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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04170153

Studienbeginn:
Dezember 2019

Letztes Update:
08.07.2021

Wirkstoff:
M1774, Niraparib

Indikation (Clinical Trials):
Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
EMD Serono Research & Development Institute, Inc.

Collaborator:
Merck KGaA, Darmstadt, Germany

Studienleiter

Medical Responsible
Study Director
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Kontakt

Studienlocations
(3 von 4)

University of Texas M. D. Anderson Cancer Center - Investigational Cancer Therapeutics - Partner
77030 Houston
United StatesRekrutierend» Google-Maps
Ansprechpartner:

E-Mail: tyap@mdanderson.org
» Ansprechpartner anzeigen
Northern Centre for Cancer Care - Sir Bobby Robson Cancer Trials Research Centre
NE7 7DN Newcastle upon Tyne
United KingdomRekrutierend» Google-Maps
Ansprechpartner:

E-Mail: ruth.plummer@newcastle.ac.uk
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

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:

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))

Studien-Arme

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

Geprüfte Regime

  • M1774:
    M1774 will be administered orally throughout the study.
  • Niraparib:
    Niraparib will be administered orally throughout the study.

Quelle: ClinicalTrials.gov


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