Tuvusertib (M1774) in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors (DDRiver Solid Tumors 301)

NCT04170153 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: MS201924_00012019-002203-182024-515848-23-00
• Study Type: interventional
• Target: 161
• Locations: 5 countries
• Sites: 16

Brief Summary

This is an open-label, Phase I, first-in-human (FIH) multicenter, clinical study conducted in multiple parts to establish the safety, tolerability and pharmacokinetic/pharmacodynamic (PK/PD) profile (with and without food) and early signs of efficacy of Tuvuseritib (M1774) as monotherapy and in combination with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib.

Conditions

Metastatic or Locally Advanced Unresectable Solid Tumors

Keywords

Tuvusertib (M1774); ATR inhibitor; Niraparib; PARP inhibitor; Metastatic or Locally Advanced Unresectable Solid Tumors

Outcome Measures

Primary Outcomes (13)

• Part A1, A4 and A5: Occurrence of Dose-Limiting Toxicities (DLTs) During the DLT Observation Period

  Day 1 to Day 21 of Cycle 1 (Each Cycle is of 21 days)

• Part A1, A3, A4, A5 and B1: Occurrence of Treatment-emergent Adverse Events (TEAEs), Treatment-related Adverse Events (AEs) and Death According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0

  Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years

• Part A1, A3, A4, A5 and B1: Number of Participants With Grade 3 or Higher Laboratory Findings According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0

  Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years

• Part A1, A3, A4, A5 and B1: Number of Participants With Abnormalities in Vital Signs

  Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years

• Part A1, A3, A4, A5 and B1: Number of Participants With Clinical Significant Abnormalities in Electrocardiogram (ECG) Findings

  Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years

• Part A2: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours Post Dose (AUC 0-24h) of Tuvusertib (M1774)

  Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A2: Area Under the Plasma Concentration Curve From Time Zero to Infinity Post Dose (AUC 0-inf) of Tuvusertib (M1774)

  Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A2: Maximum Observed Plasma Concentration (Cmax) of Tuvusertib (M1774)

  Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A2: Relative Bioavailability Based on Area Under the Plasma Concentration Curve (Frel[AUC]) of Tuvusertib (M1774) Under Fed Condition as Compared to Fasting Condition

  Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A2: Relative Bioavailability Based on Maximum Observed Plasma Concentration (Frel[Cmax]) of Tuvusertib (M1774) Under Fed Condition as Compared to Fasting Condition

  Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A3: Objective Response as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  Baseline up to 2.2 years

• Part B1: Occurrence of Dose-Limiting Toxicities (DLTs) During the DLT Observation Period

  Day 1 to Day 28 of Cycle 1 (Each Cycle is of 28 days)

• Part A1, A4, A5 and B1: To Determine the Recommended Dose Expansion (RDE) for Tuvusertib (M1774) monotherapy globally, in Japanese and in Chinese participants With Metastatic or Locally Advanced Unresectable Solid Tumors and in combination with Niraparib

  Assessed up to approximately 2.2 years

Secondary Outcomes (82)

• Part A1, A3, A4 and A5: Maximum Observed Plasma Concentration (Cmax) of Tuvusertib (M1774)

  Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A1, A3, A4 and A5: Time to Reach Maximum Plasma Concentration (tmax) of Tuvusertib (M1774)

  Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A1, A3, A4 and A5: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours Post Dose (AUC0-24h) of Tuvusertib (M1774)

  Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A1, A3, A4 and A5: Area Under Plasma Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of Tuvusertib (M1774)

  Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

• Part A1, A3, A4 and A5: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tuvusertib (M1774)

  Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days)

Study Arms (6)

Part A1: Monotherapy Dose Escalation

EXPERIMENTAL

Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

Drug: M1774

Part A2 - Preliminary Food Effect Assessment

EXPERIMENTAL

Participants in the food effect assessment will receive Tuvusertib (M1774) at the dose and schedule determined as recommended dose for expansion (RDE) in Part A1. A single dose of Tuvusertib (M1774) will be administered on Day -7 under a fed (low-fat meal) or fasted condition, followed by a 1-week washout period. After completion of the scheduled food effect assessments, participants will follow the same schedule as participants in Part A1.

Drug: M1774

Part A3 - Monotherapy Expansion

EXPERIMENTAL

Part A3 is an expansion of Part A1 where Tuvusertib (M1774) will be administered as a single agent at the RDE established in Part A1. Participants with defined loss-of-function mutation in ARID1A, ATRX and/or DAXX, and ATM will be enrolled.

Drug: M1774

Part B1: Combination Therapy Dose Finding

EXPERIMENTAL

B1a: Participants with baseline body weight less than (\<) 77 kilogram (kg) or platelets \<150,000 cubic per millimeter (mm\^3) will receive Niraparib once daily combined with different doses of Tuvusertib (M1774). B1b: Participants with baseline body weight greater than or equal to (\>=) 77 kg and or platelets \>= 150,000 mm\^3 will receive Niraparib once daily combined with different doses of Tuvusertib (M1774) and schedule determined as recommended dose for expansion (RDE) in Part B1a.

Drug: M1774; Drug: Niraparib

Part A4: Japan Dose Confirmation Monotherapy

EXPERIMENTAL

Starting at global RDE from Part A1, in Japan. Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

Drug: M1774

Part A5: China Dose Confirmation Monotherapy

EXPERIMENTAL

Starting at global RDE from Part A1, in China. Participants will initially receive Tuvusertib (M1774) once daily under fasting conditions. Additional schedules may be evaluated if needed.

Drug: M1774

Interventions

M1774 DRUG

M1774 will be administered orally throughout the study.

Also known as: Tuvusertib

Part A1: Monotherapy Dose Escalation; Part A2 - Preliminary Food Effect Assessment; Part A3 - Monotherapy Expansion; Part A4: Japan Dose Confirmation Monotherapy; Part A5: China Dose Confirmation Monotherapy; Part B1: Combination Therapy Dose Finding

Niraparib DRUG

Niraparib will be administered orally throughout the study.

Part B1: Combination Therapy Dose Finding

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with locally advanced or metastatic disease that is refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator which may convey clinical benefit
• Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (\<=) 1
• Participants with clinically controlled brain metastases, which is defined as individuals with central nervous system metastases that have been treated for, are asymptomatic, and have discontinued steroids (for the treatment of brain metastases) for greater than (\>) 28 days may be enrolled
• Participants with meningeal carcinomatosis are excluded
• In Part A3, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
• Part A3: Participants with presence of loss of function mutations in the genes for ARID1A, ATRX and /or DAXX and ATM
• Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies
• Adequate hematological, hepatic, and renal function as defined in the protocol
• Female participants are not pregnant or breastfeeding
• Part B1:
• Subpart B1a: Participants with Baseline Body weight \< 77 kg or platelets \<150,000 cubic per millimeter (mm\^3) Subpart B1b: Participants with Baseline Body weight \>= 77 kg and platelets \>=150,000 mm\^3 will be included

You may not qualify if:

• Participants with major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or if the participant has not fully recovered from the surgery within 4 weeks of the study intervention
• Presence of toxicities due to prior anticancer therapies (example, radiotherapy, chemotherapy, immunotherapies, et cetera \[etc\]) that do not recover to \<= Grade 1 with the exception of toxicities that do not pose a safety risk to the participant in the judgment of the Investigator (example: ongoing Grade 2 alopecia)
• Part B1 only: Uncontrolled arterial hypertension which is systolic blood pressure \>140 millimeter of mercury (mmHg); Diastolic blood pressure \>90mmHg
• Unstable angina, myocardial infarction, congestive heart failure \>= II or a coronary revascularization procedure within 180 days of study entry. Calculated QTc average (using the Fridericia correction calculation) of \> 450 msec for males and \> 470 msec for females that does not resolve with correction of electrolyte abnormalities
• Participants with active and/or uncontrolled infection. The following exceptions apply:
• Participants with human immunodeficiency virus (HIV) infection are eligible if they are on effective antiretroviral therapy with undetectable viral load within 6 months, provided there is no expected drug-drug interaction
• Participants with evidence of chronic hepatitis B virus (HBV) infection are eligible if the HBV viral load is undetectable on suppressive therapy (if indicated), and if they have alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels \< upper limit of normal (ULN), and provided there is no expected drug-drug interaction
• Participants with a history of hepatitis C virus (HCV) infection are eligible if they have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, and if they have ALT, AST, and total bilirubin levels \< ULN
• Treatment with live or live attenuated vaccine within 30 days of dosing (non-replicating vector vaccines are permitted)
• Part B1 only: participants diagnosed with hereditary diseases characterized by genetic defects of DNA repair mechanisms, including ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy
• Any other clinical condition, uncontrolled concurrent illness, or other situation which in the Investigator's opinion would not make the participant a good candidate for the clinical study including or may potentially impact the absorption of M1774, such as (but not limiting to) significant small bowel resection or gastric surgery and exocrine pancreatic insufficiency requiring pancreatic enzyme replacement therapy
• Prohibited concomitant medication, as per Protocol
• Another investigational drug within 28 days or 5 half-lives, whichever is shorter, prior to start of administration of study intervention
• Prior use of Ataxia telangiectasia mutated and Rad3-related (ATR) inhibitor and/or Checkpoint kinase 1 (CHK1) inhibitor
• Participants who cannot comply with restrictions for medications or food

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: collaborator
• EMD Serono Research & Development Institute, Inc.: lead

Study Sites (16)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

NEXT Oncology

Austin, Texas, 78758, United States

Location

Mary Crowley Cancer Research Centers

Dallas, Texas, 75230, United States

Location

The Methodist Hospital Research Institute

Houston, Texas, 77030, United States

Location

University of Texas M. D. Anderson Cancer Center - Investigational Cancer Therapeutics

Houston, Texas, 77030, United States

Location

Beijing Cancer Hospital

Beijing, China

Location

National Cancer Center Hospital - Dept of Experimental Therapeutics

Chūōku, Japan

Location

National Cancer Center Hospital East - Dept of Experimental Therapeutics

Kashiwa-shi, Japan

Location

Hospital Clinic de Barcelona - Servicio de Oncologia

Barcelona, Spain

Location

Hospital Universitari Vall d'Hebron - Oncology Dept.

Barcelona, Spain

Location

Centro Integral Oncologico Clara Campal - Unidad de Fase I-Oncologica

Madrid, Spain

Location

Hospital Clinico Universitario de Valencia - Servicio de Hematologia y Oncologia Medica

Valencia, Spain

Location

Addenbrooke's Hospital - Dept of Oncology

Cambridge, United Kingdom

Location

The Christie Hospital - Dept of Oncology

Manchester, United Kingdom

Location

Northern Centre for Cancer Care - Sir Bobby Robson Cancer Trials Research Centre

Newcastle upon Tyne, United Kingdom

Location

Royal Marsden Hospital - Dept of Oncology

Sutton, United Kingdom

Location

Related Links

• Trial Awareness and Transparency website
• US Medical Information website, Medical Resources
• DDRiver website

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

niraparib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Medical Responsible

  Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-Label

Study Record Dates

• First Submitted: November 18, 2019
• First Posted: November 20, 2019
• Study Start: December 20, 2019
• Primary Completion (Estimated): January 30, 2027
• Study Completion (Estimated): January 30, 2027
• Last Updated: January 30, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1); JP (2); GB (4); ES (4); US (5)