Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and Tuvusertib (M1774) for Advanced Solid Tumors
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)
4 other identifiers
interventional
66
1 country
6
Brief 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). Peposertib and tuvusertib stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Jun 2024
Typical duration for phase_1
6 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
January 14, 2023
CompletedFirst Posted
Study publicly available on registry
January 18, 2023
CompletedStudy Start
First participant enrolled
June 7, 2024
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 31, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
August 31, 2026
June 11, 2026
May 1, 2026
2.2 years
January 14, 2023
June 10, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
Incidence of dose limiting toxicity
Up to 28 days
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.
Up to week 12
Secondary Outcomes (1)
Pharmacokinetic (PK) analysis
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)
Other Outcomes (3)
Pharmacodynamics (PD)
After registration and before C1D1 and at C1D10
Overall response rate (ORR)
Up to 2 years
Progression free survival (PFS)
Up to 2 years
Study Arms (1)
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.
Interventions
Undergo PET
Given PO
Undergo tissue biopsy
Undergo CT
Undergo blood sample collection
Undergo MRI
Given PO
Eligibility Criteria
You may qualify if:
- 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%).
- 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 Ă— institutional ULN or =\< 5.0X the ULN if liver metastases are present.
- Glomerular filtration rate (GFR) \>= 60 mL/min/1.73m\^2.
- 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.
- +9 more criteria
You may not qualify if:
- 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.
- 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
- +2 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (6)
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
NYU Langone Hospital - Long Island
Mineola, New York, 11501, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Gregory M Cote
Dana-Farber - Harvard Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 14, 2023
First Posted
January 18, 2023
Study Start
June 7, 2024
Primary Completion (Estimated)
August 31, 2026
Study Completion (Estimated)
August 31, 2026
Last Updated
June 11, 2026
Record last verified: 2026-05
Data Sharing
- IPD Sharing
- Will share
"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."