospecimen Collection and Computed Tomography in people with Advanced Malignant Solid Neoplasm and Metastatic Malignant Solid Neoplasm, run by National Cancer Institute (NCI) at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 24 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of dose limiting toxicity (time frame: Up to 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05687136.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Aug 2026.

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