TulmiSTAR-02: A Phase I/II Open-label Study of Tulmimetostat in Combination With Darolutamide vs. Darolutamide, and Tulmimetostat With Abiraterone in Patients With Metastatic Hormone-sensitive Prostate Cancer (mHSPC)

Sintesi

The purpose of the study is to evaluate the safety, tolerability, and efficacy of the two different treatment combinations of tulmimetostat in participants with de novo or recurrent Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

Idoneità

Disegno dello studio

Esiti misurati

1. Esito primario

   Phase I (Group A and Group B): Dose-limiting toxicities (DLTs)

   A dose-limiting toxicity is defined as an adverse event or abnormal laboratory value, not clearly due to underlying disease or extraneous causes, that occurs within the first 28 days of treatment with tulmimetostat and meets any of the criteria specified in the protocol. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for all grading. For the purpose of dose-escalation decisions, DLTs will be considered and included in the Bayesian Logistic Regression Model (BLRM).

   Orizzonte temporale Up to 28 days

2. Esito primario

   Phase I (Group A and Group B): Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)

   The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.

   Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

3. Esito primario

   Phase I (Group A and Group B): Number of Participants with dose adjustments

   The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.

   Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

4. Esito primario

   Phase I (Group A and Group B): Dose Intensity

   Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be summarized by means of descriptive statistics

   Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

5. Esito primario

   Phase I (Group A and Group B): Duration of exposure to each study drug

   Duration of exposure (in months) to each study drug will be summarized by means of descriptive statistics

   Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

6. Esito primario

   Phase II (Group A): Prostate-Specific Antigen (PSA) response rate of < 0.2 ng/mL

   Prostate-Specific Antigen (PSA) response rate is defined as proportion of participants who achieved a decline in PSA to \< 0.2 ng/mL at month 6 months, confirmed by a second PSA measurement ≥ 3 weeks later.

   Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

7. Esito secondario

   Phase I (Group A): Plasma concentrations of Tulmimetostat and Darolutamide

   Tulmimetostat and Darolutamide pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

   Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

8. Esito secondario

   Phase I (Group A): AUC of Tulmimetostat and Darolutamide

   Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

   Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

9. Esito secondario

   Phase I (Group A): Cmax of Tulmimetostat and Darolutamide

   Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

   Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

10. Esito secondario

    Phase I (Group B): Plasma concentrations of Tulmimetostat and Abiraterone

    Tulmimetostat and Abiraterone pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours), Day 2 (0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

11. Esito secondario

    Phase I (Group B): AUC of Tulmimetostat and Abiraterone

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours), Day 2 (0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

12. Esito secondario

    Phase I (Group B): Cmax of Tulmimetostat and Abiraterone

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours), Day 2 (0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

13. Esito secondario

    Phase II (Group A): Radiographic progression free survival (rPFS)

    Radiographic progression free survival (rPFS) is defined as the time between randomization and the first occurrence of disease progression as per PCWG3-modified RECIST v1.1 or death due to any cause

    Orizzonte temporale From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 79 months

14. Esito secondario

    Phase II (Group A):Overall survival (OS)

    Overall survival (OS) is defined as the time between randomization to date of death due to any cause

    Orizzonte temporale From date of randomization until date of death from any cause, assessed up to approximately 79 months

15. Esito secondario

    Phase II (Group A): Objective response (OR)

    Objective response (OR) is defined as a confirmed Complete Response (CR) or Partial Response (PR) per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 as assessed by the Investigator

    Orizzonte temporale From date of randomization until date of confirmed Complete Response (CR) or Partial Response (PR), assessed up to approximately 79 months

16. Esito secondario

    Phase II (Group A): Best Overall response (BOR)

    Best Overall response (BOR) is defined as the best response per PCWG3-modified RECIST 1.1 as assessed by the Investigator from the start of the treatment until disease progression/recurrence

    Orizzonte temporale From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 79 months

17. Esito secondario

    Phase II (Group A): Duration of response (DOR)

    Duration of response (DOR) defined as time between first documented CR/PR and disease progression per PCWG3-modified RECIST 1.1 as assessed by the Investigator or death due to any cause

    Orizzonte temporale From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 79 months

18. Esito secondario

    Phase II (Group A): Prostate-Specific Antigen 50 (PSA50)

    Prostate-Specific Antigen 50 (PSA50) is defined as a ≥ 50% decrease in PSA levels from baseline at any timepoint, confirmed by a second PSA measurement ≥ 3 weeks without any PSA progression in between

    Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

19. Esito secondario

    Phase II (Group A): Prostate-Specific Antigen (PSA) Response of <0.1 ng/mL

    Prostate-Specific Antigen (PSA) Response of \<0.1 ng/mL is defined as PSA level \< 0.1 ng/mL at any timepoint during the trial from randomization

    Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

20. Esito secondario

    Phase II (Group A): Time to castration-resistant prostate cancer (CRPC)

    Time to castration-resistant prostate cancer (CRPC) is defined as the time from randomization to the first occurrence of one of the following events: PSA progression, radiological progression by bone lesions, or radiological progression by soft tissue and visceral lesions

    Orizzonte temporale From date of randomization until date of PSA progression, radiological progression by bone lesions, or radiological progression by soft tissue and visceral lesions, whichever comes first, assessed up to approximately 79 months

21. Esito secondario

    Phase II (Group A): Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)

    The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.

    Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

22. Esito secondario

    Phase II (Group A): Number of Participants with dose adjustments

    The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.

    Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

23. Esito secondario

    Phase II (Group A): Dose Intensity

    Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be summarized by means of descriptive statistics

    Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

24. Esito secondario

    Phase II (Group A): Duration of exposure to each study drug

    Duration of exposure to each study drug will be summarized by means of descriptive statistics

    Orizzonte temporale From date of randomization till 30 days safety fup, assessed up to approximately 79 months

25. Esito secondario

    Phase II (Group A): Plasma concentrations of Tulmimetostat and Darolutamide

    In selected number of participants receiving Tulmimetostat and Darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of Tulmimetostat is evaluated in combination with Darolutamide in Phase II, Tulmimetostat and Darolutamide pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

26. Esito secondario

    Phase II (Group A): AUC of Tulmimetostat and Darolutamide

    In selected number of participants receiving tulmimetostat and darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of tulmimetostat is evaluated in combination with darolutamide in Phase II, venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

27. Esito secondario

    Phase II (Group A): Cmax of Tulmimetostat and Darolutamide

    In selected number of participants receiving tulmimetostat and darolutamide combination therapy in Phase II, or in selected number of participants if only one dose level of tulmimetostat is evaluated in combination with darolutamide in Phase II, venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 8 hours). Cycle 1: Day 2 (Tulmimetostat only: 0 hour and 24 hours), Days 8 and 15 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

28. Esito secondario

    Phase II (Group A): Plasma concentrations of Tulmimetostat

    Tulmimetostat pharmacokinetic (PK) samples will be obtained and evaluated in all participants at all dose levels by treatment arms

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

29. Esito secondario

    Phase II (Group A): AUC of Tulmimetostat

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) and Area under the concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) will be listed and summarized using descriptive statistics.

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

30. Esito secondario

    Phase II (Group A): Cmax of Tulmimetostat

    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

    Orizzonte temporale Cycle 1-2: Day 1 (0 hour and 2 hours). Cycles 3-5: Day 1 (0 hour). 1 cycle = 28 days.

31. Esito secondario

    Phase II (Group A): Time to first symptomatic skeletal event (TTSSE)

    Time to first symptomatic skeletal event (TTSSE) is defined as the time from randomization to the first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first

    Orizzonte temporale From randomization until the first occurrence of a new symptomatic bone fracture, spinal cord compression, tumor-related orthopedic surgery, radiation therapy for bone pain, or death, assessed up to 79 months.

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