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M1774 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04170153
Recruitment Status : Recruiting
First Posted : November 20, 2019
Last Update Posted : January 8, 2021
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

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) of M1774.

Condition or disease Intervention/treatment Phase
Metastatic or Locally Advanced Unresectable Solid Tumors Drug: M1774 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Open-Label
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Multicenter Trial of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of M1774 in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors
Actual Study Start Date : December 20, 2019
Estimated Primary Completion Date : September 13, 2021
Estimated Study Completion Date : September 13, 2021

Arm Intervention/treatment
Experimental: Part A1: Monotherapy Dose Escalation
Participants will receive M1774 once daily under fasting condition.
Drug: M1774
M1774 will be administered orally throughout the study.

Experimental: Part A2 - Preliminary Food Effect Assessment
Participants in the food effect assessment will receive M1774 at the dose and schedule determined as recommended dose for expansion (RDE) in Part A1. A single dose of M1774 will be administered on Day -7 under a fed (high-fat meal) or fasted condition, followed by a 1-week washout period.
Drug: M1774
M1774 will be administered orally throughout the study.

Experimental: Part A3 - Monotherapy Expansion
After completion of the scheduled food effect assessments, participants will follow the same schedule as participants in Part A1. Participants will be administered M1774 at a dose and schedule determined as RDE in Part A1.
Drug: M1774
M1774 will be administered orally throughout the study.




Primary Outcome Measures :
  1. Part A1: Occurrence of Dose-Limiting Toxicities (DLTs) During the DLT Observation Period [ Time Frame: Day 1 to Day 21 of Cycle 1 (Each Cycle is of 21 days) ]
  2. Part A1 and A3: 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 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  3. Part A1 and A3: 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 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  4. Part A1 and A3: Number of Participants With Abnormalities in Vital Signs [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  5. Part A1 and A3: Number of Participants With Clinical Significant Abnormalities in Electrocardiogram(ECG) Findings [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  6. Part A2: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours Post Dose (AUC 0-24h) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  7. Part A2: Maximum Observed Plasma Concentration (Cmax) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  8. Part A2: Relative Bioavailability Based on Area Under the Plasma Concentration Curve (Frel[AUC]) of M1774 Under Fed Condition as Compared to Fasting Condition [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  9. Part A2: Relative Bioavailability Based on Maximum Observed Plasma Concentration (Frel[Cmax]) of M1774 Under Fed Condition as Compared to Fasting Condition [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  10. Part A3: Objective Response as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 [ Time Frame: Baseline up to 2.2 years ]

Secondary Outcome Measures :
  1. Part A1 and A3: Maximum Observed Plasma Concentration (Cmax) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  2. Part A1 and A3: Time to Reach Maximum Plasma Concentration (tmax) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  3. Part A1 and A3: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours Post Dose AUC(0-24h) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  4. Part A1 and A3: Area Under Plasma Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  5. Part A1 and A3: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  6. Part A1 and A3: Apparent Terminal Half-life (t1/2) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  7. Part A1 and A3: Apparent Total Body Clearance From Plasma (CL/f) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  8. Part A1 and A3: Apparent Clearance Body Clearance at Steady State Following Extravascular Administration (CLss/F) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  9. Part A1 and A3: Apparent Volume of Distribution During Terminal Phase Following Extravascular Administration (Vz/F) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  10. Part A1 and A3: Accumulation Ratio for Area Under the Plasma Concentration Concentration-Time Curve (Racc[AUC]) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  11. Part A1 and A3: Accumulation Ratio of Maximum Observed Plasma Concentration (Racc[Cmax]) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  12. Part A1 and A3: Dose Normalized Area Under Concentration-Time Curve Within One Dosing Interval (AUC0-tau/Dose) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  13. Part A1 and A3: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h/Dose) Post-dose of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  14. Part A1 and A3: Dose Normalized Area Under Concentration-Time Curve From Time Zero (dosing time) Extrapolated to Infinity (AUC0-inf/Dose) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  15. Part A1 and A3: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  16. Part A1 and A3: Area Under Concentration From Time tlast Extrapolated to Infinity (AUCextra%) of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  17. Part A1 and A3: Number of Participants With Corrected QT (QTc) Interval [ Time Frame: Baseline up to Day 8 ]
  18. Part A2: 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 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  19. Part A2: 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 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  20. Part A2: Number of Participants With Abnormalities in Vital Signs [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  21. Part A2: Number of Participants With Clinical Significant Abnormalities in Electrocardiogram (ECG) Findings [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  22. Part A2: Time to Reach Maximum Plasma Concentration (tmax) Under Fed/Fasted Ratio of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  23. Part A2: Area Under Plasma Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  24. Part A2: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  25. Part A2: Apparent Terminal Half-life (t1/2) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  26. Part A2: Apparent Total Body Clearance From Plasma (CL/f) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  27. Part A2: Apparent Volume of Distribution During Terminal Phase Following Extravascular Administration (Vz/F) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  28. Part A2: Dose Normalized Area Under Concentration Time Curve Within One Dosing Interval (AUC0-tau/Dose) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  29. Part A2: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h/Dose) Post dose of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  30. Part A2: Dose Normalized Area Under Concentration-Time Curve From Time Zero (dosing time) Extrapolated to Infinity (AUC0-inf/Dose) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  31. Part A2: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  32. Part A2: Area Under Concentration From Time tlast Extrapolated to Infinity (AUCextra%) of M1774 [ Time Frame: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  33. Part A2: Cumulative Amount Excreted From Time Zero (dosing time) to Infinity (Ae0-inf) of M1774 [ Time Frame: Cycle 1 Day -7: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  34. Part A2: Cumulative Amount Excreted From Time Zero to Time After Dosing (Ae0-t) of M1774 [ Time Frame: Cycle 1 Day -7: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  35. Part A2: Cumulative Percentage of Dose Excreted From Time Zero to Time After Dosing (Ae0-t%) of M1774 [ Time Frame: Cycle 1 Day -7: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  36. Part A2: Renal Clearance (CLr) of M1774 [ Time Frame: Cycle 1 Day -7: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  37. Part A2: Number of Participants With Corrected QT (QTc) Interval [ Time Frame: Baseline up to Day 8 ]
  38. Part A3: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  39. Part A3: Number of Participants With Clinical Benefit According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
    Participants with a clinical benefit, defined as an objective response or stable disease for at least 6 months, as determined by the Investigator through the use of RECIST version 1.1.

  40. Part A3: Progression-Free Survival (PFS) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  41. Part A3: Overall Survival (OS) According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (<=) 1
  • Have 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
  • Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies
  • Female participants are not pregnant or breastfeeding
  • Not a women of childbearing potential (WOCBP)
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria:

  • Continuance of toxicities due to prior anticancer therapies (example, radiotherapy, chemotherapy, immunotherapies, et cetera [etc]) that do not recover to <= Grade 1
  • 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
  • Active fungal, bacterial and/or viral infection. Individuals with known human immunodeficiency virus and/or viral hepatitis (B and/or C) are excluded. However, individual with hepatitis C treated with curative therapy are not considered actively infected
  • Treatment with live or live attenuated vaccine within 30 days of dosing
  • Any other clinical condition or uncontrolled concurrent illness which in the Investigator's opinion would not make the participant a good candidate for the clinical study
  • 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
  • No prior Ataxia telangiectasia mutated and Rad3-related (ATR) inhibitor and/or CHK1 inhibitor
  • Participants who cannot comply with restrictions for medications or food
  • Other protocol defined exclusion criteria could apply

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04170153


Contacts
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Contact: US Medical Information 888-275-7376 eMediUSA@emdserono.com
Contact: Communication Center +49 6151 72 5200 service@emdgroup.com

Locations
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United States, Texas
University of Texas M. D. Anderson Cancer Center - Investigational Cancer Therapeutics - Partner Recruiting
Houston, Texas, United States, 77030
Contact       tyap@mdanderson.org   
Principal Investigator: Timothy Yap         
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78240
Contact       atolcher@nextoncology.com   
Principal Investigator: Anthony W Tolcher         
United Kingdom
Northern Centre for Cancer Care - Sir Bobby Robson Cancer Trials Research Centre Recruiting
Newcastle upon Tyne, United Kingdom, NE7 7DN
Contact       ruth.plummer@newcastle.ac.uk   
Principal Investigator: Elizabeth R Plummer         
Royal Marsden Hospital - Dept of Oncology Recruiting
Sutton, United Kingdom, SM2 5PT
Contact       johann.debono@icr.ac.uk   
Principal Investigator: Johann S De Bono         
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Additional Information:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT04170153    
Other Study ID Numbers: MS201924_0001
2019-002203-18 ( EudraCT Number )
First Posted: November 20, 2019    Key Record Dates
Last Update Posted: January 8, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
M1774
ATR inhibitor
Metastatic or Locally Advanced Unresectable Solid Tumors
Additional relevant MeSH terms:
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Neoplasms