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

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 : April 28, 2022
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) and early signs of efficacy of M1774 as monotherapy and in combination with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib.

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

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 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 (DDRiver Solid Tumors 301)
Actual Study Start Date : December 20, 2019
Estimated Primary Completion Date : March 31, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part A1: Monotherapy Dose Escalation
Participants will initially receive M1774 once daily under fasting conditions. Additional schedules may be evaluated if needed.
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. 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.

Experimental: Part A3 - Monotherapy Expansion
Part A3 is an expansion of Part A1 where M1774 will be administered as a single agent at the RDE established in Part A1. Participants with defined loss-of-function mutation in ARIDIA, ATRX and/or DAXX, and ATM will be enrolled.
Drug: M1774
M1774 will be administered orally throughout the study.

Experimental: Part B1a: Combination Therapy Dose Finding
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 M1774.
Drug: M1774
M1774 will be administered orally throughout the study.

Drug: Niraparib
Niraparib will be administered orally throughout the study.

Experimental: Part B1b: Combination Therapy Dose Finding
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 M1774 and schedule determined as recommended dose for expansion (RDE) in Part B1a.
Drug: M1774
M1774 will be administered orally throughout the study.

Drug: Niraparib
Niraparib 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, A3 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 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  3. Part A1, A3 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 [ Time Frame: Baseline up to 30 days after the last dose of study treatment, assessed up to approximately 2.2 years ]
  4. Part A1, A3 and B1: 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, A3 and B1: 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 ]
  11. Part B1: Occurrence of Dose-Limiting Toxicities (DLTs) During the DLT Observation Period [ Time Frame: Day 1 to Day 28 of Cycle 1 (Each Cycle is of 28 days) ]
  12. Part A1 and B1: To Determine the Recommended Dose Expansion (RDE) for M1774 in Combination With Niraparib in Participants With Metastatic or Locally Advanced Unresectable Solid Tumors [ Time Frame: Assessed up to approximately 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 (AUC0-24h) 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 the Plasma Concentration Curve From Time Zero to 12 Hours (AUC0-12h) Post-Dose of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose up to 12 hours post-dose (Each Cycle is of 21 days) ]
  17. Part A1 and A3: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 12Hours (AUC0-12h/Dose) Post-dose of M1774 [ Time Frame: Cycle 1 Day 1 and Day 8: Pre-dose upto 12 hours post-dose (Each Cycle is of 21 days) ]
  18. Part A1 and A3: Area Under the Plasma Concentration Curve From Time Zero to 10 Hours Post-dose (AUC0-10h) of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 10 hours post-dose (Each Cycle is of 21 days) ]
  19. Part A1 and A3: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 10 Hours (AUC0-10h/Dose) Post-dose of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 10 hours post-dose (Each Cycle is of 21 days) ]
  20. Part A1 and A3: Area Under Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-t) of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  21. Part A1 and A3: Dose Normalized Area Under Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-t/Dose) of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  22. Part A1 and A3: Renal Clearance (CLr) of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  23. Part A1 and A3: Cumulative Amount Excreted From Time Zero to Infinity (Ae0-infinity) of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  24. Part A1 and A3: Cumulative Amount Excreted From Time Zero to Time After Dosing (Ae0-t) of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  25. Part A1 and A3: Cumulative Percentage of Dose Excreted From Time Zero to Time After Dosing (Ae0-t%) of M1774 [ Time Frame: Part A1 and A3: Cycle 1 Day 1 and Day 8: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  26. Part A1 and A3: Number of Participants With Corrected QT (QTc) Interval [ Time Frame: Baseline up to Day 8 ]
  27. 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 ]
  28. 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 ]
  29. 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 ]
  30. 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 ]
  31. 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) ]
  32. 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) ]
  33. 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) ]
  34. 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) ]
  35. 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) ]
  36. 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) ]
  37. 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) ]
  38. 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) ]
  39. 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) ]
  40. 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) ]
  41. 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) ]
  42. 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) ]
  43. 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) ]
  44. 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) ]
  45. Part A2: Dose Normalized Area Under Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-t/Dose) Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  46. Part A2: Area Under the Plasma Concentration Curve From Time Zero to 12 Hours (AUC0-12h) Post-Dose Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 12 hours post-dose (Each Cycle is of 21 days) ]
  47. Part A2: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 12Hours (AUC0-12h/Dose) Post-dose Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 12 hours post-dose (Each Cycle is of 21 days) ]
  48. Part A2: Area Under the Plasma Concentration Curve From Time Zero to 10 Hours PostDose AUC(0-10h) Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 10 hours post-dose (Each Cycle is of 21 days) ]
  49. Part A2: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 10 Hours (AUC0-10h/Dose) Post-dose Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 10 hours post-dose (Each Cycle is of 21 days) ]
  50. Part A2: Area Under Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-t) Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  51. Part A2: Apparent Clearance Body Clearance at Steady State Following Extravascular Administration (CLss/F) Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  52. Part A2: Accumulation Ratio for Area Under the Plasma Concentration Concentration-Time Curve (Racc[AUC]) Under Fed/Fasted Ratio of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  53. Part A2: Accumulation Ratio of Maximum Observed Plasma Concentration (Racc[Cmax]) Under Fed/Fasted Ratio of of M1774 [ Time Frame: Part A2: Cycle 1 Day -7 and Day 1: Pre-dose up to 24 hours post-dose (Each Cycle is of 21 days) ]
  54. Part A2: Number of Participants With Corrected QT (QTc) Interval [ Time Frame: Baseline up to Day 8 ]
  55. 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 ]
  56. 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.

  57. 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 ]
  58. 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 ]
  59. Part B1: Objective Response as Assessed by Investigator According to Response Evaluation Criteriain Solid Tumors Version (RECIST) 1.1 [ Time Frame: Baseline up to 2.2 years ]
  60. Part B1: Maximum Observed Plasma Concentration (Cmax) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  61. Part B1: Time to Reach Maximum Plasma Concentration (tmax) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  62. Part B1: Area Under the Plasma Concentration Curve From Time Zero to 24 Hours Post Dose AUC(0-24h) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  63. Part B1: Area Under Plasma Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  64. Part B1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  65. Part B1: Apparent Terminal Half-life (t1/2) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  66. Part B1: Apparent Total Body Clearance From Plasma (CL/f) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  67. Part B1: Apparent Clearance Body Clearance at Steady State Following Extravascular Administration (CLss/F) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  68. Part B1: Apparent Volume of Distribution During Terminal Phase Following Extravascular Administration (Vz/F) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  69. Part B1: Accumulation Ratio for Area Under the Plasma Concentration Concentration-Time Curve (Racc[AUC]) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  70. Part B1: Accumulation Ratio of Maximum Observed Plasma Concentration (Racc[Cmax]) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  71. Part B1: Dose Normalized Area Under Concentration-Time Curve Within One Dosing Interval (AUC0-tau/Dose) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  72. Part B1: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h/Dose) Post-Dose of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  73. Part B1: Dose Normalized Area Under Concentration-Time Curve From Time Zero (dosing time) Extrapolated to Infinity (AUC0-inf/Dose) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  74. Part B1: Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  75. Part B1: Area Under the Plasma Concentration Curve From Time Zero to 12 Hours (AUC0-12h) Post-Dose of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3 (each cycle is of 28 days) ]
  76. Part B1: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 12Hours (AUC0-12h/Dose) Post-dose of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3 (each cycle is of 28 days) ]
  77. Part B1: Area Under the Plasma Concentration Curve From Time Zero to 10 Hours PostDose AUC(0-10h) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  78. Part B1: Dose Normalized Area Under Concentration-Time Curve From Time Zero to 10 Hours (AUC0-10h/Dose) Post-dose of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  79. Part B1: Area Under Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-t) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  80. Part B1: Dose Normalized Area Under Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-t/Dose) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  81. Part B1: Renal Clearance (CLr) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  82. Part B1: Cumulative Amount Excreted From Time Zero to Infinity (Ae0-infinity) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  83. Part B1: Cumulative Amount Excreted From Time Zero to Time After Dosing (Ae0-t) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]
  84. Part B1: Cumulative Percentage of Dose Excreted From Time Zero to Time After Dosing (Ae0-t%) of M1774 as well as its Metabolites and Niraparib [ Time Frame: Part B1: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10 hours post-dose on Day 1and Day 8, Pre-dose on Day 15 of cycle 1; Pre-dose, 2, 4 hours post-dose pm Day 1 of Cycle 2; Pre-dose on Day 1 of cycle 3(each cycle is of 28 days) ]


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:

  • 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 mutation in the gene for ARIDIA, 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
  • Female participants are not pregnant or breastfeeding
  • Not a women of childbearing potential (WOCBP)
  • 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 or platelets >=150,000 mm^3

- Other protocol defined inclusion criteria could apply

Exclusion Criteria:

  • 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)
  • 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
  • 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 (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 pigmentosae, Cockayne syndrome, and trichothiodystrophy
  • 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
  • Prior use of Ataxia telangiectasia mutated and Rad3-related (ATR) inhibitor and/or CHK1 inhibitor
  • Participants who cannot comply with restrictions for medications or food. Participants B1: Participants with a known history of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) Participants B1: Participants with prostrate cancer
  • 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: April 28, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports 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 bit.ly/IPD21

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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
Niraparib
PARP inhibitor
Metastatic or Locally Advanced Unresectable Solid Tumors
Additional relevant MeSH terms:
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Neoplasms
Niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents